BRCALit

Study Information					Population			Experimental arm			Comparative arm			Results : PFS				Results : OS				Results : Adverse events		Conclusions
Title	Journal	Year	Pdf	Study phase	Stage	Molecular classification	Subpopulation	Experimental treatment	Molecule name	Setting	Comparative Treatment	Molecule name	Setting	PFS experimental	PFS comparator	PFS HR	PFS significance	OS experimental	OS comparator	OS HR	OS significance	G3-4 AE experimental	G3-4 AE comparator	Conclusion	Conclusion	Note	Note
Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation : OlympiAD	NEJM	2017		3	metastatic BC	HER2-	germline BRCA mut, maximum 2 previous CT regimens for metastatic disease	targeted therapy	olaparib	metastatic	chemotherapy	capecitabine, eribuline or vinorelbine	metastatic	7m median	4m median	0.58	yes					36	50	Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy.
Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy : PrE0102 study	JCO	2018		2	metastatic BC	HR+ HER2-	postmenopausal women, resistant to AI and no more than one prior chemotherapy regimen for metastatic disease.	endocrine therapy + targeted therapy	fulvestrant + everolimus	metastatic	endocrine therapy	fulvestrant	metastatic	10m median	5m median	0.61	yes	28m median	31m median	1.3	no	45	11	Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer		No prior CDK4/6 inhibitor therapy (0% and 3%). 25% of liver metastases and 20% had received 1 chemo line. ORR 18 vs 12% (NS). CBR 63 vs 41% (S). The most common AEs of any grade were oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), pneumonitis (17% v 0%), dyspnea (16% v 3%), hyponatremia (6% v 0%), and elevated transaminase (5% v 2%). The most common grade 3 or higher were oral mucositis (11% v 0%), fatigue (6% v 5%), and pneumonitis (6% v 0%). The median PFS for fulvestrant alone was comparable to the 5.4-month median PFS observed for fulvestrant using the same dose and schedule as in an AI-resistant population in the CONFIRM trial. This study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves PFS, as noted previously in the BOLERO-2 trial and in the TAMRAD trial. Prophylactic corticosteroid mouthwash was not used in any of these trials, but it has been shown to reduce the risk of grade 1 to 3 oral mucositis (also commonly referred to as stomatitis) to approximately 20%, with the vast majority being grade 1 (SWISH trial). The findings of our trial were confirmed by the Fulvestrant With AZD2014 or Everolimus for Advanced Breast Cancer (MANTA) trial. upregulation of the PI3K-PDK1 pathway has emerged as an important mechanism of resistance to CDK4/6 inhibitor therapy, suggesting that mTOR blockade with everolimus plus fulvestrant may represent a viable strategy for the treatment of patients who have developed resistance to prior treatment including an AI plus a CDK4/6 inhibitor.
Concurrent Veliparib With Chest Wall and Nodal Radiotherapy in Patients With Inflammatory or Locoregionally Recurrent Breast Cancer : TBCRC 024	JCO	2018		1	locoregional		inflammatory or locoregionally recurrent BC	radiotherapy + targeted therapy	RT + veliparib	adjuvant												47		Although severe acute toxicity did not exceed 30% even at the highest tested dose, nearly half of surviving patients demonstrated grade 3 adverse events at 3 years, which underscores the importance of long-term monitoring of toxicity in trials of radiosensitizing agents.		The crude rate of any grade 3 toxicity (regardless of attribution) was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, six of 15 surviving patients had severe fibrosis in the treatment field.
Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer : PANTHER	JAMA	2016		3	early BC		N+ or high-risk N- , < 65 years	chemotherapy dose-dense	4 EC - 4 docetaxel	adjuvant	chemotherapy standard-interval	3 FEC - 3 docetaxel	adjuvant	86.7 % at 5 years	82.1 % at 5 years	0.79	yes	92.1 % at 5 years	90.2 % at 5 years	0.77	no	52	36	Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence–free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group		Benefit in EFS, but not in DDFS or OS. 97% N+ disease
Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival AmongWomen With Invasive Breast Cancer and Sentinel Node Metastasis : ACOSOG Z0011	JAMA	2017		3	early BC		cT1-T2, cN0, SLND pN1	surgery	axillary node dissection			no complementary axillary node dissection		78.2 % at 10 years	80.2 % at 10 years	0.85	no	83.6 % at 10 years	86.3 % at 10 years	0.85	no			Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containingmetastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes		All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Results in % at 10 years.
Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer : APHINITY	NEJM	2017		3	early BC	HER2 pos	N+ or high-risk N-	targeted therapy	chemotherapy + 1 year of trastuzumab-pertuzumab	adjuvant		chemotherapy + 1 year of trastuzumab	adjuvant	94.1 % at 3 years	93.2 % at 3 years	0.81	yes (borderline)					64	57	Pertuzumab significantly improved the rates of 3 year invasive-disease–free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy.		benefit in subgroup of hte 63% of N+ patients : 3 year IDFS of 92% vs 90.2% (HR 0.77, p 0.02)
20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years : meta-analysis of 88 trials	NEJM	2017		MA	early BC	HR pos	disease-free after 5 years of scheduled endocrine therapy																	After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade		13% if T1N0 ; 20% if T1N1-3 ; 34% if T1N4-9 ; 19% if T2N0 ; 26% if T2N1-3 ; 41% if T2N4-9
Adjuvant Trastuzumab in HER2-Positive Breast Cancer : BCIRG-006	NEJM	2011		3	early BC	HER2 pos	high-risk, node-negative or node-positive adenocarcinoma (stage T1, T2, or T3)	chemotherapy + targeted therapy	AC-T + trastuzumab OR docetaxel-carboplatin-trastuzumab (TCH)	adjuvant	chemotherapy	AC-T : doxorubicin-cyclophosphamide followed by docetaxel	adjuvant	84 % at 5 years	75 % at 5 years	0.64	yes	92 % at 5 years	87 % at 5 years	0.63	yes			The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia		The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study.
Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer : GEICAM 9805	NEJM	2010		3	early BC		high-risk N-	chemotherapy	TAC : docetaxel, doxorubicin, and cyclophosphamide	adjuvant	chemotherapy	FAC : fluorouracil, doxorubicin, and cyclophosphamide	adjuvant	87.8 % at 6 years FU	81.8 % at 6 years FU	0.68	yes	95.2 % at 6 years FU	93.5 % at 6 years FU	0.76	no	28	17	As compared with adjuvant FAC, adjuvant TAC improved the rate of disease-free survival among women with high-risk, node-negative breast cancer.		benefit was consistent, regardless of hormone-receptor status, menopausal status, or number of high-risk factors.
Regional Nodal Irradiation in Early-Stage Breast Cancer : MA.20	NEJM	2015		3	early BC		N+ or high-risk N- treated with breast-conserving surgery and adjuvant systemic therapy	radiotherapy	whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes)	adjuvant	radiotherapy	whole-breast irradiation alone	adjuvant	82 % at 10 years	77 % at 10 years	0.76	yes	82.8 % at 10 years	81.8 % at 10 years	0.91	no			Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence.
Palbociclib and Letrozole in Advanced Breast Cancer : PALOMA-2	NEJM	2016		3	metastatic BC	HR+ HER2-	postmenopausal women 1st line for advanced disease	endocrine therapy + targeted therapy	palbociclib + letrozole	metastatic	endocrine therapy	letrozole	metastatic	24.8m median	14.5m median	0.58	yes					75	25	Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib–letrozole.
Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer : PALOMA-3	NEJM	2015		3	metastatic BC	HR+ HER2-	relapse or progression during prior endocrine therapy (pre- or post-menopausal)	endocrine therapy + targeted therapy	palbociclib + fulvestrant	metastatic	endocrine therapy	fulvestrant	metastatic	9.2m median	3.8m median	0.42	yes					68	18	Among patients with hormone-receptor–positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone.
Adjuvant Ovarian Suppression in Premenopausal Breast Cancer : SOFT	NEJM	2015		3	early BC	HR pos	premenopausal women	endocrine therapy	tamoxifen + OFS	adjuvant	endocrine therapy	tamoxifen	adjuvant	86.6 % at 5 years	84.7 % at 5 years	0.83	no							Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes.		In patients who had received prior chemotherapy : 82.5% vs 78% (HR 0.78, borderline NS)
Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials	Lancet Oncol	2018		MA	early BC			neoadjuvant chemotherapy		neoadjuvant	adjuvant chemotherapy		adjuvant	61.8 % at 15 years	62 % at 15 years	1.02	no	65.6 % at 15 years	66.3 % at 15 years	1.06	no			Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy.		Patients allocated NACT had an increased frequency of breast-conserving therapy. However, NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer : TAILORx	NEJM	2018		3	early BC	HR pos, HER2 neg	N- and consideration of adjuvant chemotherapy. Oncotype Dx RS 11 to 25	chemotherapy + endocrine therapy		adjuvant	endocrine therapy		adjuvant	84.3 % at 9 years	83.3 % at 9 years	1.08	no	93.9 % at 9 years	93.8 % at 9 years		no			Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger.		The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation : EMBRACA	NEJM	2018		3	metastatic BC	HER2-	germline BRCA1/2 mutation	targeted therapy	talazoparib	metastatic	chemotherapy	capecitabine, eribulin, gemcitabine, or vinorelbine	metastatic	8.6m median	5.6m median	0.54	yes							Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib.
A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer :	NEJM	2015		3	0 to 3		partial mastectomy	surgery	cavity shave margins resection	peroperative														Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy.		patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02).
Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer : APT	NEJM	2015		2	early BC	HER2 pos	cN- ; T < 3 cm	chemotherapy + targeted therapy	paclitaxel and trastuzumab	adjuvant				98.7 % at 3 years and 93% at 7 years. Patients with ER+ disease had slightly better outcomes than those with ER– disease (94.6% versus 90.7%).				95% at 7 years						Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%. With longer follow-up, adjuvant paclitaxel and trastuzumab is still associated with excellent long-term outcomes.		The results suggest a low risk of cancer recurrence (less than 2% at 3 years) with a regimen in which the rate of serious toxic effects was low (with an incidence of heart failure that was only 0.5%). However, the higher frequency of hormone-receptor–positive tumors in our study could have implications for late recurrence.
Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer : BOLERO-2	Ann Oncol	2012		3	metastatic BC	HR+ HER2-	refractory to previous letrozole or anastrozole	endocrine therapy + targeted therapy	exemestane + everolimus	metastatic	endocrine therapy	exemestane	metastatic	7.8m median	3.2m median	0.45	yes	31m median	27m median	0.89	no	23	12	In BOLERO-2, adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinically meaningful and statistically significant improvement in the primary end point, PFS (4.6-months prolongation in median PFS; P < 0.0001).
Prospective Validation of a 21-Gene Expression Assay in Breast Cancer : TAILORx	NEJM	2015		3		HR pos, HER2 neg	N- BC with tumors of 1.1 to 5.0 cm (or 0.6 to 1.0 cm and intermediate or high tumor grade). Oncotype Dx RS 0-10.	endocrine therapy	endocrine therapy without chemotherapy	adjuvant				93.8% at 5 years				98% at 5 years						Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone.
Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer : IMpassion130	NEJM	2018		3	metastatic BC	triple negative	first line in metastatic setting	immunotherapy + chemotherapy	atezolizumab + nab-paclitaxel	metastatic	chemotherapy	nab-paclitaxel	metastatic	7.2m median	5.5m median	0.8	yes	21.3m median	17.6m median	0.84	no	48	42	Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1–positive subgroup. Adverse events were consistent with the known safety profiles of each agent		among patients with PD-L1–positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86).
Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer : PALOMA-3 final results	NEJM	2018		3	metastatic BC	HR+ HER2-	relapse or progression during prior endocrine therapy (pre- or post-menopausal)	endocrine therapy + targeted therapy	palbociclib + fulvestrant	metastatic	endocrine therapy	fulvestrant	metastatic					34m median	28m median	0.81	no			Among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo–fulvestrant. The differences in overall survival in the entire trial group were not significant.		Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94). he median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001).
Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer : EMILIA	NEJM	2012		3	metastatic BC	HER2 pos	previously treated with trastuzumab and a taxane	antibody–drug conjugate	trastuzumab emtansine	metastatic	chemotherapy + targeted therapy	lapatinib plus capecitabine	metastatic	9.6m median	6.4m median	0.65	yes	31m median	25m median	0.68	yes	41	57	T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.		The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar erythrodysesthesia were higher with lapatinib plus capecitabine
Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer : CLEOPATRA	NEJM	2015		3	metastatic BC	HER2+	no previous chemotherapy or anti-HER2 therapy for their metastatic disease	chemotherapy + targeted therapy	docetaxel + trastuzumab + pertuzumab	metastatic	chemotherapy + targeted therapy	docetaxel + trastuzumab	metastatic	18m median	12m median	0.68	yes	56	40	0.68	yes			Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.		Most events were grade 1 or 2 and occurred during docetaxel administration and declined after discontinuation. The rate of left ventricular dysfunction was somewhat lower in the pertuzumab group than in the control group (6.6% vs. 8.6%).
Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer	NEJM	2012		3	early BC	HER2 neg	any stage of disease that was deemed to be appropriate for adjuvant chemotherapy	chemotherapy + targeted therapy	bevacizumab concomitant to epirubicin-cyclophosphamide followed by docetaxel	neoadjuvant	chemotherapy	epirubicin-cyclophosphamide followed by docetaxel	neoadjuvant									50	33	The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome.		pathological complete response : 14.9% with EC-T and 18.4% with BevEC-T (OR 1.29, P=0.04). pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor–positive tumors.
Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer : SOFT and TEXT updated results	NEJM	2018		3	early BC	HR pos	premenopausal women	endocrine therapy	exemestane + OFS	adjuvant	endocrine therapy	tamoxifen +- OFS	adjuvant	85.9% at 8 years	83.2% (T+OFS), 78.9% (T) at 8 years			92.1% at 8 years	93.3% (T+OFS), 91.5% (T) at 8 years			32	24	Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group.		Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). In the SOFT trial, now with 8 years median follow-up, tamoxifen plus ovarian suppression, compared with tamoxifen alone, significantly improved DFS, the primary study end point (P = .009). Importantly, tamoxifen plus ovarian suppression significantly improved overall survival compared with tamoxifen alone as well (HR, 0.59; 95% CI, 0.42 to 0.84). In contrast, exemestane plus ovarian suppression did not significantly improve overall survival compared with tamoxifen alone (HR, 0.79; 95% CI, 0.57 to 1.09). This discordance seen in the SOFT trial, with fewer distant recurrence events but with more deaths for exemestane plus ovarian suppression compared with tamoxifen plus ovarian suppression, suggests caution in accepting distant recurrence findings as definitive in this setting. Any explanation must focus on factors influencing breast cancer death, because only nine out of a total of 225 deaths in SOFT occurred without a preceding breast cancer event. Potential mediating mechanisms include differences in choice of subsequent therapy (which have yet to be reported), hypotheses that intermittent estrogen suppression results in more aggressive recurrent tumors or that increase in androgen precursors associated with aromatase inhibitor use induces more aggressive tumor clones, or the previously mentioned ESR1 mutation selected by aromatase inhibitor use (Pan, JCO 2019). The adequacy of estrogen suppression with gonadotropin-releasing hormone agonists in premenopausal women with early breast cancer has also been questioned (SOFT-EST trial)
Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy : CREATE-X	NEJM	2017		3	early BC	HER2 neg	residual invasive breast cancer after neoadjuvant chemotherapy	chemotherapy	capecitabine	adjuvant	placebo			74.1% at 5 years	67.6% at 5 years	0.7	yes	89.2% at 5 years	83.6% at 5 years	0.59	yes			After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing.		triple-negative disease : DFS 69.8% versus 56.1%, OS 78.8% versus 70.3%. Hand-foot syndrome in 73% (11% G3).
Contemporary Hormonal Contraception and the Risk of Breast Cancer	NEJM	2017			without BC		prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility	use of hormonal contraception			never used hormonal contraception			RR of BC 1.20 (1.09 with less than 1 year of use to 1.38 with more than 10 years of use). Increase with estrogen–progestin combinations as with progestin-only IUD.			yes							The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small.		The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year.
Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer	NEJM	2015		3	early BC		centrally or medially located primary tumor (N+ or N-), or an externally located tumor (N+)	radiotherapy	whole-breast or thoracic-wall irradiation + regional nodal irradiation	adjuvant	radiotherapy	whole-breast or thoracic-wall irradiation	adjuvant	72.1% at 10 years	69.1% at 10 years	0.89	yes	82.3% at 10 years	80.7% at 10 years	0.87	no			In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced.		the rate of distant disease-free survival was 78.0% versus 75.0% (HR 0.86; significant), and breast-cancer mortality was 12.5% versus 14.4% (HR 0.82, significant)
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer : MONALEESA-2	NEJM	2016		3	metastatic BC	HR pos HER2 neg	postmenopausal women who had not received previous systemic therapy for advanced disease	endocrine therapy + targeted therapy	ribociclib + letrozole	metastatic	endocrine therapy	letrozole	metastatic	63% at 18 months	42% at 18 months	0.56	yes					70	30	Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.		In patients with measurable disease, ORR was 52.7% and 37.1%.
Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer : SOFT & TEXT	NEJM	2014		3	early BC	HR pos	premenopausal women	endocrine therapy	exemestane + OFS	adjuvant	endocrine therapy	tamoxifen + OFS	adjuvant	91.1% at 5 years	87.3% at 5 years	0.72	yes				no	30	29	In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.
Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer : SWOG S0226	NEJM	2012		3	metastatic BC	HR pos	Postmenopausal women with previously untreated metastatic disease	endocrine therapy	anastrozole + fulvestrant	metastatic	endocrine therapy	anastrozole	metastatic	15m median	13.5m median	0.8	yes	47m median	41m median	0.81	yes	14	12	The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard.		41% of the patients in the comparator arm crossed over to fulvestrant after progression.
Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer	NEJM	2012		2	metastatic BC	triple negative	maximum 2 previous CT regimens for metastatic disease	chemotherapy + targeted therapy	carboplatin-gemcitabine + iniparib	metastatic	chemotherapy	carboplatin-gemcitabine	metastatic	5.9m median	3.6m median	0.59	yes	12.3m median	7.7m median	0.57	yes	86	81	The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects.		Improvement of clinical benefit : 34% to 56% (P=0.01) and of OR from 32% to 52% (P=0.02).
Effect of Occult Metastases on Survival in Node-Negative Breast Cancer : NSABP B32	NEJM	2011		3	early BC			surgery	sentinel-lymph-node biopsy plus axillary dissection		surgery	sentinel-lymph-node biopsy alone												Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer.		Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease–free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively.
Longer Therapy, Iatrogenic Amenorrhea, and Survival in Early Breast Cancer : NSABP B-30	NEJM	2010		3	early BC		N pos	chemotherapy	sequential ACT	adjuvant	chemotherapy	concurrent ACT or doxorubicin-docetaxel	adjuvant	74% at 8 years	69% at 8 years for both regimens		yes for both regimens	83% at 8 years	79% at 8 years for both regimens		yes compared to AT, no compared to concurrent ACT	65	45	Sequential ACT improved disease-free survival as compared with doxorubicin–docetaxel or concurrent ACT, and it improved overall survival as compared with doxorubicin–docetaxel. Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status.		Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups, independently of estrogen-receptor status.
Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer	NEJM	2010		3	early BC		N neg	radiotherapy	hypofractionated whole-breast irradiation : 42.5 Gy in 16 fractions over 22 days	adjuvant	radiotherapy	standard whole-breast irradiation : 50.0 Gy in 25 fractions over 35 days	adjuvant	6.2% of local recurrence at 10 years	6.7% of local recurrence at 10 years		no							Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes.		At 10 years, good or excellent cosmetic outcome for 69.8% in hypofractionated arm as compared to 71.3% in the standard arm.
Adjuvant Chemotherapy in Older Women with Early-Stage Breast Cancer : CALGB 49907	NEJM	2009		3	early BC		65 years of age or older and an expected survival of more than 5 years	chemotherapy	CMF or AC	adjuvant	chemotherapy	capecitabine	adjuvant	85% at 3 years	68% at 3 years	0.48	yes	91% at 3 years	86% at 3 years	0.54	yes	64	33	Standard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older.
Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer : ABCSG-12	NEJM	2009		3	early BC	HR pos	premenopausal women	endocrine therapy + targeted therapy	goserelin + tamoxifen or anastrozole + zoledronic acid	adjuvant	endocrine therapy	goserelin + tamoxifen or anastrozole	adjuvant	88% at 8 years	85% at 8 years	0.77	yes	96% at 8 years	94% at 8 years	0.66	no			The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. Ovarian suppression with endocrine therapy for 3 years can produce excellent outcomes in a population with low-to-intermediate risk.		DFS did not differ significantly between the tamoxifen and anastrozole groups. However, In the anastrozole group, OS was significantly worse versus the tamoxifen group (HR 1.63). the anticancer effects of treatment were not confined to bone. The potential mechanism for this benefit is likely related to the anticancer effect of ZOL on residual tumor cells residing within the bone marrow, which may prevent tumor cells from ‘re-seeding’ locoregional or contralateral breast tissue at a later date. The benefit for ZOL-treated patients arises early and remains persistent long after treatment cessation. This is consistent with prolonged DFS benefits seen with adjuvant endocrine therapy in patients with early BC.
Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer	NEJM	2008		3	early BC		N pos or high risk N neg	chemotherapy	doxorubicin-cyclophosphamide followed by weekly paclitaxel	adjuvant	chemotherapy	doxorubicin-cyclophosphamide followed by paclitaxel every 3 weeks	adjuvant	81.5 % at 5 years	76.9 % at 5 years	1.27	yes	89.7% at 5 years	86.5% at 5 years	1.32	yes	28	30	Weekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improves disease-free and overall survival in women with breast cancer.		docetaxel every 3 weeks : DFS 81.2% at 5 years (OR 1.23 S) and OS 87.3% (OR 1.13 NS). However, weekly docetaxel : DFS 77.6% at 5 years (OR 1.09 NS) and OS 86.2% (OR 1.02 NS). Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%).
5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.	Lancet Oncol	2016		2	early BC, locally advanced or inflammatory	HER2 pos		chemotherapy + dual targeted therapy	docetaxel + trastuzumab + pertuzumab	neoadjuvant	chemotherapy + targeted therapy	docetaxel + trastuzumab	neoadjuvant	86 % at 5 years	81 % at 5 years	0.69	no					81	73	Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer.		3 FEC received in adjuvant. This regimen can thus absolutely not be seen as an optimal neoadjuvant regimen. Patients given pertuzumab and trastuzumab plus docetaxel had a significantly improved pCR rate compared with those given trastuzumab plus docetaxel (45 vs 29%), without substantial differences in tolerability.
Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial.	Lancet Oncol	2018		3	early BC	HER2 pos		chemotherapy + dual targeted therapy	3 FEC - 6 paclitaxel-carboplatine - concurrent pertuzumab+trastuzumab	neoadjuvant	chemotherapy + dual targeted therapy	9 paclitaxel-carboplatine - concurrent pertuzumab+trastuzumab												In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results.		pCR rate of 67% in the anthracycline group and 68% in the non-anthracycline group. Febrile neutropenia was more frequent in the anthracycline group (10% vs 1%)
Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer : KATHERINE	NEJM	2018		3	early BC	HER2 pos	residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab.	targeted therapy	trastuzumab emtansine	adjuvant	targeted therapy	trastuzumab	adjuvant	88% at 3 years	77% at 3 years	0.5	yes					25	15	Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone		subgroup analysis of invasive disease–free survival revealed a consistent benefit of T-DM1 across stratification cohorts and other subgroups
Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer	NEJM	2013			early BC		adjuvant radiotherapy for BC, with and without major coronary events																	Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women.		Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray, with no apparent treshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy.
First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2–Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer : PERTAIN	JCO	2018		2	metastatic BC	HR pos, HER2 pos	no prior systemic therapy with the exception of endocrine	endocrine therapy + targeted therapy	anastrozole or letrozole + trastuzumab + pertuzumab	metastatic	endocrine therapy + targeted therapy	anastrozole or letrozole + trastuzumab	metastatic	18m median	15m median	0.65	yes					50	39	Pertuzumab plus trastuzumab and an AI is effective for the treatment of HER2-positive MBC/LABC. The safety profile was consistent with previous trials of pertuzumab plus trastuzumab.		Induction intravenous docetaxel every 3 weeks or paclitaxel every week could be administered for 18 to 24 weeks
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer : MINDACT	NEJM	2016		3	early BC		high risk clinical features and low risk gene-expression profile	no chemotherapy		adjuvant	chemotherapy		adjuvant	94.7% at 5 years (DMFS)	95.9% at 5 years (DMFS)	0.78	no							Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy.		Some 50% of the study patients were defined as being at low clinical risk. In this group, we did not find any meaningful difference in the 5-year rate of survival without distant metastasis between patients at high genomic risk who received chemotherapy and those who did not receive chemotherapy. On the basis of these data, the results for the 70-gene signature do not provide evidence for making recommendations regarding chemotherapy for patients at low clinical risk. in a large group of patients at high clinical risk for breast-cancer recurrence, the addition of the 70-gene signature to the traditional clinical and pathological factors provided valuable information for considering which patients might benefit from adjuvant chemotherapy. We found that chemotherapy with its attendant toxic effects could be avoided in these patients at high clinical risk but low genomic risk at a cost of a risk of distant metastasis at 5 years that is 1.5 percentage points higher.
Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer : BIG 1-98	NEJM	2009		3	early BC	HR pos	Postmenopausal women	endocrine therapy	letrozole 5 years	adjuvant	endocrine therapy	tamoxifen 2 years followed by letrozole 3 years	adjuvant	87.9% at 5 years	86.2% at 5 years		no							Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with letrozole and tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant.		the frequency of relapses within 2 years after randomization was significantly reduced with letrozole as compared with tamoxifen, especially among women with many involved lymph nodes, large tumors, or vascular invasion. as compared with tamoxifen alone, letrozole monotherapy significantly reduces the risk of recurrence of disease, especially at distant sites. The updated intention-to-treat analysis of monotherapy confirms these observations and shows a nonsignificant difference between letrozole monotherapy and tamoxifen monotherapy with respect to overall survival (P=0.08).
Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women : WHI	NEJM	2009		3	healthy		Postmenopausal women without a history of invasive breast cancer or hysterectomy	hormonal supplementation	estrogen + medroxyprogesterone acetate															The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy		This finding supports the hypothesis that the recent reduction in the incidence of breast cancer among women in certain age groups in the United States is predominantly related to a decrease in the use of combined estrogen plus progestin.
Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease : VITAL	NEJM	2018		3	healthy			dietary supplementation	vitamin D3		placebo						no							Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.
Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer : VITAL	NEJM	2018		3	healthy			dietary supplementation	marine n−3 fatty acids		placebo						no							Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo.
Pembrolizumab Monotherapy for Previously Treated Metastatic Triple-Negative Breast Cancer: Cohort A of the Phase 2 KEYNOTE-086 Study.	Ann Oncol	2018		2	metastatic BC	triple negative	previously treated with systemic therapy for M+ disease	immunotherapy	pembrolizumab	metastatic				2m median				9m median				13		Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.		ORR 5%. Median duration of response was not reached. 62% PDL1+, 43% >2 previous lines of treatment.
Pembrolizumab Monotherapy for Previously Untreated, PD-L1-Positive, Metastatic Triple-Negative Breast Cancer: Cohort B of the Phase 2 KEYNOTE-086 Study.	Ann Oncol	2018		2	metastatic BC	triple negative	previously untreated metastatic disease	immunotherapy	pembrolizumab	metastatic				2m median				18m median				9		Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC.		ORR 21%. median duration of response 10m
First-line vs second-line fulvestrant for hormone receptor-positive advanced breast cancer: A post-hoc analysis of the CONFIRM study	The Breast	2018		3	metastatic BC	HR pos	Postmenopausal women	endocrine therapy	fulvestrant 500 mg	metastatic 1st line	endocrine therapy	fulvestrant 250 mg	metastatic 1st line	5m median	4m median	0.8	yes	23m median	22m median		no	14	17	The superiority of fulvestrant 500 mg over fulvestrant 250 mg in patients with LA/MBC in CONFIRM was consistent in both the first- and second-line settings for PFS, and numerically greater in both settings for OS.		benefit in PFS also seen when Fulvestrant taken in 2nd line
Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer : CONFIRM trial.	JCO	2016		3	metastatic BC	HR pos	Postmenopausal women	endocrine therapy	fulvestrant 500 mg	metastatic	endocrine therapy	fulvestrant 250 mg	metastatic	6m median	5m median	0.8	yes	25m median	22m median		no			clinical value of increasing the dose of fulvestrant from 250 to 500 mg in a population of postmenopausal patients with advanced breast cancer with ER-positive tumors previously exposed to at least one endocrine therapy.		The PFS improvement seems to be the consequence of a modest increase in the rate of disease stabilization and a substantial prolongation in duration of disease stabilization. The safety and QOL analyses do not raise any concern related to fulvestrant 500 mg compared with 250 mg.
Clinical impact of adjuvant radiation therapy delay after neoadjuvant chemotherapy in locally advanced breast cancer	The Breast	2018		retrospective	early BC treated with NACT			radiotherapy < 8 weeks after surgery		adjuvant	radiotherapy 8 to 16 weeks after surgery		adjuvant			0.33	yes			0.22	yes			In this retrospective study, PORT started up to 8 weeks after surgery was associated with better DFS and OS in locally-advanced BC patients submitted to NAC.
Impact of timeliness of adjuvant chemotherapy and radiotherapy on the outcomes of breast cancer; a pooled analysis of three clinical trials	The Breast	2018		pooling of phase 3 studies	early BC		referred for adjuvant chemotherapy	chemotherapy < 6 weeks after surgery		adjuvant	chemotherapy > 6 weeks after surgery		adjuvant											Among hormone receptor-negative patients, delaying chemotherapy initiation beyond 6 weeks (after surgery) is associated with worse patient outcomes. Moreover, delaying radiotherapy initiation beyond surgery does not compromise outcomes in patients receiving long course adjuvant chemotherapy.		the longer interval was not associated with overall survival difference in hormone receptor-positive patients
Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer : FALCON	Lancet	2016		3	metastatic BC	HR pos	Postmenopausal women	endocrine therapy	fulvestrant 500 mg	metastatic 1st line	endocrine therapy	anastrozole	metastatic 1st line	16m median	13m median	0.79	yes							Fulvestrant has superior effi cacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor		fulvestrant provides a lower toxicity option than CDK4/6 inhibitors for first-line therapy that could be favoured for patients with low or intermediate risk disease with good prognosis (eg, non-visceral disease), patients with high risk disease who have comorbidities restricting the use of combination targeted therapy, patients who cannot aff ord a CDK4 or CDK6 inhibitor, or in countries where CDK4 or CDK6 inhibitors have not been approved by regulatory authorities.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis	Lancet	2014		3	early BC treated with NACT				ypT0/is ypN0			no pCR				0.48	yes			0.36	yes			Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.		The association between pCR and long-term outcomes was strongest in patients with TNBC (EFS: HR 0·24 ; OS: 0·16) and in those with HER2+ HR- tumours who received trastuzumab (EFS: 0·15 ; OS: 0·08). In the trial-level analysis, we recorded little association between increases in frequency of pCR and EFS (R2=0·03) and OS (R2=0·24). Individual-level association offers insight into the natural history of an individual's disease and is thus useful to counsel patients. Trial-level association is useful to predict population treatment benefits.
Neoadjuvant Degarelix Versus Triptorelin in Premenopausal Patients Who Receive Letrozole for Locally Advanced Endocrine-Responsive Breast Cancer	JCO	2019		2	early BC	HR pos, HER2 neg	Premenopausal women with stage cT2 to 4b, any N, M0 receiving letrozole as neoadjuvant endocrine therapy	OFS by GnRH antagonist	degarelix + Letrozole	neoadjuvant	OFS by GnRH agonist	triptorelin + Letrozole	neoadjuvant	3 days median to OFS	14 days median to OFS	3.05	yes							In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.		degarelix 240 mg SC on day 1 of cycle 1, then 80 mg SC on day 1 of cycles 2 through 6. OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1.
Tamoxifen for Prevention of Breast Cancer : NSABP-P1	JNCI	1998		3	prevention		women at increased risk for breast cancer	endocrine therapy	tamofixen	prevention	placebo		prevention			0.5	yes							Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.		Tamoxifen reduced the occurrence of ER+ tumors by 69%, but no difference in the occurrence of ER- tumors was seen. The rate of endometrial cancer was increased in the tamoxifen group (RR 2.5). The rates of stroke, PE, and DVT were elevated in the tamoxifen group. All these AE happened predominantly in women aged > 50.
Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials : EBCTCG	Lancet	2012		MA	early BC																			10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both		The postoperative administration of an anthracycline, when compared with no chemotherapy, improves the RFS at 10 years by 8%, and BCSS by 6.5%, corresponding to a relative risk reduction of 25%. The proportional risk reduction for BCSS was the same regardless of nodal spread, ER status, age and used endocrine therapy. Further adding a taxane to an anthracycline compared with anthracycline alone results in 4.6% absolute improvement in RFS and 2.8% in BCSS at 8 years, a relative reduction of 15%. Here also, the relative improvement was independent of clinicopathologic factors. Thus, absolute improvements depend on absolute risk.
Anthracyclines in Early Breast Cancer: The ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49	JCO	2017		3	early BC with adjuvant CT indication	HER2 neg		chemotherapy	TC6 : 6 cycles of docetaxel-cyclophosphamide	adjuvant	chemotherapy	TaxAC : doxorubicin, cyclophosphamide and a taxane	adjuvant	88.2% at 4 years	90.7% at 4 years	1.2	yes					4	42	The TaxAC regimens improved IDFS in patients with high-risk HER2– breast cancer compared with the TC6 regimen.		First study to specifically evaluate the role of doxorubicin in taxane-based adjuvant therapy of HER2- BC. Statistically significant improvement in IDFS with the administration of anthracyclines in patients with HER2- disease, the absolute benefits were small, and the majority of patients who received TC6 have done well without an anthracycline. The benefits appear to be meaningful in patients with HR- tumors or those with HR+ tumors and N+.
Neuropathy Is Not Associated With Clinical Outcomes in Patients Receiving Adjuvant Taxane-Containing Therapy for Operable Breast Cancer : E1199	JCO	2012		cohort analysis	early BC with adjuvant CT indication			chemotherapy	AC-T	adjuvant														There was no association between taxane-induced neuropathy and DFS or OS in patients treated with contemporary AC-taxane therapy, including weekly paclitaxel.
Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer	JCO	2015		3	early BC with adjuvant CT indication			chemotherapy	AC + taxane weekly	adjuvant	chemotherapy	AC + taxane every 3 weeks	adjuvant			0.8	yes			0.9	no			Improved outcomes initially observed for weekly paclitaxel were qualitatively similar but quantitatively less pronounced with longer follow-up, although exploratory analysis suggested substantial benefit in TNBC..		Trial designed to determine the optimal taxane and schedule in stage II to III breast cancer. The findings suggest that breast cancer heterogeneity influences benefit from adjuvant taxane therapy : Although P1 was the most effective option tested for TNBC and was also associated with early gains in hormone receptor–positive disease, the taxane regimen employed may be less important in patients at risk for late relapse, where attention to the use of extended adjuvant endocrine therapy may be more impactful. For TNBC, there was a 30% reduction in the risk of recurrence and death, which translated into approximately a 10% absolute improvement in DFS and OS at 10 years.
Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial GIM-2	Lancet	2015		3	early BC with adjuvant CT indication		N pos	chemotherapy dose-dense	(F)EC-P with G-CSF	adjuvant	chemotherapy standard-interval	(F)EC-P	adjuvant	81% at 5 years	76% at 5 years	0.77	yes	94% at 5 years	89% at 5 years	0.65	yes			In patients with N+ early breast cancer, dose-dense adjuvant chemotherapy improved DFS compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved DFS outcome.		DD CT : increased rate of grade 3–4 of anaemia (1.5%), transaminitis (2%) and myalgias (3%) but decreased rates of grade 3–4 neutropenia (15%). the addition of fl uorouracil to the EC-P regimen was associated with an increase in toxic eff ects (grade 3–4 neutropenia, fever, nausea, and vomiting). The study design does not allow separation between the effect of dose-dense (F)EC vs dose-dense paclitaxel, leaving the possibility that the intensification of either (F)EC or paclitaxel might be sufficient to obtain the full benefit observed with the whole dose-dense regimen. VERY INTERESTING EDITORIAL BY Von Minckwitz and Loibl !!!
Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer : HERA trial	NEJM	2005		3	early BC	HER2 pos	N pos, or N neg and > 1 cm, and completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy.	targeted therapy	trastuzumab : 1 or 2 years	adjuvant	placebo		adjuvant	85% at 2 years	77% at 2 years	0.54	yes					8	4	One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer.		Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab.
11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERA trial	Lancet	2017		3	early BC	HER2 pos	N pos, or N neg and > 1 cm, and completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy.	targeted therapy	trastuzumab : 1 or 2 years	adjuvant	placebo		adjuvant	69% at 10 years	63% at 10 years	0.76	yes	79% at 12 years	73% at 12 years	0.74	yes	18	9	1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term DFS and OS, compared with observation. 2 years of trastuzumab had no additional benefit.		Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 7.3% in the 2-years trastuzumab group, 4.4% in the 1-year trastuzumab group, and 0.9% in the observation group. No evidence of significant differential benefit by disease characteristics, such as nodal status or tumour hormone receptor status. Additionally, there is no evidence of late emergent side-effects, including no evidence of more cardiac endpoints emerging up to 10 years after treatment.
Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.	JCO	2014		3	early BC	HER2 pos	N pos or high risk N neg	chemotherapy + targeted therapy	AC-TH followed by H for 1 year	adjuvant	chemotherapy	AC-T	adjuvant			0.6	yes			0.63	yes			The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence. On the basis of the aggregate DFS data, 1 year of trastuzumab initiated concurrently with a taxane is considered the standard of care.		all subsets derive similar and significant benefit from the addition of trastuzumab. N9831 was the only clinical trial that was designed to compare starting trastuzumab concurrent with a taxane to after completion of a taxane. With a median follow-up of 6 years, there was a trend toward improved DFS when trastuzumab was administered concurrently with paclitaxel. The 8-year cumulative incidence rate of deaths after random assignment known to be a result of cardiac causes was 0.2% for patients with the trastuzumab-containing regimen.
Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET)	Lancet Oncol	2016		3	early BC	HER2 pos	N pos, or N neg and > 1 cm, disease-free up to 2 years after completion of chemotherapy and trastuzumab.	targeted therapy	neratinib	adjuvant	placebo		adjuvant	93.9% at 2 years	91.6% at 2 years	0.67	yes							Neratinib for 12 months signifi cantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer.		40% G3 diarrhea (tending to occur early in the course of treatment, with the highest incidence reported in cycle 1), 3% QT prolongation. More than 50% of patients had an interval of greater than 4·5 months after completion of trastuzumab and before initiation of neratinib. Potentially greater effectiveness of neratinib in the HR+ cohort. All this suggests that recurrent tumours remain addicted to the HER2 pathway, whereby an anti-HER2 drug, which acts on a different target in the same growth signalling pathway, might result in cancer cell death, suggesting an absence of cross-resistance with trastuzumab
Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer	JCO	2010		2	metastatic BC	HER2 pos	Up to 4 prior cytotoxic chemotherapy regimens for relapsed or metastatic disease, with or without prior trastuzumab	targeted therapy	neratinib	metastatic, after prior trastuzumab	targeted therapy	neratinib	metastatic, no prior trastuzumab	59% at 4 months	78% at 4 months									Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.		ORR 24 vs 56%. Of note, among patients with extensive prior trastuzumab-based chemotherapy, lapatinib monotherapy had ORR of less than 8%
Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer : ALTTO trial.	JCO	2016		3	early BC	HER2 pos	N pos, or N neg and > 1 cm	dual targeted therapy	trastuzumab + lapatinib	adjuvant	targeted therapy	trastuzumab	adjuvant	88% at 4 years	86% at 4 years	0.84	no	95% at 4 years	94% at 4 years	0.8	no	46	25	Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. Furthermore, noninferiority of the sequence of the two anti-HER2 agents compared with T was not demonstrated. One year of adjuvant T remains standard of care.		In the ITT population, a 16% reduction in the hazard of a DFS event was observed with L+T compared with T, but this effect was modest, not statistically significant at .025, and of little clinical significance in consideration of the additional toxicity.
Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer : SOLE trial	Lancet Oncol	2017		3	early BC	HR pos	Postmenopausal women, N pos, after 4–6 years of adjuvant endocrine therapy, without evidence of recurrent disease	endocrine therapy, continuous	letrozole 5 years	adjuvant	endocrine therapy, intermittent	letrozole 5 years (9m/12)	adjuvant	87.5% at 5 years	85.5% at 5 years	1.08	no							In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.		No differences were found in the incidence of adverse events and treatment compliance, but QOL outcomes consistently favoured the intermittent arm, with less worsening of sleeping problems, well-being, mood, vaginal problems, and musculoskeletal pain. Importantly, the SOLE trial was not designed to test the efficacy of an intermittent strategy, and, therefore, although the results partially sooth anxieties related to treatment interruption, a trial specifically designed to test intermittent treatment strategies will be necessary before this approach can be considered in routine clinical practice.
Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer : EGF104900 study	JCO	2010		3	metastatic BC	HER2 pos	progressive on prior trastuzumab-containing regimens	dual targeted therapy	lapatinib + trastuzumab	metastatic, after prior trastuzumab	targeted therapy	lapatinib	metastatic, after prior trastuzumab	28% at 6m	13% at 6m	0.73	yes	45% at 1 year	36% at 1 year					Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.		ORR 10 vs 7% (NS), CBR 24 vs 12% (S). The incidence of grade 1 and 2 diarrhea, the only AE with rates significantly different between treatment arms, was higher with the combination therapy. the incidence of grade 3 or higher diarrhea was similar for both treatment groups (7%). combination therapy compared with monotherapy resulted in a significant reduction in the risk of disease progression in two subgroups, including poor-prognosis patients with visceral disease in whom additional chemotherapy-based regimens might have a low tolerability and frequent toxicity.
The prognostic significance of lymphovascular invasion in invasive breast carcinoma	Cancer	2011			early BC																			LVI provided a strong predictor of outcome in patients with invasive breast cancer and should be incorporated into breast cancer staging systems		LVI was strongly associated with both breast cancer‐specific survival (BCSS) and distant metastasis‐free survival (DMFS) in the entire series and in different subgroups. Multivariate analyses identified LVI as an independent predictor of both BCSS and DMFS in patients with operable breast cancer overall; in the TNM clinical subgroups pT1a‐pT1c/pN0 and pT2/pN0; and in the molecular classes estrogen receptor (ER)‐positive, ER‐negative, human epidermal growth factor 2 [HER2]‐negative, and triple‐negative. In patients who had lymph node‐negative tumors, LVI could be used as a high‐risk criterion providing survival disadvantage equivalent to that provided by 1 or 2 involved lymph nodes (pN0 to pN1)
Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer : West German Study PlanB Trial	JCO	2019		3	early BC	HER2 neg	N pos, or N neg considered high risk	chemotherapy	4EC-4T	adjuvant	chemotherapy	6 TC	adjuvant	89.6% at 5 years	89.9% at 5 years		no	94.5% at 5 years	94.7% at 5 years		no			5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2–negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease.		RS < 11 excluded from the study if pN0/pN1. The EC-T arm versus the TC arm was characterized by significantly more dose reductions (20 vs 6%) and dose delays (7 vs 4%)
A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases : TBCRC 022	JCO	2019		2	metastatic BC	HER2 pos	lapatinib-naive or lapatinib-pretreated	chemotherapy + targeted therapy	capecitabine + neratinib	metastatic				5.5m				13m				30		Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.		92% had received CNS surgery and/or radiotherapy. Lapatinib naive vs treated : CNS ORR 49% vs 33% ; mPFS 5.5 vs 3m ;
Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer : SOLAR-1	NEJM	2019		3	metastatic BC	HR pos, HER2 neg	previously treated with endocrine therapy	endocrine therapy + targeted therapy	fulvestrant + alpelisib	metastatic	endocrine therapy	fulvestrant	metastatic	11m median if PIK3CAm, 7m median if PIK3CA wt	5m median if PIK3CAm, 5m median if PIK3CA wt	0.65	yes if PIK3CAm					75	35	Treatment with alpelisib–fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously.		The most frequent adverse events were hyperglycemia (63% all grade, 36% G3-4) ; gastrointestinal toxic effects (diarrhea 7% G3) ; and rash (10% G3). Strong treatment benefit in patients receiving second-line therapy and in patients who had received neoadjuvant or adjuvant chemotherapy previously. But only 5% had received CDK4/6i, 50% were in first line for M+, and only 15% had a primary endrocrine resistance
Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of SweBCG91RT	JCO	2019		3	early BC			breast-conserving surgery + radiotherapy		adjuvant	breast-conserving surgery		adjuvant											high values of TILs in the primary tumor independently seem to reduce the risk for an IBTR. Our findings further suggest that patients with breast cancer with low TILs may derive a larger benefit from RT regarding the risk of IBTR, although a significant interaction between RT and TILs could not be detected.		In total, only 6% received endocrine treatment, 1% received chemotherapy, and 1% received endocrine treatment and chemotherapy. This provides an opportunity to study the influence of TILs on the effect of RT alone. RT (HR 0.42; 95% CI, 0.29 to 0.61; P < .001), high TILs (HR, 0.61; 95% CI, 0.39 to 0.96, P = .033) grade (3 v 1; HR, 2.17; 95% CI, 1.08 to 4.34; P = .029), and age (≥ 50 v < 50 years; HR, 0.55; 95% CI, 0.38 to 0.80; P = .002) were predictive of IBTR. RT was significantly beneficial in the low TILs group (HR, 0.37; 95% CI, 0.24 to 0.58; P < .001) but not in the high TILs group (HR, 0.58; 95% CI, 0.28 to 1.19; P = .138). Although the low TIL group had a significantly beneficial effect of RT on IBTR in contrast to the high TIL group, no significant difference in effect of RT between the groups could be statistically confirmed : The interaction between TILs and RT was not significant (P = .317). The potentially larger benefit from RT in the low TIL group could be attributed to a larger baseline risk of IBTR compared with the high TIL group. Another mechanisms is through an enhanced RT-induced antitumoral immune response.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials : EBCTCG	Lancet	2011		MA	early BC			endocrine therapy	tamofixen 5 years	adjuvant	placebo		adjuvant				yes				yes			5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen.		Even in marginally ER-positive disease the recurrence reduction was substantial (RR 0·67). the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years).
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial	Nature	2018		3	metastatic BC	triple negative	unselected	chemotherapy	carboplatin AUC6	metastatic	chemotherapy	docetaxel	metastatic	ORR 31%	ORR 34%		no							patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy.		In subjects with gBRCA mut, carboplatin had double the ORR of docetaxel (68% versus 33%, p=0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Previous adjuvant taxane was allowed if > 12m elapsed (34% of pts) ; 72% had visceral disease. 12% gBRCA mut. There were more grade 3 and 4 AEs following treatment with docetaxel than with carboplatin. The level of response seen for docetaxel in this trial is consistent with that seen previously in breast cancer, and the level of response for carboplatin was comparable to that seen in uncontrolled trials of single-agent platinums or combinations of carboplatin with gemcitabine in unselected TNBC. A significant interaction was detected between treatment and the Prosigna–PAM50-identified subtypes that was driven by significantly increased response to docetaxel relative to poor platinum response in nonbasal forms of TNBC. This suggests an absence of targetable BRCAness in nonbasal TNBC and provides no evidence to change the standard of care from a taxane to a platinum, which our data suggest is inferior in these subtypes. In contrast, platinum is a reasonable option in individuals with basal-like TNBC, particularly in those who fail to tolerate or have previously received a taxane.
Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer : BrighTNess	Lancet Oncol	2018		3	early BC treated with NACT	triple negative	clinical stage 2-3	chemotherapy + targeted therapy	paclitaxel (W) + carboplatin AUC6 +- veliparib, followed by EC	neoadjuvant	chemotherapy	paclitaxel (W) followed by EC	neoadjuvant	pCR 53% with PCV, 58% with PC	pCR 31%		yes							Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer.		This suggests that the improvement in observed pathological complete response was due to carboplatin, without a substantial contribution from veliparib. Haematological and gastrointestinal toxicities were increased with the addition of carboplatin. An increase in the incidence of febrile neutropenia was seen during subsequent treatment with doxorubicin and cyclophosphamide following carboplatin exposure, but did not prevent delivery of the planned four cycles of doxorubicin and cyclophosphamide relative to the control group. This approach also potentially extended the duration of neoadjuvant chemotherapy by 4 weeks. As 42% required reduction of Carbo to AUC5 and 17% further to AUC4, the optimal starting dose of carboplatin every 3 weeks might be an AUC of 5. Veliparib was given at only 50mg 2x/d. With 3 RCTs (GeparSixto and CALGB 40603) consistently showing a substantially higher proportion of patients who achieve a pCR with addition of carboplatin to neoadjuvant therapy, and the improved dose delivery with manageable incremental toxicities with the approach used in BrighTNess (delaying treatment to allow time for recovery from toxicities, rather than omitting planned treatments to complete paclitaxel-based therapy within an arbitrarily defined period of 12 weeks), this regimen is a reasonable option for patients with high-risk TNBC. OF NOTE : gBRCA mut : pacli alone 41% pCR, vs 50% for carbo-pacli and 57% for carbo-pacli-veli (not significant!!)
Adjuvant Systemic Treatment of Premenopausal Women With Hormone Receptor–Positive Early Breast Cancer: Lights and Shadows	JCO	2019		editorial	early BC	HR pos	premenopausal women																			discussion on SOFT and TEXT results and rising questions
Ovarian Suppression in Adjuvant Endocrine Therapy for Premenopausal Breast Cancer	JCO	2019		editorial	early BC	HR pos	premenopausal women																			discussion on SOFT and TEXT results and rising questions
Future of checkpoint blockade in triple-negative breast cancer: combination strategies to lead the way	Ann Oncol	2019		editorial	metastatic BC	triple negative																		it seems doubtful that monotherapy will ever have a role in any line in the treatment of metastatic TNBC. It appears at present that combined therapy earlier in the course of advanced disease is superior on all accounts.		discussion on KEYNOTE-012, IMpassion 130, KEYNOTE-086
Contralateral breast irradiation in BRCA carriers: the conundrum of prophylactic versus early treatment	Ann Oncol	2019		editorial	prevention		BRCA mutated																			discussion on phase 2 trial evaluating prophylactic contralateral breast irradiation for the prevention of breast cancer in high-risk BRCA mutated cancer patients at the time of breast conserving therapy.
Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer	Ann Oncol	2019		2	prevention		BRCA mutated	radiotherapy	prophylactic irradiation to the contralateral breast in BRCAm patients with early BC treated with breast conserving therapy	adjuvant	placebo	treatment of only the ipsilateral breast		12.4% at 5y median follow-up	2.5% at 5y median follow-up	0.17	yes							Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset.		At mFU of 58m, 10/81 patients developed contralateral BC in the control arm at a median of 32m, as compared with 2/81 patients in the intervention arm who developed contralateral BC 80 and 105m after bilateral breast irradiation. Prophylactic irradiation of the contralateral breast yielded an 80% reduction of breast cancer and delayed its onset. One patient developed sarcoma in the muscle behind a contralateral breast 5y after bilateral breast irradiation. No acute grade 3 toxicity was encountered.
Defining Risk of Late Recurrence in Early-Stage Estrogen Receptor–Positive Breast Cancer: Clinical Versus Molecular Tools	JCO	2019		editorial	early BC	HR pos		endocrine therapy		adjuvant																discussion on evaluation of risk of late relapse
Two-view digital breast tomosynthesis versus digital mammography in a population-based breast cancer screening programme : a randomised, controlled trial : To-Be	Lancet Oncol	2019		3	prevention		women aged 50–69 years, excluding breast implants	screening method	digital breast tomosynthesis		screening method	digital mammography		0.66% screen-detected breast cancer	0.61% screen-detected breast cancer	1.09	no							digital breast tomosynthesis including synthetic 2D mammograms was not significantly different from standard digital mammography as a screening tool for the detection of breast cancer in a population-based screening programme. Economic analyses and follow-up studies on interval and consecutive round screen-detected breast cancers are needed to better understand the effect of digital breast tomosynthesis in population-based breast cancer screening.		32976 norwegian women in the study
Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer : a randomised, double-blind, placebo-controlled, phase 3 trial : ACE trial	Lancet Oncol	2019		3	metastatic BC	HR pos, HER2 neg	Postmenopausal women whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting)	endocrine therapy + targeted therapy	exemestane + Tucidinostat	metastatic	endocrine therapy	exemestane	metastatic	7.4m	3.8m	0.75	yes					21	6	Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3–4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients.		Chinese patients. Neutropenia G3-4 : 51% vs 2%. Leucopenia G3-4 : 19% vs 2%.
Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study	Lancet Oncol	2019		1	metastatic BC	HER2 pos	previous trastuzumab emtansine treatment	antibody drug conjugate	trastuzumab deruxtecan	metastatic				59% ORR								19		Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in trastuzumab emtansine-pretreated patients with HER2-positive breast cancer, regardless of hormone receptor status. These results suggest that further development in phase 2 and 3 clinical trials for HER2-positive breast cancer is warranted (ongoing DESTINY-Breast01 study). 62·5% of patients who received previous pertuzumab treatment achieved an objective response.		Frequent grade 3 or worse treatment-emergent adverse events included anaemia (19 [17%] of 115) and decreased neutrophil (14%), white blood cell (9%), and platelet (8%) counts. Investigators reported 20 cases (17%) of interstitial lung disease, pneumonitis, or organising pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. No cardiac toxicity observed, and rare G1 hepatotoxicity. HER2-targeted antibody–drug conjugate comprised of a humanised monoclonal antibody attached by a cleavable peptide-based linker to a potent topoisomerase I inhibitor payload. The anti-HER2 antibody in this antibody–drug conjugate has the same amino acid sequence as trastuzumab. The unique linker of trastuzumab deruxtecan is stable in plasma and selectively cleaved by lysosomal cathepsins that are upregulated in cancer cells. The topoisomerase I inhibitor payload of trastuzumab deruxtecan was ten times more potent than the active metabolite of the topoisomerase I inhibitor, irinotecan, in cell-free inhibition assays, and trastuzumab deruxtecan exhibited 99% tumor growth inhibition at a dose of 4 mg/kg in xenograft models. The payload is cell membrane permeable and has shown a short systemic half-life in preclinical in-vivo studies. This could allow for a potent cytotoxic bystander effect, whereby the released topoisomerase I inhibitor diffuses across the target-cell membrane, affecting nearby cells regardless of their HER2-expression.
Is the duration of adjuvant trastuzumab debate still clinically relevant?	Lancet	2019		editorial	early BC	HER2 pos																				discussion on 6 vs 12m of adjuvant trastuzumab : PHARE vs PERSEPHONE trials
Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study	JCO	2019		3	early BC	HER2 pos	clinical stage 2-3	antibody drug conjugate + targeted therapy	trastuzumab emtansine + pertuzumab	neoadjuvant	chemotherapy + dual targeted therapy	docetaxel-carboplatin + trastuzumab-pertuzumab	neoadjuvant	44% pCR rate	55% pCR rate		yes	85% DFS at 3 years	94% DFS at 3 years	2.6	yes	31	67	Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.		After surgery, analysis of the IDFS-evaluable population showed no difference between arms in the risk of an IDFS event; however, 95% CI is wide for the IDFS HR (0.52 to 2.40), and the 15 patients who experienced locoregional progression in the T-DM1+P arm before surgery were not included in the IDFS-evaluable population; therefore, IDFS results should be interpreted with caution. In addition, within the T-DM1+P arm, patients who had residual disease were more likely to have received adjuvant chemotherapy than patients who had a pCR (33.1% v 9.1%). Consistent with other data, pCR conferred a favorable long-term outcome compared with no pCR (stratified HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm, with 3-year IDFS event-free rates of 96.7% in the T-DM1+P arm and 97.5% in the TCH+P arm. A relationship between pCR and a favorable 3-year outcome was also apparent regardless of hormone receptor status. there were fewer grade 3 or higher adverse events with T-DM1+P during the neoadjuvant phase; however, in the adjuvant setting, there was more toxicity with T-DM1+P, which is only partially explained by the use of adjuvant chemotherapy and could represent cumulative toxicity with T-DM1 that was also observed in KATHERINE. KRISTINE suggests, but does not prove, that all pCRs are equal, no matter how achieved, setting the goal for future trials to achieve pCR with the least toxic therapy.
Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia : Tam01	JCO	2019		3	in situ	HR+	after surgery	endocrine therapy	tamoxifen 5 mg/day for 3 years	adjuvant	placebo		adjuvant	6% incidence of IBC or DCIS at 5 years	11% incidence of IBC or DCIS at 5 years	0.48	yes					4	6	Tamoxifen at 5 mg/d for 3 years, as compared to placebo, can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.		low-dose tamoxifen decreased by 75% the onset of a contralateral breast cancer, which indicates a potential primary preventive effect, and decreased invasive cancer by more than 40%, which prevents more-intensive adjuvant treatments. Women with high-grade or comedo/necrotic DCIS received adjuvant radiotherapy of 50 Gy in 25 courses (45% in both arms). there was a slight increase in daily frequency of participant-reported hot flashes in the tamoxifen arm over the 3-year treatment period (mean daily hot flash frequency of 2.1 vs 1.5, but hot flash score not different between arms). No differences in PRO (among which vaginal dryness, intercourse pain, arthralgia).
Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH trial	JAMA oncol	2019		3	early BC	HER2 pos	received neo-adjuvant chemotherapy	targeted therapy	trastuzumab SC	neoadjuvant and adjuvant for 1 year	targeted therapy	trastuzumab IV	neoadjuvant and adjuvant for 1 year	65% at 6 years	65% at 6 years	0.98	no	84% at 6 years	84% at 6 years	0.94	no	53	53	Event-free survival and OS results after 6 years of follow-up continue to support the noninferiority of subcutaneous trastuzumab to intravenous trastuzumab observed in the primary analysis. This final analysis of the HannaH trial further confirms the comparable efficacy and safety of subcutaneous and intravenous trastuzumab and highlights the suitability of subcutaneous trastuzumab as an alternative route of administration for patients with ERBB2-positive early breast cancer.		Results for EFS were consistent with those observed in the Neoadjuvant Herceptin (NOAH) trial of intravenous trastuzumab. Rates of tpCR were similar among patients receiving subcutaneous trastuzumab and those receiving intravenous trastuzumab; achieving pCR was associated with longer EFS and OS in both study groups, consistent with long-term efficacy in other studies, such as the CTNeoBC study. The overall and cardiac safety profiles of subcutaneous trastuzumab at 6 years’ follow-up remains consistent with that of intravenous trastuzumab and with the safety profile of subcutaneous trastuzumab observed in the SafeHer and PrefHer studies.
The Effects of Ganglioside-Monosialic Acid in Taxane-induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial	JNCI	2019		3	early BC		taxane-based adjuvant chemotherapy	neuroprotective factor	GM1	during taxane treatment (D-1 to D+2)	placebo													The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after 4-cycles of taxane-containing chemotherapy in patients with breast cancer.		Grade ≥ 1 peripheral neurotoxicity in CTCAE v4.0 scale was statistically significantly lower in GM1 group (14.3% vs 100.0%, P < .001). Additionally, GM1 group reported a statistically significantly lower incidence of grade ≥ 1 neurotoxicity assessed by ENS sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001). Besides, better mean FACT-Ntx subscale scores (43 vs 34, p < 0.001)
Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancer	Lancet Oncol	2019		editorial	early BC	HER2 pos or TNBC																		neoadjuvant systemic therapy should be considered as the new standard of care for HER2-positive and oestrogen receptor negative breast cancer, even for patients who present with operable (T1 or T2) disease. Administering chemotherapy before surgery provides an opportunity to directly observe the efficacy of a particular chemotherapy regimen. Patients who have extensive residual invasive cancer after neoadjuvant chemotherapy are at a high risk of recurrence for metastatic disease, which, in turn, make these patients ideal candidates for clinical trials. The opportunity for residual-disease guided therapy is lost when patients undergo surgery first.		Discussion about the clinical implications of the CREATE-X and KATHERINE trials, placed into context with other developments in the adjuvant setting of early-stage breast cancer.
Nab-Paclitaxel: A New Standard of Care in Neoadjuvant Therapy of High-Risk Early Breast Cancer?	JCO	2019		editorial	early BC treated with NACT			chemotherapy	nab-paclitaxel	neoadjuvant	chemotherapy	paclitaxel	neoadjuvant											discussion about GeparSepto and ETNA trials, and interesting discussion about its probably limited role in HER2+, as compared to HER2-, with comparison to carboplatin in TNBC (GeparSixto, CALGB40603, BrighTNess)		As expected, substantially fewer patients with pCR status than those with residual disease had iDFS events. Of interest, although there were minimal differences in iDFS according to the formulation of paclitaxel in patients with pCR, there were substantially fewer iDFS events among patients with non–pCR status in the nab-paclitaxel cohort, which suggests that patients with residual disease received greater benefit from nab-paclitaxel than from s-paclitaxel. In subset analyses, patients with TNBC who had statistically significant improvements in pCR also saw improved iDFS, which supports the potential surrogacy of pCR for long-term outcome in this population. However, a similar reduction in risk for iDFS events was demonstrated in the other subtypes in which a significant increase in pCR had not been demonstrated. Thus, a failure to substantially increase pCR may not be an appropriate metric to use for no-go decisions in the development of new agents in early breast cancer.
NAB-Paclitaxel Improves Disease-Free Survival in Early Breast Cancer: GBG 69–GeparSepto	JCO	2019		3	early BC treated with NACT			chemotherapy	nab-paclitaxel (W) followed by EC	neoadjuvant	chemotherapy	paclitaxel (W) followed by EC	neoadjuvant	84% at 4 years	76% at 4 years	0.66	yes	89% at 4 years	87% at 4 years	0.87	no			The significantly higher pathologic complete response rate with NAB-paclitaxel translated into a significantly improved iDFS in patients with early BC as compared with sb-paclitaxel. PSN improved much faster under NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2.		Significantly increased pCR rate in patients treated with weekly NAB-paclitaxel 125 mg/m2 compared with weekly sb-paclitaxel 80 mg/m2 (38 vs 29%), with the largest increase observed in TNBC (48 vs 26%, ns). Patients achieving a pCR had fewer iDFS events than patients without pCR (8.9 vs 25.6%). Patients not achieving a pCR had a significantly better iDFS with NAB-paclitaxel than with sb-paclitaxel (HR 0.67), whereas there was no difference between the two taxanes in the pCR group (but only 20 and 16 events). The dose reduction from 150 mg/m2 to 125 mg/m2 did not compromise the pCR rate or the iDFS compared with sb-paclitaxel. Overall, the rate of PSN was more frequent after NAB-paclitaxel than after sb-paclitaxel treatment. However, short- as well as long-term analyses of PSN support the use of NAB-paclitaxel 125 mg/m2, because this dose was associated with earlier PSN resolution compared with NAB-paclitaxel 150 mg/m2. Patients with Ki-67 20% or less and treated with NAB-paclitaxel did not show a higher pCR rate but had a better iDFS compared with those with sb-paclitaxel. This effect cannot fully be explained by the pCR hypothesis but points to a higher efficacy of NAB-paclitaxel beyond its effect on pCR alone. There were more nonhematologic adverse events after NAB-paclitaxel, and more patients receiving sb-paclitaxel completed taxane treatment. However, NAB-paclitaxel 125 mg/m2 compared with 150 mg/m2 led to decreased toxicity, especially less high-grade neutropenia and infections, as well as a lower discontinuation rate and a higher total dose intensity.
Does adjuvant therapy reduce postmetastatic survival?	Ann Oncol	2019		editorial																						discussion about the reduced survival in the metastatic setting seen for a subgroup of patients treated with (neo)adjuvant therapy
Antibody–drug conjugates for cancer	Lancet	2019		editorial
Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial	JCO	2019		3	early BC		65 years of age or older and an expected survival of more than 5 years	chemotherapy	CMF or AC	adjuvant	chemotherapy	capecitabine	adjuvant	56% at 10 years	50% at 10 years	0.8	yes	62% at 10 years (88% BC-specific)	56% at 10 years (82% BC-specific)		no for OS, yes for BC-specific			With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.		With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). We have learned much about adjuvant therapy since the initial development and publication of our study. First, many of the patients enrolled in our trial would not currently be recommended to receive chemotherapy, especially many node-negative patients in whom genetic-based assays would likely suggest no benefit. In addition, although CMF and AC result in similar outcomes, the majority of lower risk patients receiving chemotherapy today are treated with docetaxel and cyclophosphamide, a combination that is superior to AC (and CMF) and that showed similar benefits for patients older and younger than 65 years.
Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis	Lancet Oncol	2019		MA	metastatic BC	HR pos, HER2 neg	first-line or second-line treatments, in postmenopausal women																	In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer.		Palbociclib plus letrozole (HR 0·42; 95% credible interval [CrI] 0·25–0·70), ribociclib plus letrozole (0·43; 0·24–0·77), abemaciclib plus anastrozole or letrozole (0·42; 0·23–0·76), palbociclib plus fulvestrant (0·37; 0·23–0·59), ribociclib plus fulvestrant (0·48; 0·31–0·74), abemaciclib plus fulvestrant (0·44; 0·28–0·70), everolimus plus exemestane (0·42; 0·28–0·67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0·39; 0·22–0·66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. No significant differences in efficacy and overall activity were observed among the three CDK4/6 inhibitors. To date, few data are available from randomised controlled trials directly comparing hormone therapies to chemotherapy-based treatment regimens in this disease subset. Indeed, in the past three decades, only two randomised controlled trials addressing this issue have been published. Besides those two trials, only one large retrospective analysis was done of patients with hormone-receptor-positive, HER2-negative metastatic breast cancer who were sensitive to aromatase inhibitors, which compared front-line hormone therapies to induction chemotherapy.
Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603	JCO	2014		2	early BC	triple negative	stage II to III scheduled for neoadjuvant chemotherapy	chemotherapy	paclitaxel 80 + carboplatin AUC6 - dd doxorubicin+cyclophosphamide	neoadjuvant	chemotherapy	paclitaxel 80 - dd doxorubicin+cyclophosphamide	neoadjuvant	54% pCR	41% pCR		yes							In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.		Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin. No TNBC study has compared carboplatin doses and schedules (AUC 6 every 3 weeks v AUC 2 once per week) concurrently with single-agent wP, but given results in other malignancies, the once-per-week regimen would likely cause less severe hematologic toxicities and might be as effective. Two thirds had clinical stage II disease. The majority had T2 tumors; slightly > half were clinically node positive; 76% had high-grade disease; > 90% had invasive ductal carcinomas, whereas few had ER (6%) or PgR (4%) expression > 1%.
Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial	Lancet Oncol	2014		2	early BC	triple negative or HER2+	stage II to III scheduled for neoadjuvant chemotherapy	chemotherapy + targeted therapy	carboplatin AUC 1.5 + paclitaxel 80mg/m² - non-pegylated liposomal doxorubicin 20mg/m² + bevacizumab or trastuzumab and lapatinib	neoadjuvant	chemotherapy + targeted therapy	paclitaxel 80mg/m² - non-pegylated liposomal doxorubicin 20mg/m² + bevacizumab or trastuzumab and lapatinib	neoadjuvant	53% pCR for TNBC, 32% pCR for HER2+	37% pCR for TNBC, 36% pCR for HER2+		yes for TNBC, no for HER2+							The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. As a phase 2 study with a level of significance of 0·2 it cannot provide confirmative evidence of the activity of carboplatin.		anaemia, neutropenia, thrombocytopenia, and nausea, occurred more commonly in the group given carboplatin. The addition of carboplatin was also associated with a higher rate of diarrhoea and anorexia, whereas hand-foot syndrome, skin rash, nail changes, pneumonitis, and other cardiac disorders were more common in the group not treated with carboplatin (who achieved higher mean relative total dose intensity).
Outcomes by Tumor Subtype and Treatment Pattern in Women With Small, Node-Negative Breast Cancer: A Multi-Institutional Study	JCO	2014		prospective cohort study	early BC	all	T1a,b N0 M0	chemotherapy		adjuvant	no chemotherapy		adjuvant											Women with T1a,b tumors have an excellent prognosis without chemotherapy. Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy. These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks. Although chemotherapy with or without trastuzumab may be beneficial in some patients, the absolute benefit for most patients with T1a,bN0M0 is relatively small, and potential toxicities should be a factor in treatment decisions, which ultimately should be driven by a well-informed patient.		less than 5% 5-year risk of distant recurrence in T1bN0 patients with HR-positive/HER2-negative tumors treated without chemotherapy strongly suggest that further prognostic tests are likely unnecessary in the vast majority of such patients, unless there are other high-risk features of concern. The situation is somewhat different in patients who have HER2-positive tumors for whom the potential benefits for therapy among these subsets and the variability in prognostic estimates have resulted in uncertainty on the appropriate threshold for adjuvant chemotherapy with or without trastuzumab recommendations. For untreated patients with T1aN0 HR-negative/HER2-positive tumors (n = 49), 5-year DRFS was 93%; for untreated patients with T1bN0 HR-negative/HER2-positive tumors (n = 17), 5-year DRFS was 94%. Among patients with HR-positive/HER2-positive tumors untreated with chemotherapy or trastuzumab, the 5-year DRFS was 96% in T1a (n = 102) tumors and 94% in T1b (n = 89) tumors, which may be impacted by the use of endocrine treatment (85% received endocrine therapy). Overall, among patients with HER2-positive or HR-negative/HER2-negative tumors, we observed numerically higher 5-year DRFS in treated patients. Overall we found excellent prognosis across all subgroups; however, this data also suggests that particularly those with larger and HR-negative tumors may derive benefit from treatment.
Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer : NeoPAL	Ann Oncol	2018		2	early BC	HR pos, HER2 neg	Prosigna-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery	endocrine therapy + targeted therapy	letrozole + palbociclib	neoadjuvant	chemotherapy	3FEC - 3 docetaxel	neoadjuvant	3.8% pCR, 7.7% RCB 0-1, 75% clinical response, 69% breast conserving surgery	5.9% pCR, 15.7% RCB 0-1, 75% clinical response, 69% breast conserving surgery									LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in ProsignaVR -defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. the results of this hypothesis-generating trial were negative on the primary end point with a low rate of pathological responses in both arms. However, they showed similar biological and clinical effects between a CDKi-ET combination and chemotherapy for the neoadjuvant treatment of high-risk LBC patients. It is our belief that the favourable benefit–risk profile of the letrozole–palbociclib combination observed in this early, pilot trial will help define CDKi-ET combinations as candidates for chemotherapy replacement in high-risk LBC.		Breast surgery was carried out 24 h after the last palbociclib and letrozole doses, and 4 weeks after the last chemotherapy infusion. The geometric mean of Ki67 expression was sharply decreased with both therapies, with scores of 1.17% and 3.7% at surgery, respectively. Adverse events were almost twice as frequent in the chemotherapy arm. It is striking that these poor results with chemotherapy were obtained in a highly selected population, where high risk was defined by a second-generation transcriptomic signature, underlining the need for alternative therapies in this population. The hypotheses regarding the primary end point in this proof-of-concept trial were clearly too optimistic (p0=20%, p1=40%). This might likely be attributable to the cytostatic mode of action of endocrine therapies and CDK4/6 inhibitors. The treatment duration with the letrozole–palbociclib combination is also questionable. It has long been shown that extending duration of neoadjuvant ET improves clinical response and breast conservation, though with no demonstration of improvement in pathological response.
Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial	Lancet Oncol	2019		2	metastatic BC	HR pos HER2 neg	premenopausal patients that had relapsed or progressed during tamoxifen, treated with max 1 line of chemotherapy in the metastatic setting	endocrine therapy + targeted therapy	palbociclib + exemestane + GNRH agonist	metastatic	chemotherapy	capecitabine	metastatic	20m	14m	0.66	yes					2	17	Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.		Most of the patients who received tamoxifen as a component of their adjuvant endocrine therapy had disease recurrence during adjuvant therapy or within 12 months after completion or discontinuation of the therapy, which differs to the findings of other studies of first-line CDK4/6 inhibitor treatment, such as PALOMA-2 and MONALEESA-2. In these studies, most populations had endocrine-sensitive relapse, in which their disease had recurred 12 months after completion of adjuvant endocrine therapy (with DFS of at least 6 years). More than half of the patients in our trial had not received previous chemotherapy for their metastatic disease, and approximately a third of the patients had stage IV disease as their initial diagnosis of breast cancer. These results are also supported by those of the BOLERO-6 trial in which capecitabine treatment led to a median PFS of 9·6 months, although in that trial exemestane plus everolimus showed no advantage over capecitabine. In a post-hoc subgroup analysis, the patients who had not undergone chemotherapy before enrolment and who did not have visceral metastases derived the largest benefits from palbociclib combination endocrine therapy compared with capecitabine.
CDK4/6 inhibitors in breast cancer: a role in triple-negative disease?	Lancet Oncol	2019		editorial	metastatic BC	triple negative																		The trial did not meet its primary objective, because trilaciclib did not reduce either the occurrence or duration of severe neutropoenia. However, patients in the trilaciclib groups had a longer PFS (9·4 months in group 2 and 7·3 months in group 3 vs 5·7 months in group 1) and OS was significantly longer than those in the control group (median 20·1 months in group 2 and 17·8 months in group 3 vs 12·6 months in group 1; group 3 vs group 1 two-sided p=0·0023). A biological hypothesis exists that could also explain the OS improvement—namely, the enhancement of antitumour immunity by trilaciclib. CDK4/6 inhibitors, including trilaciclib, have been shown to enhance antitumour immune responses through several mechanisms including the direct stimulation of T-cell effector function and a preferential suppression of regulatory T-cell proliferation. Furthermore, by only administering trilaciclib just before chemotherapy infusions, prevention of chemotherapy-induced T-cell apoptosis and bone marrow myeloid skewing (both immunosuppressive occurrences) might be possible while preserving intra-tumoural cytotoxic T-cell proliferation.		Tan A, Lancet oncol 2019 : three-arm, randomised, phase 2 trial. Patients in the control group (group 1) received conventional chemotherapy (intravenous carboplatin and gemcitabine), and those in the two experimental groups received the same chemotherapy plus trilaciclib (a selective, intravenously administered CDK4/6 inhibitor), given either as a single dose before each chemotherapy infusion (group 2) or on the day before and day of each chemotherapy infusion (group 3). The primary objective of the trial was actually to determine whether trilaciclib reduced chemotherapy-related neutropoenia : induction of G1 arrest in bone marrow progenitors to protect them from the cytotoxic effects of chemotherapy. This without inducing G1 arrest in tumour cells CDK4/6 inhibitors that can antagonise the effect of chemotherapies that typically exert their effects in the S, G2, or M phases.
Bevacizumab for Advanced Breast Cancer	JCO	2011		editorial	metastatic BC	HER2 neg		chemotherapy + targeted therapy	bevacizumab	metastatic	chemotherapy		metastatic											AVADO and RIBBON-1 have been valuable in demonstrating that the benefits for adding bevacizumab to every 3 week docetaxel or nab-paclitaxel therapy or to anthracycline-based chemotherapy are rather minimal and are associated with greater toxicity than is seen using paclitaxel once per week. There may be modest gain, at best, in adding bevacizumab to capecitabine, but the existence of a previous negative study makes this a less appealing option. Bevacizumab has not enhanced survival in advanced breast cancer. Crossover likely confounds survival analyses from RIBBON-1, but it was not a major issue in other studies. The lack of a survival difference is more likely rooted in the poorly correlated and weak relationship between PFS and overall survival in most studies of advanced breast cancer as well as in the efficacy of subsequent lines of chemotherapy, the implicit development of resistance to bevacizumab plus chemotherapy, and the modest clinical effects of bevacizumab.		Two placebo-controlled, randomized phase III trials of first-line chemotherapy (AVADO and RIBBON-1) were designed to validate the findings of ECOG E2100 while exploring the use of bevacizumab with chemotherapy backbones that differed from weekly paclitaxel. These trials demonstrated statistically significant improvement in PFS and RR with the addition of bevacizumab to chemotherapy. Although the AVADO and RIBBON-1 trials produced P values that were statistically significant, the outcomes were arguably not clinically compelling. Besides, lack of overall survival advantage in any of them. There is a greater risk of hypertension with any bevacizumab regimen, and adverse effects such as headache and nasal congestion, although rarely scored as grade 3 or 4, are also more frequent with bevacizumab. When bevacizumab is paired with taxanes taken once every three weeks, there is a greater chance of neutropenia. Because of vascular-related adverse effects of bevacizumab, congestive heart failure remains a potential concern. In all three randomized trials, hazard ratios for TTP among patients with triple-negative breast cancers were similar to those for patients with hormone-receptor positive tumors. neither prior adjuvant therapy nor tumor subtype will serve as selection factors for bevacizumab-based treatment. Despite being a targeted therapy, bevacizumab lacks a robust, predictive, biologic, or clinical marker of activity.
Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer : MONALEESA-7	Lancet Oncol	2018		3	metastatic BC	HR pos HER2 neg	premenopausal or perimenopausal women, up to one line of chemotherapy for advanced disease	endocrine therapy + targeted therapy	ribociclib + goserelin + tamoxifen, letrozole or anastrozole	metastatic	endocrine therapy	goserelin + tamoxifen, letrozole or anastrozole	metastatic	24m	13m	0.55	yes					18	12	Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients.		Symptomatic visceral diseases were excluded. Two other studies (PALOMA-3 and MONARCH-2) have investigated inhibitors of CDKs 4 and 6 combined with endocrine therapy and a gonadotropin-releasing hormone agonist such as goserelin in premenopausal patients. However, these trials were in the setting of a later treatment line than MONALEESA-7, premenopausal patients comprised a subset of the overall study, and the studies used a different endocrine therapy combination partner (fulvestrant) and comparator group (placebo plus fulvestrant) to MONALEESA-7. In PALOMA-3 and MONARCH-2, eligible premenopausal patients were required to receive a gonadotropin-releasing hormone agonist such as goserelin for at least 28 days before initiating study treatment. In MONALEESA-7, goserelin could be initiated on the same day as the other study drugs so that patients could begin the full treatment regimen without delay. The longer duration of progression-free survival in the ribociclib group was observed regardless of the endocrine therapy partner (tamoxifen or NSAI), and in most of the prespecified subgroups. Improvements in EORTC QLQ-C30 health-related quality-of-life scores were also observed in the ribociclib group compared with the placebo group. Such improvements in health-related quality of life with the addition of an inhibitor of CDKs 4 and 6 have not been observed in the postmenopausal population in the setting of initial endocrine therapy for advanced disease. A higher incidence of notable QTcF values was observed in patients receiving tamoxifen compared with those receiving an NSAI.
Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer : MONALEESA-7	NEJM	2019		3	metastatic BC	HR pos HER2 neg	premenopausal or perimenopausal women, up to one line of chemotherapy for advanced disease	endocrine therapy + targeted therapy	ribociclib + goserelin + tamoxifen, letrozole or anastrozole	metastatic	endocrine therapy	goserelin + tamoxifen, letrozole or anastrozole	metastatic					70% at 3.5 years (median NR)	46% at 3.5 years (median 40m)	0.71	yes			This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor–positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. The OS results are consistent with those of PFS.		Significant OS benefit, even though 18.6% of patients who discontinued the trial regimen in the placebo group received CDK4/6 inhibitors as subsequent therapy. PFS was also longer during receipt of second-line therapy or to death in the ribociclib group than in the placebo group (HR 0.69). Key grade 3 or 4 adverse events of special interest were neutropenia (in 63.5% of patients in the ribociclib group and 4.5% in the placebo group), hepatobiliary toxic effects (in 11% and 6.8%, respectively), and prolonged QT interval (in 1.8% and 1.2%, respectively).
palbociclib in combination with letrozole versus letrozole alone as ﬁ rst-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer : PALOMA-1/TRIO-18	Lancet Oncol	2015		2	metastatic BC	HR pos HER2 neg	postmenopausal women who had not received any systemic treatment for their advanced disease	endocrine therapy + targeted therapy	palbociclib + letrozole	metastatic	endocrine therapy	letrozole	metastatic	20m	10m	0.49	yes					76	21	The addition of palbociclib to letrozole in this phase 2 study signiﬁ cantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer.		In cohort 2 of this study, we investigated the potential for CCND1 amplification or CDKN2A loss to be used to improve patient selection beyond use of oestrogen receptor-positive status alone. However, our results did not substantiate this hypothesis. This analysis conﬁ rmed that oestrogen receptor positivity is currently the best and most eﬀ ective predictive marker for the identiﬁ cation of patients likely to respond to CDK4/6 inhibition. in view of the large proportion of patients in our study who achieved a clinical beneﬁ t response (more than 80%), the beneﬁ t of additional biomarkers could be diﬃ cult to ascertain. Negative-selection biomarkers of resistance might be more easily identiﬁ ed and will also be assessed in ongoing and future molecular studies. One of the most important markers of sensitivity to palbociclib is the presence of an intact Rb pathway; however, since pRb loss is uncommon in oestrogen receptor-positive, HER2-negative breast cancers, it was not used as a prospective independent biomarker for patient selection in the present study.
Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer : BOLERO-3	Lancet Oncol	2014		3	metastatic BC	HER2 pos	trastuzumab-resistant and previously received taxane therapy	chemotherapy + targeted therapy	weekly vinorelbine + trastuzumab + daily everolimus	metastatic	chemotherapy + targeted therapy	weekly vinorelbine + trastuzumab	metastatic	7m	5.8m	0.78	yes					42	20	The addition of everolimus to trastuzumab plus vinorelbine signiﬁcantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical beneﬁt should be considered in the context of the adverse event proﬁle in this population. The results of this study support the concept that, at least in part, resistance to trastuzumab is sustained by altered intracellular signalling.		Activation of the PI3K/Akt/mTOR pathway is a HER2 escape mechanisms. Higher incidence of stomatitis, fatigue, diarrhoea, pyrexia, and decreased appetite and weight. Higher incidence of haematological adverse events, including neutropenia, anaemia, leucopenia, thrombocytopenia, and febrile neutropenia, in the everolimus group. Although non-infectious pneumonitis was reported in this trial, the incidence was somewhat lower than that seen in BOLERO-2. The eﬃ cacy of everolimus was more pronounced in patients with oestrogen-receptornegative breast cancer than in those with oestrogenreceptor-positive cancer, similar to previous studies with trastuzumab-containing therapy. Substantial cross-talk exists between HER2 and oestrogen-receptor pathways such that inhibition of HER2 alone increases signalling through the oestrogen receptor, which aﬀ ects eﬃ cacy of HER2-directed agents. Low PTEN expression and high pS6 seemed to be signiﬁ cantly associated with higher sensitivity to everolimus. These data suggest that everolimus was able to counter PI3K/Akt/mTOR pathway activation in trastuzumab-resistant breast cancer, and that identiﬁ cation of patients who might derive the greatest beneﬁt from everolimus-containing therapy is plausible.
Updated Results From MONALEESA-2, a Phase III Trial of First-Line Ribociclib Plus Letrozole Versus Placebo Plus Letrozole in Hormone Receptor-Positive, HER2-negative Advanced Breast Cancer	Ann Oncol	2018		3	metastatic BC	HR pos HER2 neg	postmenopausal women who had not received previous systemic therapy for advanced disease	endocrine therapy + targeted therapy	ribociclib + letrozole	metastatic	endocrine therapy	letrozole	metastatic	25m	16m	0.57	yes							After 26.4 months of follow-up, the improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.		Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease.
HR+, HER2– Advanced Breast Cancer and CDK4/6 Inhibitors: Mode of Action, Clinical Activity, and Safety Profiles	Current Cancer Drug Targets	2017		review	metastatic BC	HR pos HER2 neg		endocrine therapy + targeted therapy																Discussion about the mode of action of the three CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib. Description of their efficacy and safety data relating to their use in HR+, HER2– advanced breast cancer, as well as their key side effect
Health-related Quality of Life of Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Ribociclib + Letrozole: Results From MONALEESA-2	Breast Cancer Res Treat	2018		3	metastatic BC	HR pos HER2 neg	postmenopausal women who had not received previous systemic therapy for advanced disease	endocrine therapy + targeted therapy	ribociclib + letrozole	metastatic	endocrine therapy	letrozole	metastatic											HRQoL was consistently maintained from baseline in postmenopausal women with HR+, HER2- advanced breast cancer receiving ribociclib plus letrozole and was similar to that observed in the placebo plus letrozole arm. Together with the improved clinical efficacy and manageable safety profile, these PRO results provide additional support for the benefit of ribociclib plus letrozole in this patient population.		In addition to maintaining overall QoL, ribociclib plus letrozole was associated with a clinically meaningful reduction in pain in the overall population, which was observed as early as Week 8 and maintained for at least 15 cycles. Significant improvements in pain score were also observed in all patients and subgroups of patients with measurable disease at baseline in the ribociclib plus letrozole arm.
Ribociclib With Letrozole vs Letrozole Alone in Elderly Patients With Hormone Receptor-Positive, HER2-negative Breast Cancer in the Randomized MONALEESA-2 Trial	Breast Cancer Res Treat	2018		3	metastatic BC	HR pos HER2 neg	elderly postmenopausal women who had not received any systemic treatment for their advanced disease	endocrine therapy + targeted therapy	ribociclib + letrozole	metastatic	endocrine therapy	letrozole	metastatic	NR	18m	0.61	yes							Of the 668 included patients, 295 were aged ≥ 65 years. Addition of ribociclib to letrozole is a valid therapeutic option for elderly patients with HR+, HER2- advanced breast cancer in the first-line setting.		There was no significant difference in ribociclib treatment effect between older and younger patients receiving ribociclib. In both age groups, patients derived early clinical benefit from ribociclib plus letrozole, with separation of the PFS curves occurring from 8 weeks onwards. In the placebo plus letrozole arm, median PFS was over 5 months longer in patients aged > 65 years than in patients < 65 years (18.4 vs 13.0 months), despite a similar distribution of metastatic site involvement, supporting previous suggestions that elderly patients may have a more indolent course of disease. Ribociclib plus letrozole was well tolerated in elderly patients, with no new safety concerns raised and a safety profile comparable to that observed in the overall population. The incidence of neutropenia was comparable in patients aged C 65 years and patients aged\65 years in contrast to chemotherapy regimens, which often increase the risk of neutropenia in elderly patients. The overall incidence rates of dose interruptions and reductions were comparable in both age groups.
Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3	JCO	2018		3	metastatic BC	HR pos HER2 neg	postmenopausal women, treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting.	endocrine therapy + targeted therapy	ribociclib + fulvestrant	metastatic	endocrine therapy	fulvestrant	metastatic	20m	13m	0.59	yes							Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. Ribociclib and fulvestrant may represent a new therapeutic option in this subtype of advanced breast cancer, both for patients receiving treatment in the first-line setting (ie, treatment naïve for advanced breast cancer; including patients whose disease relapsed >12 months after completion of [neo]adjuvant therapy or patients with de novo advanced/metastatic disease [no prior exposure to endocrine therapy]) and for those receiving treatment in the second-line setting or who had an early relapse (ie, received up to one line of prior endocrine therapy in the advanced setting [early relapse defined as disease relapse on or ≤12 months since the completion of (neo)adjuvant endocrine therapy]).		Consistent treatment effects were observed in patients who were treatment naïve (50% of pts : patients with de novo disease and those who experienced relapse > 12 months from completion of [neo]adjuvant endocrine therapy with no treatment for advanced disease) in the advanced setting, as well as in patients who had received up to one line of prior endocrine therapy for advanced disease.
Abemaciclib as a Single Agent in Patients With Refractory HR +/HER2 - Metastatic Breast Cancer : MONARCH 1	Clin Cancer Res	2017		2	metastatic BC	HR pos HER2 neg	Women ≥18 years of age who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting	targeted therapy	abemaciclib	metastatic				6m				17m				24		In this poor-prognosis, heavily pretreated population with refractory HR+/HER2− metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity.		90% had visceral disease, and 50.8% of patients had 3 or more metastatic sites. In the metastatic setting, patients had received a median of 3 (range, 1–8) prior lines of systemic therapy including a median of 1 (1–3) lines of chemotherapy and 2 (1–6) lines of endocrine therapy. Objective response rate was 19.7%. Clinical benefit rate (CR+PR+SD≥6 months) was 42.4%. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). The ORR observed in MONARCH 1 is consistent with the approximate ORR range of 10%–20% observed with approved cytotoxic chemotherapy treatments in taxane-pretreated patients with MBC. The most frequent TEAE reported was diarrhea, which generally occurred in the first treatment cycle. Although dose reductions and omissions were most commonly due to diarrhea, most patients with an AE of diarrhea did not require a dose modification due to it; many patients received antidiarrheal medications as indicated in the protocol. This, along with the generally limited duration of diarrhea, suggests that in many cases, diarrhea was manageable.
Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer : EMBRACE	Lancet	2011		3	metastatic BC		between 2 and 5 previous chemotherapy regimens, including an anthracycline and a taxane	chemotherapy	eribulin	metastatic	chemotherapy	treatment of physician's choice	metastatic	3.7m	2.2m	0.87	no	13m	10m	0.81	yes	25	26	Eribulin showed a signiﬁ cant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This ﬁ nding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting.		Median of 4 previous chemotherapy regimens. 51% had >= 3 metastatic sites. 73% had received capecitabine. 16% HER2+, 19% TNBC. ORR 12 vs 5%. Most common AE : neutropenia (52%, 24% G4, 5% NF), anemia, alopecia, neuropathy (35%, 8% G3-4), fatigue. Eribulin is a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. It is a structurally modiﬁ ed synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin has a novel mode of action that is distinct from those of other tubulin-targeting agents, inhibiting the microtubule growth phase without aﬀ ecting the shortening phase, and causing tubulin sequestration into non-productive aggregates.
Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane	JCO	2015		6	metastatic BC		up to three prior chemotherapy regimens and up to two prior chemotherapy regimens for advanced and /or metastatic disease ; prior therapy with an anthracycline and a taxane	chemotherapy	eribulin	metastatic	chemotherapy	capecitabine	metastatic	4m	4m	1.08	no	16m	15m	0.88	no	17	21	In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.		ORR similar 11%. The most common AEs with eribulin were neutropenia, alopecia, leukopenia, global peripheral neuropathy, and nausea. The most common AEs with capecitabine were hand-foot syndrome, diarrhea, and nausea. Febrile neutropenia occurred at low incidence with both eribulin (2.0%) and capecitabine (0.9%). Most AEs were grade 1 or 2. The most common grade 3 or 4 AEs were neutropenia, leukopenia, asthenia, and global peripheral neuropathy for eribulin, and hand-foot syndrome, diarrhea, neutropenia, dyspnea, and asthenia for capecitabine. Grade 3 or 4 global peripheral neuropathy occurred in 7.0% of patients receiving eribulin and 0.9% of patients receiving capecitabine. Incidences of alopecia and peripheral neuropathy were higher for eribulin compared with capecitabine, but incidences of diarrhea and vomiting were lower. Over time, average GHS/QoL scores improved in both arms, but without difference between the groups. Patients in the eribulin arm could cross over and receive capecitabine (49.6%), whereas cross over from capecitabine to eribulin (0.4%) was limited by eribulin only being approved toward the end of the study. The OS data in patients with HER2-negative disease were similar to those reported in EMBRACE.
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer	NEJM	2019		1/2	metastatic BC	triple negative	patients had received at least two lines of previous therapy, including previous taxane therapy.	antibody drug conjugate	sacituzumab govitecan	metastatic				5.5m				13m				80		Sacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions.		antibody–drug conjugate in which SN-38 (an active metabolite of irinotecan), a topoisomerase I inhibitor, is coupled to the humanized antitrophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody hRS7 IgG1κ through the cleavable CL2A linker. Trop-2, a transmembrane calcium signal transducer, is overexpressed in many epithelial cancers, and it stimulates cancer-cell growth. Its expression is reported in more than 85% of tumors. On binding to Trop-2, hRS7 (in free or conjugated form) is internalized and delivers SN-38 into the tumor cell.23 In addition, because of the cleavable linker, SN-38 is released in tumors both intracellularly and in the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the drug in bystander cells to which the conjugate has not bound. Sacituzumab-bound tumor cells are killed by intracellular uptake of SN-38, and adjacent tumor cells are killed by the extracellular release of SN-38. ORR 33%, CBR 45%, median DOR 7.7m. The most common adverse events were nausea, diarrhea, fatigue, neutropenia, and anemia, and the most common adverse events of grade 3 or higher (>5% incidence) included neutropenia (NF 7%), anemia, and a decreased white-cell count. Diarrhea (predominantly grade 1) was a common adverse event (in 62% of the patients overall); the incidence of CTCAE grade 2 diarrhea was 14%, and the incidence of at least grade 3 diarrhea was 8%. No peripheral neuropathy of grade 3 or higher was reported. Adverse events leading to interruption of treatment occurred in 44% of patients.
Bevacizumab Moonshots: An Important Outcome From the Latest Ovarian Cancer Mission	JCO	2019		editorial				targeted therapy	bevacizumab																	Discussion about the absence of OS benefit of bevacizumab in 9 cancer types, out of 11 deeply studied !
Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors : TAMRAD	JCO	2012		2	metastatic BC	HR pos HER2 neg	postmenopausal women, resistant to AI. Patients could have previously received any chemotherapy.	endocrine therapy + targeted therapy	tamoxifen + everolimus	metastatic	endocrine therapy	tamoxifen	metastatic	8m	4m	0.54	yes							This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.		CBR at 6m 61 vs 42% (S). RR 14 vs 13%. In an exploratory subgroup analysis, patients with secondary hormone resistance had a higher CBR with tamoxifen plus everolimus (20 of 27 patients; 74%) than tamoxifen alone (14 of 29 patients; 48%). Patients with primary hormone resistance had only a slightly higher CBR with tamoxifen plus everolimus (12 of 26 patients; 46%) than tamoxifen alone (10 of 28 patients; 36%). the most common nonhematologic AEs were fatigue (72%, tamoxifen plus everolimus v 53%, tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). Most common hematologic AEs were decreased hemoglobin (69%, tamoxifen plus everolimus v 35%, tamoxifen alone) and decreased lymphocyte (48% v 21%) and leukocyte (54% v 18%) counts.
Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy : MONARCH 2	JCO	2017		3	metastatic BC	HR pos HER2 neg	any menopausal status. Progression while receiving neoadjuvant or adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for ABC. Maximum 1 line of ET and no chemotherapy. Exclusion of visceral crisis.	endocrine therapy + targeted therapy	fulvestrant + abemaciclib	metastatic	endocrine therapy	fulvestrant	metastatic	16m	9m	0.55	yes							Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.		Pre- or perimenopausal women received a GNRH agonist. 55% had visceral disease. 25% had primary ET resistance. 9% progressed within 12 months after completing adjuvant therapy. ORR 48 vs 21%, and 3% complete response. The most frequent adverse events of any grade were diarrhea, neutropenia, nausea, fatigue, and abdominal pain. Grade 1 or 2 diarrhea occurred in 73% of abemaciclib arm, and G3 in 13%. Diarrhea events typically occurred in the first treatment cycle (median onset of diarrhea was 6 days). 14.5% of patients who experienced an initial grade 2 diarrhea event and 1.1% of patients who experienced an initial grade 3 diarrhea event also experienced a recurrence at the same or higher grade. 70% of patients in the abemaciclib arm with an AE of diarrhea did not require treatment modification (ie, dose interruption, reduction, or discontinuation); however, 2.9% of patients discontinued study drug because of diarrhea. 25% G3-4 neutropenia and 1% febrile neutropenia : greater relative potency of abemaciclib for cyclin D1/CDK4 compared with cyclin D3/CDK6. This PFS is the longest reported in a population with ABC whose disease had progressed while they were receiving prior ET.
Abemaciclib As Initial Therapy for Advanced Breast Cancer : MONARCH 3	JCO	2017		3	metastatic BC	HR pos HER2 neg	postmenopausal women who had not received previous systemic therapy for advanced disease. Endocrine therapy in the neoadjuvant or adjuvant setting was permitted if the patient had a disease-free interval > 12 months from the completion of endocrine therapy. Exclusion of visceral crisis.	endocrine therapy + targeted therapy	anastrozole or letrozole + abemaciclib	metastatic	endocrine therapy	anastrozole or letrozole	metastatic	NR	14m	0.54	yes							Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.		53% visceral disease. 40% de novo MBC. 47% had previously received neoadjuvant or adjuvant endocrine therapy. 27% had received prior AI therapy. ORR 48 vs 34%, CBR 78 vs 71%. 70% of G1-2 diarrhea, with a median offset of 8 days and duration of 10 days. 76% who experienced diarrhea did not undergo any treatment modifications. Discontinuation of study drug as the result of diarrhea was 2.3%. 41% of patients in the abemaciclib arm experienced neutropenia (21% G3-4), generally observed by cycle two, and grade 3 and 4 neutropenia was uncommonly observed during later cycles. G3-4 increases of hepatic enzymes in 10% of patients. The MONARCH 3 antidiarrheal management plan recommended suspension of abemaciclib until diarrhea resolved to at least grade 1. Antidiarrheal medication (eg, loperamide) was advised at the first onset of diarrhea. Recurrent or high-grade diarrhea required dose reductions. This management seemed to be effective, with the majority (83.8%) of patients with initial grade 2 or 3 diarrhea not experiencing a subsequent event of the same or greater severity.
Pertuzumab Plus Trastuzumab in Combination With Standard Neoadjuvant Anthracycline-Containing and Anthracycline-Free Chemotherapy Regimens in Patients With HER2-positive Early Breast Cancer: A Randomized Phase II Cardiac Safety Study : TRYPHAENA	Ann Oncol	2013		2	early BC	HER2 pos	operable (T2-3, N0-1, M0), locally advanced (T2-3, N2 or N3, M0; T4a-c, any N, M0), or inflammatory (T4d, any N, M0) breast cancer and a primary tumor size >2 cm.	chemotherapy + dual targeted therapy	3 FEC - 3 docetaxel-trastuzumab-pertuzumab (further randomized in trastu-pertu during FEC (arm A) or not (arm B))	neoadjuvant	chemotherapy + dual targeted therapy	6 docetaxel-trastuzumab-pertuzumab (arm C)	neoadjuvant	61% pCR arm A, 57% pCR arm B	66% pCR arm C									The combination of P with H and standard chemotherapy resulted in low rates of symptomatic left ventricular systolic dysfunction.		LVEF decline ≥10% points from baseline to <50% : During NACT : 5.6% arm A, 5.3% arm B, 3.9% arm C. During adjuvant period : 5.9% arm A, 12.3% arm B, 3.9% arm C. All improved at data cutoff. pertuzumab does not increase the rate of cardiac dysfunction observed in combinations of trastuzumab plus standard chemotherapy. These observations are supported by a meta-analysis of patients treated with pertuzumab or trastuzumab. The combination of trastuzumab and pertuzumab was generally well tolerated regardless of whether it was given sequentially or concomitantly with anthracycline-based, or combined with carboplatin-based, chemotherapy. The study was not intended to evaluate superiority of any arm, and all three arms were experimental. Therefore, comparison of toxic effect and response rates with a control arm is not possible which limits the interpretation of the study. Nevertheless, the response rates achieved with each regimen are encouraging, with pCR rates of 57%–66%.
Efﬁcacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine	JCO	2007		2	metastatic BC		resistant to anthracycline, taxane, and capecitabine.	chemotherapy	ixabepilone	metastatic				3m				8m						Ixabepilone demonstrated clear activity and a manageable safety proﬁle in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.		Semisynthetic epothilone analog designed to optimize the pharmacologic proﬁle of the natural epothilone B compound : class of antineoplastic agent, derived from the myxobacterium Sorangium cellulosum. These compounds have some similarities to taxanes in targeting and stabilizing microtubules, but also have important differences; the class is structurally unrelated to taxanes. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia(13%),myalgia(8%),andstomatitis/ mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks. ORR 18%, SD 50%, median DOR 5m.
Safety and Efﬁcacy of Two Different Doses of Capecitabine in the Treatment of Advanced Breast Cancer in Older Women	JCO	2005		2	metastatic BC		65 years or older	chemotherapy	capecitabine 1,250mg/m2 twice daily on days 1 to 14 every 21 days	metastatic	chemotherapy	capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 21 days	metastatic	4m	4m			10m	16m					Older patients may frequently exhibit diminished capacity to eliminate drugs, resulting in unusual sensitivity to standard dosing regimens. In light of this, the overall results of the study suggest that although the dose groups are small and nonrandomized, the capecitabine dose of 1,000 mg/m2 twice daily merits consideration as “standard” for women aged 70 years and older who are candidates to cytotoxic therapy for metastatic breast cancer and do not have severely impaired renal function.		first report specifically dealing with the use of capecitabine in a elderly population with breast cancer (75% > 70 years). When we started the study, available clinical data indicated a capecitabine dose of 2,500 mg/m2/d, as appropriate. Due to the occurrence of lethal toxicities, a lower starting dose (2,000 mg/m2/d) was considered more appropriate for older women included in the study. Dose reductions due to toxicities were required in 30% of patients in the standard-dose group but only 5% in the reduced-dose group. The most common adverse events included diarrhea, PPE, fatigue, nausea, and vomiting that were generally mild to moderate. Overall, the tolerability profile seemed more satisfactory in the low-dose group, for which a higher dose intensity could be delivered.
Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor–Positive, HER2-Negative Advanced Breast Cancer : BOLERO-6	JAMA oncol	2018		2	metastatic BC	HR pos HER2 neg	postmenopausal women that had progressed during treatment with letrozole or anastrozole, and maximum 1 prior line of chemotherapy for advanced breast cancer	endocrine therapy + targeted therapy	exemestane + everolimus	metastatic	targeted therapy or chemotherapy	everolimus or capecitabine	metastatic	8m	6m for everolimus, 9m for capecitabine		yes / no							These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring. Everolimus plus exemestane combination therapy offers an efficacy benefit vs everolimus alone, but the efficacy difference between combination therapy and capecitabine alone is still uncertain.		PFS of the combination was consistent with BOLERO-2, but capecitabine outcome was inconsistent with previous capecitabine studies (PFS range, 4.1-7.9 months), but the median OS with capecitabine in the present study was consistent with previous capecitabine studies (18.6-29.4 months). Stomatitis and the related AE of mouth ulceration were more common with everolimus plus exemestane and everolimus alone than with capecitabine (but study initiated before SWISH). The most common grade 3 to 4 AEs were anemia with everolimus plus exemestane (13%), elevated γ-glutamyl transferase with everolimus alone (12%), and PPE syndrome with capecitabine (27%). Pneumonia occurred in 8% in the combination arm and 4% in everolimus alone.
pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer : PELICAN	BCRT	2017		3	metastatic BC		no prior chemotherapy for metastatic disease, not eligible anymore for endocrine therapy or trastuzumab, and no anthracycline-resistant disease (relapse in < 12 months)	chemotherapy	pegylated liposomal doxorubicin	metastatic	chemotherapy	capecitabine	metastatic	6m	6m	1.2	no	23m	26m	1.2	no			Both PLD and capecitabine are effective first-line agents for MBC.		The benefit from PLD was present regardless of prior anthracycline use (median TTP 7.1 months with prior exposure versus 5.8 months without; P = 0.64). Surprisingly, prior anthracycline use affected the efficacy of capecitabine; those without prior anthracycline exposure had a statistically significantly higher TTP than those with previous exposure (P = 0.04; median 8.3 vs. 4.8 months). The difference between groups is driven by an unexpectedly long TTP in unexposed patients. The most common adverse events of any grade included PPE, stomatitis, and fatigue in the PLD arm and PPE, fatigue, and diarrhea in the capecitabine arm. The incidence of cardiac events was not statistically significantly different between arms, irrespective of prior anthracycline exposure. However, among patients with prior anthracycline exposure, the proportion of cardiac events was somewhat elevated in the capecitabine arm (18 vs. 8 %; P = 0.31). Alopecia was absent in a majority of patients in both arms (28 vs 10%). And similar QoL between both arms.
Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor–Positive Metastatic Breast Cancer : MANTA	JAMA oncol	2019		2	metastatic BC	HR pos	Progression after prior aromatase inhibitor treatment (metastatic or < 12m after adjuvant). 1 line of prior chemotherapy for metastatic disease was allowed.	endocrine therapy + targeted therapy	fulvestrant + vistusertib	metastatic	endocrine therapy +- targeted therapy	fulvestrant +- everolimus	metastatic	8m	12m with everolimus, 5m without		yes vs everolimus, no vs fulvestrant alone							he combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant. The trial did not meet its primary end point and failed to demonstrate a benefit of vistusertib plus fulvestrant compared with fulvestrant alone. These clinical results are in contrast with the evidence from in vitro and in vivo preclinical models, showing substantial synergistic activity between fulvestrant and vistusertib and also superior activity of vistusertib compared with everolimus in endocrine-sensitive and -resistant breast cancer models.		Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus. ORR 41% for everolimus, 30% for vistusertib and 25% for fulvestrant alone. The most common grade 3 or 4 AEs in the combination groups were stomatitis (11% in everolimus), rash (5% in everolimus), asthenia (3%), diarrhea (2%), hyperglycemia (3%), infection (7%) and dyspnea (1%).
Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash : SWISH	Lancet Oncol	2017		2	metastatic BC	HR pos HER2 neg	postmenopausal women	mouthwash	alcohol-free dexamethasone 0·5 mg per 5 mL oral solution : 10 ml swish for 2 min and spit, four times daily.	metastatic														Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy. It reduced the proportion of all-grade stomatitis by 65% and grade 2 or worse stomatitis by 91% compared with BOLERO-2 by 8 weeks. Steroid prophylaxis should be considered a new standard of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer, especially in the first 8 weeks of treatment and as needed thereafter.		y 8 weeks, the incidence of grade 2 or worse stomatitis was 2%, vs 33% in BOLERO-2. Patient-reported outcomes (ability to maintain a normal diet and oral pain scores) further substantiated the efficacy of dexamethasone mouthwash. Reduction of stomatitis and tolerability of the dexamethasone mouthwash might have contributed to the favourable dose intensities for everolimus recorded in this trial; everolimus dose intensity was slightly higher than in BOLERO-2. Good oral hygiene, compliance with administration of mouthwash, and patient education about early onset and management of stomatitis might have further improved tolerability and adherence. In a meta-analysis of phase 3 trials across indications, 89% of first episodes of stomatitis occurred by 8 weeks.
Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer : BOLERO-4	JAMA oncol	2018		2	metastatic BC	HR pos HER2 neg	first-line treatment, in postmenopausal women. Prior neoadjuvant endocrine therapy was permitted, but therapy with nonsteroidal aromatase inhibitors must have been completed 1 or more years before enrollment.	endocrine therapy + targeted therapy	letrozole + everolimus	metastatic				22m in first line				79% at 24m (median NR)						The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer.		In an exploratory analysis of BOLERO-2, median PFS was also improved in patients receiving first-line treatment with everolimus plus exemestane following recurrence after adjuvant therapy (HR, 0.39). Here, 68% had 3 or more metastatic sites, 60% had visceral disease. ORR 45%, CBR 75%
Incidence of Late Relapses in Patients With HER2-Positive Breast Cancer Receiving Adjuvant Trastuzumab: Combined Analysis of NCCTG N9831 and NSABP B-31	JCO	2019		3	early BC	HER2 pos	operable node-positive (both studies) or high-risk node-negative (N9831)	chemotherapy + targeted therapy	AC-TH followed by H for 1 year	adjuvant	chemotherapy	AC-T	adjuvant											This analysis demonstrated persistent benefit of adjuvant trastuzumab in the long term. Furthermore, similar degree of benefit from adjuvant trastuzumab was observed among patients with HR+ and HR− HER2+ breast cancer. Patients with HR− HER2+ breast cancer had a significantly higher annualized hazard rate of relapse in the first 5 years compared with patients with HR+ HER2+ disease. However, after 5 years, patients with HR+ HER2+ breast cancer who received adjuvant trastuzumab-based chemotherapy had no significant difference in the annualized hazard rate of relapse compared with patients with HR− HER+ breast cancer. There was a higher RoR between years 5 to 10 in patients with HR+ HER2+ breast cancer with more lymph node involvement. Currently, there is no prospective, randomized, controlled clinical trial specifically addressing the benefit of extended adjuvant endocrine therapy in HER2+ patients. Nevertheless, because patients who were treated with adjuvant trastuzumab and completed 5 years of adjuvant endocrine therapy without recurrence had low RoR, particularly patients with N0 and N1 disease, it is unclear whether the benefit of extended adjuvant endocrine therapy will outweigh the risks and adverse effects associated with these extended therapies. This highlight the need to develop better risk-prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer.		For HR+ HER2+ breast cancer, 10-year RFS was 81%, in patients who were treated with adjuvant trastuzumab-based chemotherapy, compared with 65% in patients who received chemotherapy alone (HR 0.46). Comparable benefit was observed in HR− HER2+ breast cancer, with 10-year RFS of 77% in patients who received adjuvant trastuzumab-based chemotherapy, compared with 59% in patients who received chemotherapy alone (HR 0.47). benefit of adjuvant trastuzumab-based chemotherapy was seen in both trials in years 0 to 5 (HR 0.42) and years 5 to 10 (HR 0.69). In the multivariable analysis of both treatment groups, HR+ was significantly associated with improved RFS during the first 5 years (HR 0.65). However, there was no significant difference during years 5 to 10 (HR 1.32).
The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor–Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy : MONARCH 2	JAMA oncol	2019		3	metastatic BC	HR pos HER2 neg	any menopausal status. Progression while receiving neoadjuvant or adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for ABC. Maximum 1 line of ET and no chemotherapy. Exclusion of visceral crisis.	endocrine therapy + targeted therapy	fulvestrant + abemaciclib	metastatic	endocrine therapy	fulvestrant	metastatic					46m	37m	0.75	yes			Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.		Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR 0.68) and primary resistance to prior ET (HR 0.68 : this contrasts with PALOMA 3 results : numerical better OS for ET-sensitive disease only (disease control for 24 weeks or more of prior ET for ABC or 24 months or more of adjuvant ET before recurrence)). Same results in pre/perimenopausal (17% of pts) and postmenopausal patients. Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. Postdiscontinuation therapy was well balanced. Median duration of single-agent ET was 5.3 months in the abemaciclib arm and 4.8 months in the placebo arm, and median duration of everolimus-based therapy was 4.5 months and 8.8 months in the abemaciclib arm and placebo arm, respectively. 17% of pts in the placebo arm received a CDK4 and CDK6 inhibitor as postdiscontinuation therapy.
Prognostic impact of metastatic pattern in stage IV breast cancer at initial diagnosis	BCRT	2017		retrospective	metastatic BC																			There were substantial differences in OS according to metastatic pattern. Tumor subtypes have a clear influence among other factors on specific sites of metastasis. We identified several prognostic factors that could guide therapy selection in treatment naïve patients.		9143 patients. Bone represented 37.5% of patients, visceral 21.9%, BV 28.8%, and other 11.9%. Median OS by metastatic pattern was as follows : bone 38 months, visceral 21 months, BV 19 months, and other 33 months (P < 0.0001). Univariate analysis showed that higher number of metastatic sites had worse prognosis. In multivariate analysis, older age (hazard ratio 1.9), black race (hazard ratio 1.17), grade 3/4 tumors (hazard ratio 1.6), triple-negative (hazard ratio 2.24), bone and visceral metastatic pattern (hazard ratio 2.07), and unmarried patients (hazard ratio 1.25) had significantly shorter OS. As compared with HR+/HER2- tumors, triple-negative and HR-/HER2+ had higher odds of brain, liver, lung, and other metastases. HR+/HER2+ had higher odds of liver metastases. All three subtypes had lower odds of bone metastases.
Prognostic factors in 1,038 women with metastatic breast cancer	Ann Oncol	2008		retrospective	metastatic BC																			These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.		hormonal status receptor, site of metastasis, adjuvant chemotherapy, patient age, size of primary tumor and SBR grade constituted independent prognostic factors which were significant in multivariate analysis, while metastatic diagnosis period and metastasis-free interval were significant only in the univariate analysis. Among these factors, the site of metastasis seems to be the most significant independent prognostic factor. Positive HRs were more likely to recur in bone while negative receptor status occurred more often in brain and multiple sites. Adjuvant chemotherapy appears to be an unfavorable independent prognostic factor for survival (but could be confounded by N+ status). Metastasis-free interval may be considered an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease.
Use of anastrozole for breast cancer prevention : long-term results of a randomised controlled trial : IBIS-II	Lancet	2019		3	prevention		Postmenopausal women at increased risk of developing breast cancer (RR depending on age)	endocrine therapy	anastrozole daily for 5 years	prevention	placebo	placebo	prevention	4.4% incidence at 131m median FU	8.5% incidence at 131m median FU	0.51	yes							This analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.		The reduction in incidence in the first 5 years of follow-up was 61%, and a smaller but still significant 37% reduction was seen in subsequent years, which was still larger than that seen for tamoxifen in previous trials. After 12 years of follow-up, the number needed to treat for 5 years to prevent one breast cancer was 29. 81% of the breast cancers were invasive, and of these were reported as oestrogen receptor-positive. No effect was seen on any other major adverse event. In particular, there was no excess of fractures overall. All women have completed the active follow-up period of the trial and now are followed for long-term outcomes by various methods.
Exemestane for Breast-Cancer Prevention in Postmenopausal Women : NCIC CTG MAP.3	NEJM	2011		3	prevention		postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% ; prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy.	endocrine therapy	exemestane	prevention	placebo	placebo		0.35% annual incidence of invasive and in situ breast cancer	0.77% annual incidence of invasive and in situ breast cancer									Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life.		Median age was 62.5 years and median Gail risk score was 2.3%. No significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed.
Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial	Lancet Oncol	2015		3	prevention		premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer	endocrine therapy	tamoxifen daily for 5 years	prevention	placebo	placebo		7% BC incidence after median FU of 16 years	9.8% BC incidence after median FU of 16 years	0.71	yes							Tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention.		The risk of developing breast cancer was similar between years 0–10 and after 10 years. The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer and ductal carcinoma in situ, but no effect was noted for invasive oestrogen receptor-negative breast cancer.
Neoadjuvant Endocrine Therapy for Estrogen Receptor–Positive Breast Cancer	JAMA oncol	2016		MA	early BC	HR pos		endocrine therapy		neoadjuvant														Neoadjuvant endocrine therapy, even as monotherapy, is associated with similar response rates as neoadjuvant combination chemotherapy but with significantly lower toxicity, suggesting that NET needs to be reconsidered as a potential option in the appropriate setting. Additional research is needed to develop rational NET combinations and predictive biomarkers to personalize the optimal neoadjuvant strategy for ER+ breast cancer.		The analysis included 20 studies with 3490 unique patients. Compared with combination chemotherapy, NET as monotherapy with aromatase inhibitors had a similar clinical response rate, radiological response rate and BCS rate but with lower toxicity. Aromatase inhibitors were associated with a significantly higher clinical response rate, radiological response rate and BCS rate compared with tamoxifen. The incidence of pathologic complete response was low (<10%). Dual combination therapy with growth factor pathway inhibitors was associated with a higher radiological response rate but not clinical response rate than endocrine monotherapy. A traditional treatment paradigm that might warrant reconsideration is the general recommendation that NET should not be offered to premenopausal women and that NACT should be preferred. This area is understudied. Most of the randomized trials reviewed in this analysis focused on postmenopausal women. A potential concern is the time (approximately 4 weeks) needed for the combination of AI and luteinizing hormone-releasing hormone agonists to induce estradiol suppression. Determination of the correct patient population for NET remains in question. Tools such as Oncotype Dx Breast Recurrence Score and the Breast Cancer Index have been validated in the adjuvant setting and could be explored in the neoadjuvant setting as a potential mechanism to predict response to endocrine therapy.
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer : DESTINY-Breast01	NEJM	2019		2	metastatic BC	HER2 pos	after previous treatment with trastuzumab emtansine	antibody drug conjugate	trastuzumab deruxtecan (DS-8201) : 5.4 mg/kg	metastatic				16m										Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring.		Composed of a humanized monoclonal antibody specifically targeting HER2, with the same amino acid sequence as trastuzumab, a cleavable tetrapeptide-based linker, and a potent topoisomerase I inhibitor as the cytotoxic drug (payload). Unlike trastuzumab emtansine, trastuzumab deruxtecan has a released payload that easily crosses the cell membrane, which potentially allows for a potent cytotoxic effect on neighboring tumor cells regardless of target expression. Patients had undergone a median of six previous treatments (65% had received pertuzumab). 52% were HR+. 36% had not responded to TDM1. ORR 61%. Efficacy results were consistent across key subgroups, including patients who had received previous pertuzumab therapy. The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). Interstitial lung disease happened in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). median time until the onset of lung disease was 193 days (range, 42 to 535). A decrease in the left ventricular ejection fraction occurred in 3 patients (2 with grade 2 and 1 with grade 3); all the patients were asymptomatic and had recovered or were recovering after an interruption in the study treatment. 48% alopecia. All-grade, 30% anemia, 35% neutropenia (20% G3-4), 20% thrombopenia.
Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer : TH3RESA	Lancet Oncol	2014		3	metastatic BC	HER2 pos	had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting	antibody drug conjugate	trastuzumab emtansine	metastatic	chemotherapy + targeted therapy	treatment of physician's choice	metastatic	6m	3m	0.53	yes							Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib.		Although all patients in EMILIA had previously received trastuzumab, previous lapatinib was an exclusion criterion. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice. Thrombocytopenia (5% vs 2%) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. Although rare, the reporting of a grade 5 haemorrhage event in TH3RESA suggests that trastuzumab emtansine has the potential to lead to severe haemorrhage with fatal outcome, including CNS bleeding. ORR 31 vs 9%.
Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results	Lancet Oncol	2017		3	metastatic BC	HER2 pos	had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting	antibody drug conjugate	trastuzumab emtansine	metastatic	chemotherapy + targeted therapy	treatment of physician's choice	metastatic					23m	16m	0.68	yes			In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.		Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (1 vs 4%), neutropenia (3 vs 16%), febrile neutropenia (<1 vs 4%), whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (6 vs 3%) and haemorrhage of any type (4 vs <1%). The 31 patients in the treatment of physician's choice group who received single-agent chemotherapy had shorter overall survival.
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer : HER2CLIMB	NEJM	2019		3	metastatic BC	HER2 pos	Previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. patients who had received lapatinib more than 12 months before initiating a trial regimen were eligible.	chemotherapy + dual targeted therapy	capecitabine 1000 mg/m² + trastuzumab + tucatinib (300 mg po 2x/d continuously)	metastatic	chemotherapy + targeted therapy	capecitabine 1000 mg/m² + trastuzumab	metastatic	7.8m	5.6m	0.54	yes	22m	17m	0.66	yes			In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. In combination with capecitabine, simultaneous targeting of the internal domain of HER2, as well as the external domain with trastuzumab, led to substantially better survival outcomes than did targeting the external domain alone.		oral tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of epidermal growth factor receptor, which may alter the toxicity profile. In a phase 1b doseescalation trial, tucatinib in combination with trastuzumab and capecitabine showed encouraging antitumor activity in patients with HER2- positive metastatic breast cancer, including those with brain metastases. Patients with brain metastases were included unless they were in need of immediate local intervention, in which case they could receive local therapy and be enrolled subsequently. Patients with leptomeningeal disease were excluded. 48% of patients had brain metastases at baseline. The most common adverse events observed among the patients in the tucatinib-combination group were diarrhea (68 vs 44% G1-2), palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. The most common adverse events of grade 3 or higher observed among the patients in the tucatinib- combination group were palmar–plantar erythrodysesthesia syndrome, diarrhea (13 vs 8%), elevations in alanine aminotransferase (ALT, 6 vs 0.5%)) and aspartate aminotransferase (AST, 5 vs 0.5%)) levels, and fatigue. Tucatinib has been shown to inhibit the multidrug and toxin extrusion protein 1 and 2-K (MATE1 and MATE2-K) transporters, which increases the serum creatinine level without affecting glomerular function. Increases in the serum creatinine level occurred early, remained clinically nonsignificant during the treatment period with no intervention to lower the level, were reversible, and were not the cause of discontinuation of therapy in any patient. The survival benefit with tucatinib was observed in the total HER2CLIMB trial population and across all subgroups tested. Survival outcomes in the placebo-combination group were similar to those in other contemporary trials of HER2-targeted therapy
Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer : CEREBEL (EGF111438)	JCO	2015		3	metastatic BC	HER2 pos	Patients were required to have received prior anthracycline and/or taxanes for (neo)adjuvant or metastatic disease. Prior trastuzumab was allowed but not required. No history of CNS metastases or presence of CNS metastases at baseline was permitted;	chemotherapy + targeted therapy	capecitabine 1250 mg/m² 2x/d + trastuzumab	metastatic	chemotherapy + targeted therapy	capecitabine 1000 mg/m² 2x/d + lapatinib 1250 mg 1x/d	metastatic	8m	6.6m		yes	27m	22m		no			CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.		40% of the population was trastuzumab-naïve. 45% of the patients had not received prior treatment for MBC. Incidence of CNS metastases as first site of relapse was 3% for lapatinib-capecitabine and 5% for trastuzumab-capecitabine. ORR 30% in both arms. The most common adverse events (AEs) were consistent between treatment arms with the exception of diarrhea, nausea, rash, and hyperbilirubinemia, which had a higher incidence with lapatinib-capecitabine than with trastuzumab-capecitabine. The 3% and 5% rates of CNS as first site of relapse with lapatinib-capecitabine and trastuzumab-capecitabine, respectively, were far lower than the expected rates of 12% and 20%, respectively. The study was underpowered for its primary end point as a result of an overestimation of the incidence of CNS recurrence, likely because of exclusion of patients with asymptomatic CNS metastases (20% of screening failures) detected by brain MRI review at study entry. An additional influencing factor might be related to the proportion of patients treated in the first-line setting in CEREBEL. Routine screening for asymptomatic CNS lesions (performed here) is controversial without knowledge of the proportion of patients who would eventually develop symptoms or would derive benefit from early intervention. Trends favoring trastuzumab-capecitabine were observed in the overall population, in the trastuzumab-naive subgroup, and in the subgroup receiving first-line treatment. Similar results between the two arms were observed in the subgroup of patients who experienced progression after trastuzumab therapy.
Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer : MONALEESA-3	NEJM	2019		3	metastatic BC	HR pos HER2 neg	postmenopausal women, treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting.	endocrine therapy + targeted therapy	ribociclib + fulvestrant	metastatic	endocrine therapy	fulvestrant	metastatic	33m	19m	0.55	yes	median NR (58% at 42m)	median 40m (46% at 42m)	0.72	yes			Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor–positive, HER2-negative advanced breast cancer.		The overall survival benefit was generally consistent across patient subgroups, including those who received first-line treatment and those who received second- line treatment or who had early relapse after adjuvant or neoadjuvant endocrine therapy. Most patients received a subsequent therapy after discontinuation of trial treatment, a finding consistent with those of other trials investigating a CDK4/6 inhibitor. Both time to subsequent chemotherapy and progression-free survival 2 were longer in the ribociclib group than in the placebo group, despite the percentage of patients with subsequent CDK4/6 inhibitor use being higher in the placebo group (25.4%) than in the ribociclib group (11.0%).
De-escalation strategies in HER2-positive early breast cancer : final analysis of the WSG-ADAPT HER2+/HR− phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel	Ann Oncol	2017		2	early BC	HR neg HER2 pos	any stage, but participation was strongly recommended in patients with cT2+ (or cT1 with cN+)	dual targeted therapy	trastuzumab + pertuzumab	neoadjuvant	chemotherapy + dual targeted therapy	paclitaxel (80 mg/m² weekly) + trastuzumab + pertuzumab	neoadjuvant	pCR 34%	pCR 90%									Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR− EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.		early-response criterion after one therapy cycle : relative Ki-67 decrease ≥30% versus baseline (‘proliferation response’) or <500 invasive tumor cells in the 3-week biopsy (“cellularity response”). After surgery, treatment according to national standards was recommended: 4× epirubicin/cyclophophamide (→12xPac weekly in the T + P-arm), 40 weeks trastuzumab and radiotherapy. Regarding early response and pCR: In the T + P arm, 26% were classified as non-responders, leading to 8.3% pCR. Early response occurred in 41%, and these had 44% pCR. In the T + P+pac arm, neither of the two non-responders achieved ‘total’ pCR, though one achieved ypT0/is, ypN0. The pCR rate of 34.4% in the chemotherapy-free arm is consistent with other trials: 27% after 12 weeks of T + P, 43% after 18 weeks of T + L. However, 90.5% pCR in the chemotherapy-containing arm was considerably higher than anticipated. These results suggest that Ki-67 drop has good negative predictive value for pCR in HR−/HER2-positive EBC: i.e. non-response is a clearly identifiable signal, and there is little doubt that early non-response to neoadjuvant dual blockade is a strong predictor of poor pCR. Given our substantial pCR rate after only 12 weeks of T + P+pac, the optimal chemotherapy backbone for the dual HER2 blockade with T + P needs to be defined.
Management of toxicity of PIK3CA inhibitors	Ann Oncol	2019		review				targeted therapy	PIK3CA inhibitors / PI3K inhibitors															Alterations in the phosphoinositide 3-kinase (PI3K)/AKT pathway are frequently found in cancer and are especially common in breast cancer, where it is estimated that 70% of tumors have some type of genetic alteration that could lead to pathway hyperactivation. A variety of PI3K pathway inhibitors have been developed in an attempt to target this pathway and improve cancer control. One of the challenges in treating patients with PI3K/AKT pathway inhibitors is the associated toxicity from on-target and off-target effects. Such side-effects are common, but reversible, and include hyperglycemia, rash, stomatitis, diarrhea, nausea, and fatigue. As a result, dose reductions, treatment delays, and treatment discontinuation are frequently reported. This impairs not only patients’ quality of life but also treatment efficacy. Most side-effects are reversible with drug interruption, since these drugs typically have a short half-life and are manageable with early intervention. An interdisciplinary approach with proactive management of patients receiving PI3K pathway inhibitors should include comprehensive education of patients about the range of toxicities, frequent monitoring, early toxicity recognition, active intervention, as well as prophylactic strategies.
Dose intensification of chemotherapy for early breast cancer in the age of de-escalation	Lancet	2019		editorial	early BC			chemotherapy dose-dense		adjuvant	chemotherapy standard-interval		adjuvant													discussion about the EBCTCG meta-analysis on dose dense chemotherapy : reduction in breast cancer recurrences and breast cancer mortality with dose intensification versus with standard-schedule chemotherapy
Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials : EBCTCG	Lancet	2019		MA	early BC		patients treated with adjuvant chemotherapy	chemotherapy dose-dense		adjuvant	chemotherapy standard-interval		adjuvant	28% recurrence at 10 years	31% recurrence at 10 years	0.86	yes	19% BC mortality at 10 years	21% BC mortality at 10 years	0.87	yes			Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.		Previous meta-analyses from the EBCTCG have shown that anthracycline and taxane-based combination chemotherapy reduces the risk of breast cancer mortality by about a third compared with no chemotherapy. Cell biology suggests that increasing the dose intensity of chemotherapy—for example, by shortening the interval between treatment cycles or by giving higher doses of drugs individually rather than lower doses concurrently—might improve outcomes. These results suggest that these strategies reduce the 10-year risk of recurrence and of death from breast cancer by about 10–15%. This reduction is only moderate but since the standard chemotherapy comparator is already known to reduce the risk of breast cancer death by about a third, preventing a further 10–15% of deaths would imply that, compared to no chemotherapy, dose-intense adjuvant chemotherapy schedules with anthracycline and taxane could prevent about 40% of deaths from breast cancer during the first decade. The largest proportional reduction in breast cancer mortality was seen in the group of trials that used both 2-weekly and sequential scheduling, which also achieved the highest dose-intensity ratios. There are no trials assessing dose-intensification of taxane regimens without anthracycline, such as the now widely used docetaxel-cyclophosphamide combination. The proportional reductions in recurrence were similar in ER-positive and ER-negative disease. The proportional recurrence reductions were also similar for N1–3 and N4+ disease and appeared to be similar in node-negative disease, although comparatively few women with node-negative disease were enrolled in these trials. Too few patients aged older than 70 years, or with low-grade disease, were entered in these trials to directly assess the benefits of dose-intensification in these subgroups. HER2 positive cases cannot be assessed as testing was not standard for a large part of the trials, and adjuvant trastuzumab was not yet available. There was no indication of any increase in death without recurrence with dose intensification, overall or during the period when chemotherapy was administered. No increase in cardiovascular mortality or deaths from haematological malignancies was apparent in patients who received dose-intense treatment, although information on cause of death was incomplete.
Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?	Ann Oncol	2019		review	early BC	HR pos HER2 neg																		Traditional clinicopathological factors such as tumor size, nodal stage, age and ER status are NOT PREDICTIVE for benefit from adjuvant chemotherapy. Even within the ER-positive subgroup, the relative effect is the same regardless of age and tumor grade. Although CLEARLY PROGNOSTIC, these routine factors alone may be inadequate to identify patients with sufficiently low absolute risk for recurrence so as the use of adjuvant chemotherapy is not justified, especially if the patients have node-positive disease. Gene expression profiling provide additional PROGNOSTIC information when added to clinical factors, supporting their role in THERAPY SELECTION at least for node-negative disease. But the estimation of a 1% risk of chemotherapy-related severe morbidity/death might be exagerated, and thus the treshold for clinical meaningfulness might be lower. However, advances in adjuvant endocrine therapy improve the efficacy of chemotherapy free strategies and may increase the number of potential candidates without excess risk.		discussion about the prognostic and predictive information given by gene expression profiling in early breast cancer. Further emphasis on the lack of data for node-positive patients
Anthracycline and taxane-based chemotherapy versus docetaxel and cyclophosphamide in the adjuvant treatment of HER2-negative breast cancer patients: a systematic review and meta-analysis of randomized controlled trials	BCRT	2019		MA	early BC	HER2 neg		chemotherapy	6x docetaxel + cyclophosphamide	adjuvant	chemotherapy	anthracycline-cyclophosphamide + docetaxel	adjuvant			1.08	no			1.05	no			As adjuvant treatment of HER2-negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher-risk patients (e.g., those with hormone receptor-negative disease or N2 status) may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients.		Pooling of the results from 7 RCTs including a total of 12,741 patients. A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93–1.34) and N2 patients (HR 1.25; 95% CI 0.82–1.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T. Although there was no significant difference between TC and A+T, we observed a trend favoring TC in the premenopausal subgroup. Notably, the RCTs included in this analysis used 6 cycles of cyclophosphamide (a highly gonadotoxic agent) for TC as compared with 3 to 4 for A+T : In patients with hormone receptor-positive disease, the hormonal deprivation induced by chemotherapy can contribute to its anti-tumoral effects. Therefore, although this information was not available in the RCTs, it can be speculated that the higher cumulative dose of cyclophosphamide with TC may have resulted in higher incidence of chemotherapy-induced amenorrhea and subsequent ovarian suppression in premenopausal patients, which may justify the observed trend favoring TC in this subgroup. After excluding the DBCG 07-READ (the only RCT with mandatory prophylactic G-CSF in the TC arm), TC was associated with higher rates of febrile neutropenia than A+T. These results further reinforce the current recommendations to use prophylactic G-CSF when the TC regimen is used.
Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials	Lancet	2015		MA	early BC			bisphosphonates	iv zoledronic acid, po clodronate	adjuvant	placebo						yes			0.91	yes (borderline)			Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.		Taking all women together, regardless of menopausal status, this collaborative meta-analysis of individual patient data from 18 766 women randomised in trials of adjuvant bisphosphonates found a highly significant reduction only in bone recurrence, and not in other breast cancer outcomes. Subgroup analyses suggested benefit just in postmenopausal women, among whom there were highly significant reductions not only in bone recurrence but also in any distant recurrence (bone or other), breast cancer mortality, and overall mortality. Neither in the overall results nor in the results just among postmenopausal women, however, was there any significant effect on distant recurrence at extra-osseous sites, on locoregional recurrence, or on the incidence of contralateral breast cancer. The effects on bone recurrence emphasise the potential importance of host microenvironment factors to metastasis. Further studies are needed to clarify why menopausal status should importantly affect the response to bisphosphonates. The complex interactions between reproductive hormones, tumour biology, bone cell function, and bone marrow stem cells could well change as patients progress from the premenopausal setting, where oestradiol and inhibin are of major importance in bones, to the postmenopausal setting, where activin and other members of the TGF-β superfamily become the main regulators of bone cell metabolism. The proportional reductions in bone recurrence and breast cancer mortality with treatment did not depend significantly on other patient or clinicopathological primary tumour characteristics, including ER status, axillary lymph node involvement, and tumour grade. Similar reductions were seen in the presence and absence of chemotherapy, suggesting that the benefits of bisphosphonates are approximately additive to those of chemotherapy. Both for all women and for postmenopausal women, subgroup analyses of bone recurrence suggested similar effects of oral clodronate and of the aggregate of all aminobisphosphonate regimens (mainly intravenous zoledronic acid). Likewise, they suggested no significant heterogeneity in efficacy between the different aminobisphosphonates, though no benefit was seen with oral pamidronate (which could be real, as oral pamidronate is poorly absorbed, has little effect on bone resorption biomarkers or the underlying metastatic bone disease, and failed to show efficacy in myeloma). The use of adjuvant bisphosphonates was associated with a small reduction in fracture incidence. We were unable to assess the incidence of osteonecrosis of the jaw, but previous reports suggest it ranges from under 1% with clodronate, ibandronate, or 6-monthly zoledronic acid to about 2% with more intensive zoledronic acid schedules.
Overall Mortality After Diagnosis of Breast Cancer in Men vs Women	JAMA Oncol	2019		cohort study			comparison of male and female patients with BC using a US registry-based cohort of 2004-2014																	This study found that mortality after cancer diagnosis was higher among male patients with breast cancer compared with their female counterparts. Such disparity appeared to persist after accounting for clinical characteristics, treatment factors, and access to care, suggesting that other factors (particularly additional biological attributes, treatment compliance, and lifestyle factors) should be identified to help in eliminating this disparity.		16 025 male and 1 800 708 female patients with breast cancer. The goal was to compare mortality between male and female patients with breast cancer and quantitatively evaluate the factors associated with sex-based disparity in mortality. Compared with female patients, male patients had higher mortality across all stages. Overall, clinical characteristics and undertreatments were associated with a 63.3% excess mortality rate for male patients. A higher proportion of excess deaths in men were explained by these factors in the first 3 years after breast cancer diagnosis (66.0%) and in all patients with early-stage cancer (30.5% for stage I and 13.6% for stage II). However, sex remained a significant factor associated with overall mortality (adjusted hazard ratio [HR], 1.19; 95% CI, 1.16-1.23) as well as mortality at 3-year (adjusted HR, 1.15; 95% CI, 1.10-1.21) and 5-year (adjusted HR, 1.19; 95% CI, 1.14-1.23) analyses, even after adjustment for clinical characteristics, treatment factors, age, race/ethnicity, and access to care.
Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer : CORALLEEN	Lancet Oncol	2020		2	early BC	HR pos, HER2 neg	postmenopausal women, luminal B subtype by PAM50	endocrine therapy + targeted therapy	ribociclib + letrozole for 6 cycles	neoadjuvant	chemotherapy	4EC - 12 paclitaxel	neoadjuvant											Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy.		The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery. At baseline, 44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group had high ROR. At surgery, 23 (46·9%) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%) of 52 patients in the chemotherapy group were low-ROR. These results provide evidence for further studies in high-risk disease that aim to evaluate the long-term survival outcomes of a chemotherapy-free strategy after selecting patients based on variables such as the patient's baseline risk of relapse and the pathological and biological response of the tumour to treatment. In addition, the concept of molecular downstaging could be explored to determine the success of combining novel biological agents as done in the I-SPY 2 framework. As the residual cancer burden 0–1 rates in the NEOPAL neoadjuvant trial following CDK4/6 inhibition and endocrine therapy were very low (ie, <10%), the authors decided to choose a standardised and validated prognostic tool that integrates biology and tumour burden into a single score and is associated with long-term prognosis independently of treatment received.
Is It Appropriate to Use the Result of an Unplanned, Exploratory, Nonstatistically Significant Subgroup Analysis to Support a Treatment Recommendation in an ASCO Treatment Guideline?	JCO	2020		editorial	early BC	HR pos, HER2 neg		chemotherapy		adjuvant	endocrine therapy		adjuvant											The TAILORx exploratory analysis regarding the relationship between age and recurrence score (RS) was used to suggest the use of chemoendocrine therapy to women who are younger than age 50 years and have an RS of 16 to 25. However, this conclusion is based on an unplanned and nonstatistically significant difference, as clearly stated by the TAILORx authors in the supplement that accompanied the publication		discussion about the subgroup of women younger than 50 with a RS between 21 and 25
Outcomes of Older Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis	JCO	2019		MA	metastatic BC	HR pos, HER2 neg	patients age 75 years or older	endocrine therapy + targeted therapy	aromatase inhibitor + CDK4/6 inhibitor	metastatic	endocrine therapy	aromatase inhibitor	metastatic	31m median	13m median	0.49	yes							There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.		Patients age 75 years and older comprise only 4% of clinical trial participants despite representing 19% of new cases in the United States. Whereas the studies included in this analysis enrolled approximately 43% of patients age 65 years and older (range, 39.3% to 45%), limited numbers of older patients age 70 years and older and 75 years and older were included (n = 198). Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. More than one half of patients older than age 70 years required two or more dose reductions and interruptions, with most occurring during the first three cycles. Of interest, these patients had similar or better outcomes than the overall population. Similar results have been observed in a retrospective analysis of patients older than age 70 years who were treated at a large academic institution with palbociclib. Patients older than age 75 years experienced higher rates of fatigue and diarrhea than their younger counterparts.
Bridging the Data-Free Zone: Decision Making for Older Adults With Cancer	JCO	2019		editorial			geriatric																			discussion about treatment in geriatric population. Editorial regarding "Outcomes of older women with hormone receptor–positive, human epidermal growth factor receptor–negative metastatic breast cancer treated with a CDK4/6 inhibitor and an aromatase inhibitor: An FDA pooled analysis".
Role of Capecitabine in Early Breast Cancer	JCO	2019		editorial	early BC			chemotherapy	capecitabine	adjuvant														currently the only indication for the use of capecitabine in early-stage breast cancer is as postneoadjuvant therapy in patients with TNBC who have not achieved pCR after standard neoadjuvant chemotherapy based on the CREATE-X trial. Current data do not support combining capecitabine with standard chemotherapy or its use as monotherapy for patients with early-stage breast cancer in the neoadjuvant or adjuvant setting. Going forward, it will be important to elucidate biomarkers with which to prospectively identify those patients for specific treatment strategies.		Discussion about the role of capecitabine in early BC : trials ICE, CALGB 49907, FINXX, CREATE-X, GEICAM/2003-11_CIBOMA/2004-01. Trials exploring the role of capecitabine monotherapy in the adjuvant setting demonstrated a lack of efficacy or inferiority to standard combination chemotherapy. Several randomized controlled trials (RCTs) investigated the addition of capecitabine to standard adjuvant or neoadjuvant therapies. Limitations of some of these trials were a low-risk patient population or substituting a standard chemotherapy drug for capecitabine instead of adding capecitabine. Overall, most of these trials demonstrated no clinical benefit using capecitabine in the adjuvant or neoadjuvant settings. Two recent meta-analyses of major RCTs incorporating capecitabine in adjuvant or neoadjuvant therapy demonstrated a trend toward improved outcomes with the addition of capecitabine to the TNBC subgroups.
Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline BRCA Pathogenic Variant	JCO	2019		2	early BC	HER2 negative	BRCA germline mutation	targeted therapy	talazoparib	neoadjuvant														Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial.		16 BRCA1, 4 BRCA2 ; 15 TNBC, 5 HR pos ; Five patients had clinical stage I disease, 12 had stage II, and three had stage III, including one patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma. pCR 53%, RCB 0-1 of 63%. Eight patients (40%) had grade 3 anemia and required a transfusion, three patients had grade 3 neutropenia, and 1 patient had grade 4 thrombocytopenia. Common grade 1 or 2 toxicities were nausea, fatigue, neutropenia, alopecia, dizziness, and dyspnea. Nine patients required dose reductions. Additional studies, however, are needed to determine if pCR to PARP inhibitor therapy has the same favorable prognosis as that seen with chemotherapy. Importantly, excellent pathologic responses were seen across BRCA mutation types, in both HR-positive and TNBC tumors, as well as subtypes known for chemotherapy resistance to neoadjuvant therapy, such as inflammatory breast cancer, metaplastic cancer, and invasive lobular carcinoma. For these younger patients with TNBC, whether to omit chemotherapy after a pCR cannot be answered by this study, because many did receive adjuvant chemotherapy; this question merits additional investigation. Outcomes and long-term symptoms in a larger, multicenter trial are needed to determine if single-agent talazoparib is sustainable as a de-escalation of therapy.
Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial	JCO	2020		2	metastatic BC	triple negative	first line	chemotherapy + targeted therapy	paclitaxel 90 3W/4 + capivasertib (AKT inhibitor) 4 days on, 3 days off	metastatic	chemotherapy	paclitaxel 90 3W/4	metastatic	5.9m	4.2m	0.74	no	19m	12m	0.61	yes			Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.		In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). Hyperglycemia was more commonly observed with capivasertib but rarely had sequelae; of note, patients with clinically significant abnormalities of glucose metabolism were excluded. Capivasertib (AZD5363) is a potent highly selective, orally active small-molecule kinase inhibitor with similar activity against the isoforms AKT1, AKT2, and AKT3. The results of PAKT are remarkably consistent with the results of the LOTUS study, providing additional evidence for the role of AKT inhibitors in TNBC. The diagnostic prevalence of PIK3CA/AKT1/PTEN alterations in PAKT was 25%. There was no significant difference in the incidence of PIK3CA/AKT1/PTEN alterations between primary tumor samples and tissue from metastases.
Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial : ASTRRA	JCO	2020		3	early BC	HR pos, HER2 neg	premenopausal women treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy.	endocrine therapy	tamoxifen + goserelin	adjuvant	endocrine therapy	tamoxifen	adjuvant	91.1% DFS at 5 years	87.5% DFS at 5 years	0.69	yes	99.4% at 5 years	97.8% at 5 years	0.31	yes			Ovarian function needs to be monitored longitudinally for at least 2 years in premenopausal patients who have been administered chemotherapy. The addition of 2 years of OFS to TAM significantly improved DFS compared with TAM alone in patients who remained premenopausal or resumed ovarian function after chemotherapy.		One of the challenges of an OFS trial is the selection of appropriate patients because the definition of premenopause often is complicated in women who have received chemotherapy and are receiving adjuvant TAM. After chemotherapy, a large proportion of premenopausal patients experience a period of chemotherapy-induced amenorrhea. The rate and pattern of ovarian function recovery after amenorrhea vary widely dependent on patient age and type of chemotherapy. Accordingly, serum FSH levels, serum E2 levels, and vaginal bleeding history are assumed to need longitudinal monitoring to decide whether to suppress ovarian function after adjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment on the basis of follicular-stimulating hormone levels and vaginal bleeding history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomly assigned to complete 5 years of TAM alone (TAM-only) group or 5 years of TAM with OFS for 2 years. Patients who continued to have chemotherapy-induced amenorrhea for 2 years from the time of enrollment were categorized into the permanent menopause group (group A) and were excluded from the survival analysis. Once the patients were evaluated as having resumed ovarian function, they were randomly assigned to complete 5 years of TAM alone (group B) or 5 years of TAM with OFS for 2 years (group C) at the time of each visit. If the FSH level was less than 30 mIU/mL at the time of enrollment, ovarian function was regarded as being maintained, and these patients were randomly assigned either to complete 5 years of TAM alone (group D) or 5 years of TAM with OFS for 2 years (group E) in a 1:1 ratio. The patients of groups B and D were classified into a TAM-only group (TAM-only), and the patients of groups C and E were classified into a TAM plus OFS (TAM + OFS) group. The ASTRRA study showed similar results as SOFT with a shorter follow-up period and smaller number of patients, which can be explained by the difference in the characteristics of patients in each study. The participants in ASTRRA had a relatively higher risk of disease recurrence than those in SOFT. The subgroup analysis of SOFT showed that most of the survival benefit from the addition of OFS was attributed to the patients who received chemotherapy. Of note, the characteristics of the chemotherapy-treated subgroup in SOFT were similar to those of ASTRRA. The overall adherence rate with OFS for patients assigned to the TAM + OFS group was 74.1%.
Mammaprint™: a comprehensive review	Future Oncology	2018		review																						This review describes how mammaprint works, its application in the clinic and its limitations
HER2CLIMB and DESTINY-Breast01 trials - editorial	NEJM	2020		editorial	metastatic BC	HER2 positive																				discussion about the results of tucatinib and trastuzumab deruxtecan in HER2CLIMB and DESTINY-Breast01 trials
NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2+	JCO	2020		3	early BC	HER2 negative		chemotherapy + targeted therapy	docetaxel-cyclophosphamide-trastuzumab or doxorubicin-cyclophosphamide followed by paclitaxel-trastuzumab	adjuvant	chemotherapy	docetaxel-cyclophosphamide or doxorubicin-cyclophosphamide followed by paclitaxel	adjuvant	89.8% at 5 years	89.2% at 5 years	0.98	no	94.8% at 5 years	96.3% at 5 years	1.1	no			The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.		Eligibility for the B-31 trial was based on HER2 testing results from local-site pathology laboratories. Central testing of archived tumor specimens from NSABP B-31 demonstrated that 174 of 1,787 cases (9.7%) had neither HER2 gene copy ratios ≥ 2.0 nor 3+ IHC overexpression of HER2. These patients appeared to derive similar magnitude of benefit from the addition of trastuzumab compared with patients centrally confirmed to have HER2-positive tumors. Similar findings were also reported from the N9831 trial, in which 103 cases were HER2 negative by both IHC and FISH by the central assay. Findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status.
Pharmacogenomics and Endocrine Therapy in Breast Cancer	JCO	2020		editorial		HR pos		endocrine therapy	tamoxifen															CYP2D6 genotype should not be used to guide ET for women with ER-positive early or metastatic breast cancer. Any tumor biomarker test should be introduced into clinical practice only when it is shown with high levels of evidence to have clinical utility. The confounding results of the He et al study are insufficient to be a conclusive validation of the hypothesis. The prospective nature of the Tamura et al study provides more high-level evidence that CP2D6 status does not affect the efficacy of tamoxifen in patients with ER-positive breast cancer.		discussion about the value of CYP2D6 genotyping to guide endocrine therapy
Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer	JAMA Oncol	2020		cohort study	early BC		treated with anthracycline and taxane-based chemotherapy																	Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis. The primary outcome was low relative dose intensity (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer–specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.		Although most chemotherapies are dosed according to body surface area, body composition may identify patients at risk for lower relative dose intensity, which could compromise therapeutic efficacy and may be one of multiple pathways through which adiposity is associated with increases in breast cancer mortality.
Late Recurrences After Estrogen Receptor–Positive Breast Cancer	JAMA Oncol	2020		editorial	early BC	HR pos, HER2 neg		endocrine therapy	tamoxifen	adjuvant	placebo	placebo	adjuvant											In the various subgroups, we see that the lower the risk of recurrence, themore prolonged the period of recurrence and the later the peak rate of recurrence. THEORY : Cancers initially enter the metastatic niche in a dormant state and then are reactivated (at random) to proliferate according to a fixed parameter, α (the annual reactivation rate). The lower the risk group, the lower the reactivation rate. As a consequence, low-risk cancers have a longer mean time to reactivation, a more prolonged time course, and a more unpredictable time to recurrence. We propose that the annual risk of reactivation is attenuated by tamoxifen. In the high-risk group, use of tamoxifen delays the reactivation of cancers, but at the end of active treatment more residual dormant cancers are present in the metastatic niche than in the untreated group. We predict that after tamoxifen cessation, the dormant cancers will slowly emerge from quiescence, and we will observe a switch from tamoxifen being a protective factor to a risk factor in the later years of follow-up.		Editorial about a study calculating the hazard rates for distant recurrence in the 25-year period following a diagnosis of estrogen receptor– positive breast cancer, where patients were subdivided into whether they received tamoxifen or no endocrine therapy (randomly assigned) and if they had a luminal A or luminal B tumor subtypes.
Pembrolizumab for Early Triple-Negative Breast Cancer	NEJM	2020		3	early BC	triple negative	stage II or stage III	chemotherapy + immunotherapy	4 pembrolizumab (200 mg) every 3 weeks plus paclitaxel 80 mg/m² weekly and carboplatin (AUC5/ 3 weeks or AUC1.5 weekly), then 4 pembrolizumab with epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks	neoadjuvant	chemotherapy	placebo every 3 weeks plus paclitaxel 80 mg/m² weekly and carboplatin (AUC5/ 3 weeks or AUC1.5 weekly), then 4 placebo with epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks	neoadjuvant	92.5% at 15 months	88% at 15 months	0.63	yes	65% pCR	51% pCR		yes			Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.		50% premenopausal. 80% PDL1 positive. 75% stage 2. The benefit of pembrolizumab–chemotherapy with respect to pathological complete response was generally consistent across subgroups, including PD-L1–expression subgroups. This finding differs from the results of the IMpassion130 trial, which showed efficacy of a PD-L1 inhibitor only in patients with PD-L1–positive metastatic triple-negative breast cancer. The percentage of patients with a pathological complete response in the placebo–chemotherapy group was consistent with percentages reported in other studies of platinum-containing neoadjuvant regimens in patients with early breast cancer. The present results are consistent with findings from previous studies of neoadjuvant pembrolizumab for the treatment of triple-negative breast cancer (KEYNOTE-173, I-SPY2). The addition of pembrolizumab did not increase chemotherapy-related toxic effects such as myelosuppression, nausea and vomiting, renal insufficiency, and neuropathy.
Prognostic Impact of the 21-Gene Recurrence Score Assay Among Young Women With Node-Negative and Node-Positive ER-Positive/HER2-Negative Breast Cancer	JCO	2020		cohort study	early BC	HR pos, HER2 neg	young women < 40 years																	The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.		Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively.
Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION)	Lancet Oncol	2020		2	metastatic BC	HR pos, HER2 neg	postmenopausal women who had relapsed or progressed on an aromatase inhibitor	endocrine therapy + targeted therapy	fulvestrant + capivasertib	metastatic	endocrine therapy	fulvestrant	metastatic	10m	4m	0.58	yes							Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials.		PI3K pathway alteration status, predefined in the protocol as PIK3CA hotspot mutation in exons 9 or 20 or PTEN null by immunohistochemistry, did not seem to change the effect size of capivasertib, although there was not enough statistical power within the subgroups to confirm this finding. This contrasts with the reported activity of capivasertib or ipatasertib (another pan-AKT inhibitor) in combination with paclitaxel in the PAKT and LOTUS studies in metastatic triple-negative breast cancer. Both studies reported a significant improvement in progression-free survival in the overall population, but the benefit was predominantly recorded in tumours with activating mutations in PIK3CA or AKT1 or inactivating alterations in PTEN. However, deficient PTEN expression is a more frequent alteration in triple-negative breast cancer than in oestrogen receptor-positive, HER2-negative breast cancer and is associated with increased AKT pathway activation, suggesting that the relative benefit of AKT inhibition is context dependent. The cross-talk between the oestrogen receptor and AKT signalling pathways, which seems to be irrespective of mutational status, provides a rational basis for effectiveness of the investigational combination beyond a mutant population. The most common G3-4 AE were hypertension (32 vs 24%), diarrhea (14 vs 4%), rash (20 vs 0%), infection (6 vs 3%) and fatigue (4% each). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment.
Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS)	Lancet Oncol	2017		2	metastatic BC	triple negative	previously untreated with systemic therapy	chemotherapy + targeted therapy	paclitaxel + ipatasertib	metastatic	chemotherapy	paclitaxel	metastatic	6m	5m	0.6	yes							Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer.		In the LOTUS trial, the effect of ipatasertib in the subgroup of patients with PTEN-low tumours by immunohistochemistry was no greater than in those with PTEN-non-low tumours or in the intention-to-treat population. However, efficacy analysis in the population with PIK3CA/AKT1/PTEN-altered tumours supporting the study's secondary objectives showed an encouraging progression-free survival HR of 0·44 and an increase of 4·1 months in the median progression-free survival (median 9m vs 4·9m). The most common grade 3 or worse adverse events were diarrhoea (23% vs 0%), neutropenia (10 vs 2%). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. The 4·9-month median progression-free survival in the control group of the intention-to-treat population was within the range reported in subgroup analyses of patients with triple-negative breast cancer in previous randomised trials.
Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future	Lancet	2020		review		HR pos, HER2 neg																				discussion about CDK 4/6 inhibitors in breast cancer
MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer	NPJ Breast Cancer	2019		3	metastatic BC	HR pos, HER2 neg	postmenopausal women who had not received previous systemic therapy for advanced disease. Endocrine therapy in the neoadjuvant or adjuvant setting was permitted if the patient had a disease-free interval > 12 months from the completion of endocrine therapy. Exclusion of visceral crisis.	endocrine therapy + targeted therapy	anastrozole or letrozole + abemaciclib	metastatic	endocrine therapy	anastrozole or letrozole	metastatic	28m	14m	0.54	yes							Abemaciclib plus a nonsteroidal AI was an effective initial treatment with an acceptable safety profile for HR+, HER2−ABC.		The ORR was 61.0% in the abemaciclib arm versus 45.5% in the placebo arm (measurable disease, p=.003). The median duration of response was longer in the abemaciclib arm (27.39 months) compared to the placebo arm (17.46 months). The most frequent grade≥3 adverse events in theabemaciclib versus placebo arms were neutropenia (23.9% versus 1.2%), diarrhea (9.5% versus 1.2%), and leukopenia (8.6% versus0.6%).
Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy : A Secondary Analysis of TAILORx	JAMA Oncol	2020		3	early BC	HR pos HER2 neg	high score of 26 to 100 by 21-gene assay who received adjuvant chemotherapy plus endocrine therapy	chemotherapy followed by endocrine therapy		adjuvant				at 5 years, 93% DDFS, 87.6% IDFS				at 5 years, 95.9%						The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. Findings indicate that about one-half of all events in this population included events other than distant recurrence.		Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). Limitations include the lack of randomization to endocrine therapy alone to prospectively confirm an interaction between chemotherapy benefit and high RS, and the limited follow-up and consequent potential for bias in reporting events beyond 5 years. The TAILORx trial results demonstrated that endocrine therapy alone was noninferior to adjuvant chemotherapy plus endocrine therapy in the overall population with an RS of 11 to 25, the primary trial end point, with some chemotherapy benefit noted for trial participants who were aged 50 years or younger with an RS of 16 to 25 in exploratory analysis. The trial also demonstrated a low distant recurrence rate of 1% at 5 years and 3% at 9 years with endocrine therapy alone if the RS was 0 to 10 irrespective of age, and that integration of clinical features with RS provided additional prognostic information for recurrence but not prediction of chemotherapy benefit.
Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia : PEONY	JAMA Oncol	2020		3	early BC	HER2 pos	Asian population ; treated in the neoadjuvant setting	chemotherapy + dual targeted therapy	4x docetaxel-trastuzumab-pertuzumab in neoadjuvant ; 3 FEC followed by 13 trastuzumab-pertuzumab in adjuvant.	neoadjuvant	chemotherapy + targeted therapy	4x docetaxel-trastuzumab in neoadjuvant ; 3 FEC followed by 13 trastuzumab in adjuvant.	neoadjuvant	39% pCR	21% pCR		yes							Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen.
Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221)	JCO	2020		3	early BC		Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134).																	Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.		The strength of DELCaP is that it was conducted in the context of a therapeutic clinical trial, with surveys before beginning chemotherapy and at completion of treatment. This allowed to directly assess the potential interaction of dietary supplements with chemotherapy. Furthermore, all patients in the trial received the same drugs, a common chemotherapy regimen, but with varying dosing schedules. This relative homogeneity in treatments allowed for more direct inferences about supplement use in relation to treatment outcomes, unlike population-based studies where treatments may be extremely heterogeneous. There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (HR 1.4, p=0.06) and, to a lesser extent, death (HR 1.4, p=0.14). For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (HR 1.8, p<0.01) and overall survival (HR 2, P<0.01). Use of iron during chemotherapy was significantly associated with recurrence (HR 1.79, p<0.01) as was use both before and during treatment (HR 1.9, p=0.06). Multivitamin use was not associated with survival outcomes, consistent consistent with the only other study of lifestyle factors embedded in a clinical trial for colon cancer CALGB89803. There also, use of omega-3 fatty acid supplements, iron, and vitamin B12 both before and during chemotherapy was associated with DFS and OS. Concerns that use of antioxidants during chemotherapy could reduce the cytotoxic effects of ROS generated by numerous chemotherapy agents. Iron plays unique roles in tumor initiation and progression directly and through effects on the tumor microenvironment. Iron enables the production of ROS, which can contribute to malignant transformation, and once established, tumors require high amounts of iron for proliferation. Iron may also impair antitumor immunity. How the use of vitamin B12 both before and during chemotherapy could be associated with poorer outcomes remains to be understood. In a cohort study of > 25,000 patients with measured cobalamin levels before diagnosis, elevated levels were associated with higher mortality, but it is unknown whether the higher levels were indicators of underlying pathologic conditions. Patients who took supplements during treatment could have differed from those who did not, which would result in uncontrolled confounding. However, adjustment for age, additional lifestyle factors, and tumor characteristics only somewhat attenuated risk estimates and widened the CIs.
MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2–Positive and/or Hormone Receptor–Negative Breast Cancers in the I-SPY 2 Trial	JCO	2020		2	early BC	HER2 positive and/or HR negative	clinical stage 2 or 3 (T > 2.5 cm)	chemotherapy + targeted therapy	paclitaxel 80 + MK-2206 (135 mg/week) (+ trastuzumab) - doxorubicin+cyclophosphamide	neoadjuvant	chemotherapy	paclitaxel 80 (+ trastuzumab) - doxorubicin+cyclophosphamide	neoadjuvant											The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.		I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies. MK-2206 is a pan-Akt inhibitor. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Safety and clinical activity of MK-2206 in combination with paclitaxel, trastuzumab, or both have been described in phase I trials. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). MK-2206 graduated in HER2-positive, HR-negative/HER2-positive, and HR-negative disease. Our final results predict a 76%, 85%, and 82% probability, respectively, that MK-2206 will successfully demonstrate superiority to controls in a 300-person phase III neoadjuvant trial in each subtype. Consistent with other trials, data from I-SPY 2 suggest that pCR is strongly prognostic for EFS. An exploratory analysis suggests that MK-2206 improves EFS in patients with the sensitive biomarker signatures. However, the numbers of patients within each arm and signature are small, EFS is a secondary end point, and I-SPY 2 was not powered to evaluate EFS differences between arms.
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study	Lancet Oncol	2020		3	metastatic BC	HER2 positive	no previous chemotherapy or anti-HER2 therapy for their metastatic disease	chemotherapy + dual targeted therapy	docetaxel + trastuzumab + pertuzumab	metastatic	chemotherapy + targeted therapy	docetaxel + trastuzumab	metastatic					57m	40m	0.69	yes			previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Clinical and biomarker features that were more prevalent among patients with long-term disease control (defined as progression-free survival 35 months or longer) in the CLEOPATRA trial included non-measurable, non-visceral, progesterone receptor-positive, HER2 3+ disease, longer time from breast cancer diagnosis to relapse, high HER2 mRNA, low serum HER2 extracellular domain, and PIK3CA-wild-type tumours. Nevertheless, these were only descriptive, non-adjusted observations and most of these markers were previously identified prognostic factors. The achievement of longer survival outcomes further highlights the crucial role of incorporating survivorship issues into routine care for patients with metastatic breast cancer.		8-year landmark overall survival rates were 37% in the pertuzumab group and 23% in the placebo group. With the pertuzumab-based regimen, 8 years after diagnosis of metastatic disease, 16% were still free from disease progression. Of note, more than half (54%) of the enrolled patients did not receive any previous adjuvant or neoadjuvant treatment, and only 11% were previously exposed to trastuzumab.
Breast conservation therapy versus mastectomy for breast cancer : PRO	Lancet Oncol	2020		editorial	early BC			surgery	lumpectomy and radiotherapy		surgery	mastectomy												Recent data suggest that breast-conserving therapy might actually be superior to mastectomy in terms of cancer-specific and overall survival. The answer lies in the technical evolution of breast-conserving therapy over the past 20 years (to be a more comprehensive locoregional therapy) versus mastectomy (to be less comprehensive) in treating the breast, regional nodes, and surrounding tissues.		discussion about the benefits of lumpectomy and the improvements in multidisciplinary approach
Breast conservation therapy versus mastectomy for breast cancer : CON	Lancet Oncol	2020		editorial	early BC			surgery	lumpectomy and radiotherapy		surgery	mastectomy												Breast conservation is usually followed by radiotherapy to reduce local recurrence and reach equivalent survival to mastectomy. Patients without nodal metastasis who undergo mastectomy rarely receive radiotherapy. Given this key difference, the toxic effects and safety of radiotherapy merit particular consideration.
Small molecules, big impact: 20 years of targeted therapy in oncology	Lancet	2020		review
Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor–Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903	JCO	2020		2	DCIS	HR pos	postmenopausal patients diagnosed with ER-positive DCIS without invasion	endocrine therapy	letrozole 6 months	neoadjuvant														In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.		Women with elevated breast cancer risk are routinely recommended to consider endocrine therapy to reduce future risk of breast cancer. However, these studies did not address whether endocrine therapy by itself could provide benefit in unresected DCIS. In the adjuvant endocrine therapy setting, two randomized trials have demonstrated up to a 30% reduction in new ipsilateral or contralateral breast events with 5 years of tamoxifen compared with placebo in women undergoing BCS. In contrast, neoadjuvant endocrine therapy has only been studied for invasive cancer, in which it has been shown to improve resectability and increase rates of breast conservation. Here, significant radiologic and histologic changes were noted after 6 months of therapy. Eighty-five percent of patients had residual DCIS at surgery, possibly reflecting a limitation of the relatively short 6-month duration of letrozole treatment. However, 15% of patients had pathologic complete response, despite a baseline extent of calcifications ranging from 15-59 mm. The majority of MRI changes were seen early in letrozole treatment, with a significant median reduction in tumor volume of 61% by 3 months. 10% of patients who underwent surgery after preoperative endocrine therapy had invasive cancer. Although it is possible that invasive progression may have occurred during the 6-month window of letrozole treatment, it is more likely that this represents undersampling of concurrent invasive cancer at baseline and compares favorably with the upstaging rate of 26% reported in a meta-analysis of 7,350 women with a core biopsy diagnosis of DCIS.
Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT	JCO	2020		3	early BC	HR pos	premenopausal women	endocrine therapy	exemestane + OFS	adjuvant	endocrine therapy	tamoxifen	adjuvant											Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.		The clinicopathologic characteristic with the greatest contribution to the multivariable model for the composite measure of recurrence risk, relative to the complementary reference category, was four or more positive nodes followed by tumor grade 2 or 3 and younger age. one to three positive nodes, tumor size greater than 2 cm, PgR less than 20%, and Ki-67 of 26% or more contributed similarly. The 8-year freedom from distant recurrence rate varied markedly across patient populations, ranging from approximately 100% to 63% among patients in the subpopulations with lowest composite risks to highest composite risks. The majority of distant recurrences occurred among patients who received chemotherapy. Those who received only adjuvant endocrine therapy had lower composite risks. On average, 2.1% absolute improvement in freedom from distant recurrence at 8 years in premenopausal women treated with an aromatase inhibitor versus tamoxifen with OFS, comparable to that observed for postmenopausal women. Among women with HR-positive/HER2-negative tumors who received chemotherapy, an average 5% absolute improvement was achieved by escalating endocrine therapy to exemestane plus OFS in both TEXT and SOFT. The composite risk for a high-risk scenario was represented in subpopulations that had an absolute improvement greater than the average (range, 7% to 10%). In contrast, in low-risk patients, who did not receive chemotherapy, the 8-year freedom from distant recurrence was improved on average by approximately 1% in patients who received exemestane plus OFS compared with tamoxifen alone or tamoxifen plus OFS. Most intermediate-risk patients in SOFT and TEXT received chemotherapy. Here, the absolute improvement with exemestane plus OFS was estimated to be less than the average improvement of 5%. Of note, intermediate-risk patients in TEXT who did not receive chemotherapy were estimated to have an improvement with exemestane plus OFS that exceeded 4%; these patients also achieved approximately 10% improvement in freedom from any breast cancer recurrence at 5 years with exemestane plus OFS.
Early Discontinuation and Nonadherence to Adjuvant Hormonal Therapy in a Cohort of 8,769 Early-Stage Breast Cancer Patients	JCO	2010		cohort study	early BC	HR pos		endocrine therapy		adjuvant														Only 49% of patients with BC took adjuvant hormonal therapy for the full duration at the optimal schedule. Younger women are at high risk of nonadherence. Interventions to improve adherence and continuation of hormonal therapy are needed, especially for younger women.		8,769 patients. Medication possession ratio < 80% was considered as nonadherence. Younger or older age, lumpectomy (v mastectomy), and comorbidities were associated with earlier discontinuation, while Asian race, being married, earlier year at diagnosis, receipt of chemotherapy or radiotherapy, and longer prescription refill interval were associated with completion of 4.5 years of therapy. Women age younger than 40 years had the highest risk of discontinuation (HR 1.5). By 4.5 years, 32% discontinued therapy, and of those who continued, 72% were fully adherent.
Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor–Positive Breast Cancer : A Secondary Analysis of TransATAC	JAMA Oncol	2018		3	early BC	HR pos, HER2 neg	postmenopausal women																	For women with node-negative disease, the ROR, BCI, and EPclin were significantly more prognostic for overall and late distant recurrence. For women with 1 to 3 positive nodes, limited independent information was available from any test. These data might help oncologists and patients to choose the most appropriate test when considering chemotherapy use and/or extended endocrine therapy.		within-patient comparison of the prognostic value of 6 multigene signatures (Oncotype Dx recurrence score, PAM50-based Prosigna risk of recurrence (ROR), Breast Cancer Index (BCI), EndoPredict (EPclin), Clinical Treatment Score, and 4-marker immunohistochemical score) in women with early ER-positive breast cancer who received endocrine therapy for 5 years. In this biomarker analysis of data from a randomized clinical trial, a combination of multigene expression tests with clinical information was associated with improved prognostic value for distant recurrences and risk stratification specifically in women with node-positive disease. Differences in the prognostic value for late distant recurrence were observed. The RS and BCI include only molecular information in their signatures, whereas the ROR (tumor size) and EPclin (tumor size and number of positive nodes) integrate clinical information. The comparison was performed separately for women with node-negative disease and those with 1 to 3 positive nodes because the most significant prognostic clinical indicator for early-stage breast cancer is the presence or absence of lymph node involvement.
De-Escalating Treatment of Low-Risk Breast Ductal Carcinoma In Situ	JCO	2020		editorial																						discussion about deescalating treatment in low risk in situ DCIS. SEER data indicate that the 20-year actuarial breast cancer–specific mortality rate after DCIS is only 3.3%, and there is a lack of significant benefit of adjuvant radiotherapy on this outcome. The incidence of DCIS has increased by more than seven times from 1980 to 2007, but treatment of DCIS has not translated into a decreased incidence of invasive breast cancer during this period. A more aggressive approach, including surgery and radiotherapy, could still be offered to patients age younger than 50 years or with additional risk factors for mortality such as African American ethnicity, high grade, estrogen receptor negativity, large tumor size, or the presence of comedonecrosis. Randomized trials clearly show the benefit of adjuvant radiation on local recurrence, but an effect of radiation on disease-specific survival could not be demonstrated. If a computational risk projection model based upon published estimates for natural history parameters and SEER data for outcomes is used, active surveillance could be a viable management strategy for carefully selected patients with DCIS, particularly among older age groups and those with substantial competing mortality risks. In addition, the effectiveness of active surveillance could be markedly improved by reducing the rate of understaging (up to 26% of patients with a biopsy diagnosis of DCIS present a synchronous invasive carcinoma component in the subsequent resection specimen). Because it is difficult to determine which DCIS lesions are likely to progress to invasive cancer (currently the worst prognostic factor for long-term mortality)3 and which ones will remain indolent, the options of active surveillance or endocrine treatment are not generally offered to patients with DCIS.
Improving Adjuvant Endocrine Treatment Tailoring in Premenopausal Women With Hormone Receptor–Positive Breast Cancer : discussion about SOFT-TEXT update 2020	JCO	2020		editorial	early BC	HR pos	premenopausal women	endocrine therapy	OFS + exemestane or tamoxifen	adjuvant	endocrine therapy	tamoxifen	adjuvant													discussion about the challenges in management of premenopausal BC. Summary of the available literature and proposal of an algorithm for the prognostication of these patients.
Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial	JAMA Oncol	2020		2	early BC	HER2 positive and/or HR negative	clinical stage 2 or 3 (T > 2.5 cm)	chemotherapy + immunotherapy	taxane + pembrolizumab followed by AC	neoadjuvant	chemotherapy	taxane- and anthracycline-based NACT	neoadjuvant	44%, 30%, 60% pCR in the HER2-neg, HR pos HER2 neg, ant TNBC group, respectively	17%, 13%, 22% pCR in the HER2-neg, HR pos HER2 neg, ant TNBC group, respectively		yes							When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.		Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years’ median follow-up).
Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer A Secondary Analysis of the GeparOcto Randomized Clinical Trial	JAMA Oncol	2020		3	early BC	HER2 positive or triple negative ; luminal B if node positive	cT1c-cT4a-d	chemotherapy	intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) : epirubicin 150 mg/m2 every 2 weeks (q2w) for three cycles followed by paclitaxel 225 mg/m2 q2w for three cycles followed by cyclophosphamide 2000 mg/m2 q2w for three cycles	neoadjuvant	chemotherapy	paclitaxel 80 mg/m2 weekly in combination with non-pegylated liposomal doxorubicin (M) 20 mg/m2 weekly and, in case of TNBC, additional carboplatin AUC 1.5 weekly for 18 weeks.	neoadjuvant	pCR in the TNBC subgroup, 65% if BRCA mut vs 45% if BRCA wt	pCR in the TNBC subgroup, 74% if BRCA mut vs 47% if BRCA wt									Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor–positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start.		Patients with HER2-positive disease received trastuzumab and pertuzumab simultaneously to all chemotherapy cycles other than E in the iddEPC arm. Overall, in this study, no difference in pathologic complete response (pCR) rates was observed between study arms. In this secondary analysis of 914 patients included in a randomized clinical trial, women with triple-negative breast cancer with BRCA1/2 variants benefited most from both treatment regimens (paclitaxel and nonpegylated liposomal doxorubicin plus carboplatin, 74.3%; epirubicin, paclitaxel, and cyclophosphamide, 64.7%). A positive BRCA1/2 variant status also was associated with higher response rates in ERBB2-negative, hormone receptor–positive breast cancer. A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor–positive BC (31.8% vs 11.9%).
Intense Dose-Dense Epirubicin, Paclitaxel, Cyclophosphamide Versus Weekly Paclitaxel, Liposomal Doxorubicin (Plus Carboplatin in Triple-Negative Breast Cancer) for Neoadjuvant Treatment of High-Risk Early Breast Cancer (GeparOcto-GBG 84): A Randomised Phase III Trial	Eur J Cancer	2019		3	early BC	HER2 positive or triple negative ; luminal B if node positive	cT1c-cT4a-d	chemotherapy	intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) : epirubicin 150 mg/m2 every 2 weeks (q2w) for three cycles followed by paclitaxel 225 mg/m2 q2w for three cycles followed by cyclophosphamide 2000 mg/m2 q2w for three cycles	neoadjuvant	chemotherapy	paclitaxel 80 mg/m2 weekly in combination with non-pegylated liposomal doxorubicin (M) 20 mg/m2 weekly and, in case of TNBC, additional carboplatin AUC 1.5 weekly for 18 weeks.	neoadjuvant	48.3% pCR	48% pCR	0.99	no							In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice. PM(Cb) did not result in higher pCR rates compared with iddEPC but led to more treatment discontinuations and was associated with significantly higher rates of non-haematological, especially pulmonal, toxicity. The observed pCR rates of 14.4% for HR-positive/HER2-negative, 60.2% for HER2-positive and 50.1% for TNBC, respectively, are in line with pCR rates reported from other randomised trials evaluating dual-blockade in high-risk early-stage HER2-positive disease and carboplatin in TNBC, respectively.		no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P < 0.001), mainly due to adverse events; 2/470 patients on PM(Cb) died. Grade 3–4 haematological AEs were more frequent with iddEPC compared with PM(Cb) : 90 vs 29%. Non-haematological grade ≥3 AEs were higher in the PM(Cb) arm: 43 vs 52%. Despite a pronounced and significantly higher incidence of haematological toxicity, iddEPC is a more feasible regimen with better treatment adherence due to the lower rate of non-haematological toxicities. patients with high TILs achieved a significantly higher pCR rate with iddEPC than with PM(Cb).
Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01)	Lancet Oncol	2020		3	DCIS		completely excised non-low-risk ductal carcinoma in situ	radiotherapy		adjuvant	radiotherapy	tumour bed boost following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy	adjuvant	no tumour bed boost following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy										Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending.		All patients were followed up at 2 years for the HRQOL analysis. Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10, persisting at 24 months). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08) but did not persist at 24 months. None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference –1·10).
Anticoagulant Therapy for Venous Thromboembolism in Cancer	NEJM	2020		editorial																				Given the heterogeneity of available trials, it is inappropriate to conclude that one direct oral anticoagulant is better than another without a head-to-head comparison. So how do we choose which anticoagulant to use? Carefully! Clinicians need to rely on a detailed clinical history, ascertaining the cancer type, status, and treatment, along with bleeding risk, concomitant medications, and the patient’s experiences and values. For example, patients with primary brain tumors, known intracerebral metastases, or acute leukemia were excluded from participating in the Caravaggio trial but not from the Hokusai VTE Cancer trial or SELECT-D trial. For patients who are treated with edoxaban, an initial week of low-molecular-weight heparin is required, although fewer drug–drug interactions are expected than with rivaroxaban or apixaban. Depending on the specific direct oral anticoagulant that was studied in each trial, patients who were receiving strong inducers or inhibitors of P-glycoprotein or CYP3A4 were often excluded, and very few patients were receiving newer cancer therapies, such as checkpoint inhibitors. Low-molecular-weight heparin is preferred in patients in whom drug–drug interaction is a concern and in those who have undergone surgery involving the upper gastrointestinal tract because absorption of all direct oral anticoagulants occurs in the stomach or proximal small bowel. Our experience with low-molecular-weight heparin in patients with bleeding or thrombocytopenia, recurrent venous thromboembolism, central nervous system cancers, or severe renal impairment and in those in the perioperative setting will keep this parenteral agent in use.		open-label, randomized, controlled trials have evaluated the direct factor Xa inhibitors edoxaban (in the Hokusai VTE Cancer trial), rivaroxaban (SELECT-D trial), and apixaban (ADAM VTE trial, CARAVAGGIO trial) for patients with cancer and acute VTE. These studies have shown somewhat conflicting results, since they differed in their primary outcomes, duration of treatment, and patient selection (cancer type and prognosis). Nonetheless, guidelines were quick to recommend the use of edoxaban and rivaroxaban as alternatives to low-molecular-weight heparin in patients with cancer, not only because of the clinically acceptable results but also because of the discomfort and cost associated with the use of LMWH. But higher risk of clinically important bleeding reported with both edoxaban and rivaroxaban, particularly in patients with gastrointestinal cancers (including pancreatic cancer), the uncertainty regarding the clinical significance of drug–drug interactions with anticancer therapeutics, and the concern about adequate absorption in patients with gastrointestinal toxicity and in those who have undergone surgery involving the upper gastrointestinal tract. The Caravaggio trial excluded patients with primary and metastatic brain lesions and included few patients with cancers of the upper gastrointestinal tract and hematologic cancers. The ADAM VTE trial, in which investigators found no major bleeding events with apixaban, was a smaller study with an enrollment of 300 patients. It included patients with other thrombotic sites (e.g., upper extremity), and the overall mortality (13.2%) was much lower than that in other trials, which suggests patient selection.
Association Between 21-Gene Assay Recurrence Score and Locoregional Recurrence Rates in Patients With Node-Positive Breast Cancer : a secondary analysis a retrospective analysis of the Southwest Oncology Group S8814	JAMA Oncol	2020		3	early BC	HR pos HER2 neg	postmenopausal node positive patients treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone.																	This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.		Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (HR 2.36, p=0.04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051).
Association of Germline Genetic Testing Results With Locoregional and Systemic Therapy in Patients With Breast Cancer	JAMA Oncol	2020		cohort study	early BC		stage 0 to 3 BC with genetic testing within 3 months after diagnosis																	Women with pathogenic variants in BRCA1/2 and other breast cancer–associated genes were found to have distinct patterns of breast cancer treatment; these may be less concordant with practice guidelines, particularly for radiotherapy and chemotherapy.		SEER registries of Georgia and California between 2014 and 2016. A total of 20 568 women (17.3%) of 119 198 were eligible. Compared with women whose test results were negative, those with BRCA1/2 pathogenic variants were more likely to receive bilateral mastectomy for a unilateral tumor (61.7% vs 24.3%; OR, 5.52), less likely to receive postlumpectomy radiotherapy (50.2% vs 81.5%; OR, 0.22) nd more likely to receive chemotherapy for early-stage, ER/PR-positive disease (38.0% vs 30.3%; OR, 1.76). Similar patterns were seen with pathogenic variants in other breast cancer–associated genes (ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, and TP53) but not with variants of uncertain significance.
Overall Mortality After Diagnosis of Breast Cancer in Men vs Women	JAMA Oncol	2019		cohort study																				This study found that mortality after cancer diagnosis was higher among male patients with breast cancer compared with their female counterparts. Such disparity appeared to persist after accounting for clinical characteristics, treatment factors, and access to care, suggesting that other factors (particularly additional biological attributes, treatment compliance, and lifestyle factors) should be identified to help in eliminating this disparity.		large cohort study of 16 025 male and 1 800 708 female patients with breast cancer in the US, diagnosed between January 1, 2004, and December 31, 2014. Compared with female patients, male patients had higher mortality across all stages. For men, the overall survival rate was 45.8%, the 3-year rate was 86.4% and the 5-year rate was 77.6%. For women, the overall survival rate was 60.4%, the 3-year rate was 91.7% and the 5-year rate was 86.4%. Overall, clinical characteristics and undertreatments were associated with a 63.3% excess mortality rate for male patients. However, sex remained a significant factor associated with overall mortality (HR 1.19) as well as mortality at 3-year (HR 1.15) and at 5-year (HR 1.19) even after adjustment for clinical characteristics, treatment factors, age, race/ethnicity, and access to care.
Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial	JCO	2020		3	early BC		high risk according to clinical and/or genomic features	chemotherapy	docetaxel + capecitabine	adjuvant	chemotherapy	anthracycline-based regimen, with or without taxanes	adjuvant	90.7% DFS at 5 years, 86% in clinically and genomic high group	88.8% DFS at 5 years, 88% in clinically and genomic high group	0.83	no							Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.		In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. DC led to more grade 1 neuropathy (27.1% v 11.2%) and more grade 2 hand/foot syndrome (28.5% v 3.3%) and diarrhea (13.7% v 5.8%).
State-of-the-Art Strategies for Targeting RET-Dependent Cancers	JCO	2020		review - NGS			RET rearrangements or mutations																	Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non–small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
Dietary Modification and Breast Cancer Mortality: Long-Term Follow-Up of the Women’s Health Initiative Randomized Trial	JCO	2020		3																				Adoption of a low-fat dietary pattern associated with increased vegetable, fruit, and grain intake, demonstrably achievable by many, may reduce the risk of death as a result of breast cancer in postmenopausal women.		In the WHI DM trial, 48,835 postmenopausal women, ages 50-79 years, with no prior breast cancer, and a dietary fat intake of ≥ 32% of energy were randomly assigned at 40 US centers to a usual diet comparison group (60%) or dietary intervention group (40%). The goals were to reduce fat intake to 20% of energy and increase vegetable, fruit, and grain intake. After a long-term, cumulative 19.6-year (median) follow-up, the significant reduction in deaths after breast cancer persists (0.12 vs 0.14%) and a statistically significant reduction in deaths as a result of breast cancer emerged (0.037% annualized risk vs 0.047%).
TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)	JCO	2020		2	early BC	HER2 negative	BRCA germline mutation, cT1-3 (≥ 1.5 cm), cN0-3	chemotherapy	Cisplatin (75 mg/m2 every 3 weeks × 4 doses)	neoadjuvant	chemotherapy	AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses)	neoadjuvant	18% pCR, 33% RCB 0-1	26% pCR, 46% RCB 0-1									pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease. Caution must be used when interpreting results for the higher pathologic response observed with AC than with CDDP among those with ER+ disease, given the small sample size of that cohort.		This is the largest prospective randomized study to date of neoadjuvant chemotherapy in BRCA carriers with newly diagnosed breast cancer and the only one to compare the pathologic response of a platinum agent to an anthracycline-based regimen. 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. These results are consistent with those reported from the Geparsixto and BrighTNess studies. Both of those trials evaluated the benefit of adding platinum to a neoadjuvant anthracycline- and taxane-based regimen in patients with TNBC, and analyzed results according to BRCA status. Both studies reported that, in contrast to patients without a germline BRCA mutation, among BRCA carriers, the addition of platinum did not significantly improve the pCR rate. In Geparsixto, the addition of platinum led to a significant improvement in disease-free survival only for patients without a BRCA mutation. In both studies, the pCR rate was higher with the nonplatinum-containing regimen among BRCA carriers than among noncarriers. One potential explanation for the lack of additional benefit with platinum for BRCA carriers in these studies is that breast cancer in BRCA carriers is more sensitive to DNA-damaging agents, whether CDDP or anthracyclines plus alkylating agents, than breast cancer in noncarriers, and the superior response to anthracycline and alkylating agent reduces any additional benefit from platinum chemotherapy. BRCA deficiency (ie, homologous recombination deficiency) may simply predict chemosensitivity, at least to DNA-damaging agents, rather than to platinum agents specifically. Consistent with prior reports, we found that a higher level of baseline TILs was associated with a higher pathologic response to both CDDP and AC. Of note, a recent pooled analysis of neoadjuvant trials using platinum-based therapy in TNBC found that stromal TIL level and homologous recombination deficiency were independently associated with therapy response.
Adjuvant Capecitabine With Docetaxel and Cyclophosphamide Plus Epirubicin for Triple-Negative Breast Cancer (CBCSG010)	JCO	2020		3	early BC	triple negative		chemotherapy	3 cycles of capecitabine and docetaxel followed by 3 cycles of capecitabine, epirubicin, and cyclophosphamide	adjuvant	chemotherapy	3 cycles of docetaxel followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide	adjuvant	86.3% DFS at 5 years	80.4% DFS at 5 years	0.66	yes	93.3% at 5 years	90.7% at 5 years		no			Capecitabine when added to 3 cycles of docetaxel followed by 3 cycles of a 3-drug anthracycline combination containing capecitabine instead of fluorouracil significantly improved DFS in TNBC without new safety concerns.		Adjuvant taxane- and anthracycline-based chemotherapy is the standard of care after TNBC resection. The ECOG 1199 and SWOG S0221 studies reported that doxorubicin plus cyclophosphamide followed by paclitaxel yielded substantial benefits in patients with TNBC. A meta-analysis (8 studies, 9,302 patients) showed that capecitabine plus standard chemotherapy significantly improved DFS in TNBC (HR, 0.72). However, in the GeparQuattro and NSABP B40 trials, the addition of capecitabine to neoadjuvant therapy did not improve the rates of pathologic complete response. Overall, 39.1% of patients had capecitabine dose reductions, and 8.4% reported grade ≥ 3 hand-foot syndrome. The most common grade ≥ 3 hematologic toxicities were neutropenia (45.8% vs 41.0%) and febrile neutropenia (16.8% vs 16.0%).
Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer : a Secondary Analysis of the GeparSixto Randomized Clinical Trial	JAMA Oncol	2017		2	early BC	triple negative	stage II to III scheduled for neoadjuvant chemotherapy	chemotherapy + targeted therapy	carboplatin AUC 1.5 + paclitaxel 80mg/m² - non-pegylated liposomal doxorubicin 20mg/m² + bevacizumab	neoadjuvant	chemotherapy + targeted therapy	paclitaxel 80mg/m² - non-pegylated liposomal doxorubicin 20mg/m² + bevacizumab	neoadjuvant											Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin.		Objective : To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004).
Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto	Ann Oncol	2019		2	early BC	triple negative	stage II to III scheduled for neoadjuvant chemotherapy	chemotherapy + targeted therapy	carboplatin AUC 1.5 + paclitaxel 80mg/m² - non-pegylated liposomal doxorubicin 20mg/m² + bevacizumab	neoadjuvant	chemotherapy + targeted therapy	paclitaxel 80mg/m² - non-pegylated liposomal doxorubicin 20mg/m² + bevacizumab	neoadjuvant	86 % DFS at 3 years for TNBC	75.8 % DFS at 3 years for TNBC			91.9 % at 3 years for TNBC	86 % at 3 years for TNBC	0.6	no			The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.		HR deficiency, defined as either tmBRCA mutation or a high HRD score, was detected in 136 (70.5%) of 193 triple-negative tumors (higher than the 50% in unselected cohorts), of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency was associated with younger patients’ age, node-negative disease at diagnosis, and a higher family risk for developing breast and/or ovarian cancer. HR deficiency independently predicted pCR [(OR) 2.60, 95% CI 1.26–5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059). In contrast, in the CALGB 40603 study, higher pCR rates following addition of carboplatin to standard neoadjuvant chemotherapy yielded a nonsignificant improvement of DFS by absolute 5% only. The difference between these trials may arise from inclusion of lower risk patients in the CALGB study. In addition, none of the studies were powered to detect a survival difference a priori. Furthermore, GeparSixto used a nonconventional treatment, whereas the CALGB study added carboplatin to another alkylating agent (cyclophosphamide). Due to the small subgroups, no final conclusions can be drawn regarding the HRD score as predictor of carboplatin response. This finding was recently supported by results from a larger cohort in the Brightness study where addition of carboplatin led to higher pCR rates in both HR deficient and nondeficient subsets.
Cognitive Impairment in Patients With Breast Cancer: Understanding the Impact of Chemotherapy and Endocrine Therapy	JCO	2020		editorial	early BC			chemotherapy or endocrine therapy		adjuvant														Overall, the results of this study make an important contribution toward understanding the potential adverse cognitive effects of chemotherapy in combination with ET and ET alone. The finding of different responses to chemotherapy plus ET and ET alone in the 2 menopausal groups suggests that we need to be considering menopausal status as a covariate or stratification variable when examining cognitive changes after breast cancer treatment. Estrogen receptors are widespread throughout the brain, and hormonal effects are important for brain function. Sudden changes in circulating estradiol, such as in chemotherapy-induced amenorrhea in premenopausal women, may exacerbate the cognitive effects of subsequent ET. In postmenopausal women who begin their ET with low levels of circulating estradiol, the effects are likely different, but may be confounded by age-related cognitive decline that might also be exacerbated by chemotherapy.		Discussion about the subanalysis on cognitive impairment in TAILORx in women with intermediate values (11-25) randomized to endocrine therapy with or without chemotherapy. Of note, at the 3-month assessment, most women assigned to chemotherapy would not yet have started their ET; therefore, this is a direct comparison of the chemotherapy versus ET rather than the combined exposure. In prespecified subgroup analyses by menopausal status, an interesting and divergent pattern occurred for the premenopausal and postmenopausal groups. In the postmenopausal women, there was a significant difference between the ET-alone and chemotherapy-plus-ET groups at both 3 and 6 months, with a sustained pattern of lowered PCI scores in the combined treatment group out to 36 months. In contrast, for the premenopausal women, the only significant difference between the 2 groups was at 3 months, with subsequent overlap in PCI decline of the 2 treatment groups, primarily due to a continued decline in PCI for the ET-only group, which was greater in magnitude than what was observed in the postmenopausal women. Interestingly, the modest decline in PCI observed in the postmenopausal ET-alone group is comparable to what was observed in the NSABP B-35 trial that compared anastrozole and tamoxifen in postmenopausal women with ductal carcinoma in situ.
Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx	JCO	2020		3	early BC	RH pos, HER2 neg	21-gene recurrence score of 11 to 25	chemotherapy + endocrine therapy		adjuvant	endocrine therapy		adjuvant											Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.		FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant.
Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low–Expressing Advanced Breast Cancer: Results From a Phase Ib Study	JCO	2020		1	metastatic BC	HER2-low–expressing : IHC 1+ or 2+	refractory to standard therapies	antibody drug conjugate	trastuzumab deruxtecan	metastatic				37% ORR with a median duration of response of 10 months.										The novel HER2-targeted ADC, trastuzumab deruxtecan, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. Interstitial lung disease is an important identified risk and should be monitored closely and proactively managed.		54 extensively pretreated patients (median, 7.5 prior therapies). Treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis. Although only 16 patients in our study had any prior CDK4/6i therapy, approximately 44% responded to treatment with T-DXd, suggesting that prior CDK4/6i may not interfere with clinical activity of T-DXd. Other HER2-targeted therapies, including trastuzumab and ado-trastuzumab emtansine (T-DM1), which are clinically effective in HER2-positive breast cancer, have, thus far, failed to show activity in the context of HER2-low disease. Confirmed tumor responses were similar in both the HER2 IHC 1+ and IHC 2+ subgroups. Although preliminary, this suggests that HER2 IHC may not be the optimal test to define the lower boundary of expression level needed to predict clinical activity of T-DXd. Between 40% and 50% of patients with breast cancer have tumors with low HER2 expression (defined as IHC 1+ or IHC 2+ and ISH−), which is a heterogeneous population including both luminal-type and triple-negative breast cancers. Trastuzumab deruxtecan is a novel HER2-targeted antibody drug conjugate (ADC) that was designed to effectively deliver a potent topoisomerase I inhibitor payload (an exatecan derivative) to HER2-expressing cancer cells and thereby limit potential systemic toxicity. The payload is linked to a humanized anti-HER2 antibody by a unique cleavable peptide-based linker that is stable in plasma and cleaved by lysosomal cathepsins, which are upregulated in cancer cells. After cleavage, the released drug is cell membrane permeable by design, allowing for a bystander effect in which the released payload can affect tumor cells in close proximity regardless of their HER2 expression status.
HER2-Low Breast Cancer: Pathological and Clinical Landscape	JCO	2020		review																				Discussion about HER2 low breast cancer		The clinical definition of HER2 low is intrinsically dependent on the testing technique and currently can only be applied with the standard IHC/ISH approach, because clear parameters that would define a tumor as HER2 low using other assays have not been formally established.Abundant evidence from studies using frozen tissue suggests a direct relationship between HER2 gene amplification and protein expression, and essentially no protein overexpression is observed in the absence of gene amplification. In the context of HER2-low tumors, RT-qPCR could potentially complement the semiquantitative data obtained by IHC. However, Comparisons with the recommended techniques have yielded conflicting results thus far. Quantitative assays have highlighted a continuous distribution of HER2 expressions in nonamplified BC cells, with higher degrees of expression found in luminal tumors and stem cells.Crosstalk between HER2 and estrogen receptor pathwaysalong with modifications induced by endocrine treatments may promote HER2 protein overexpression as a potential mechanism of tumor adaptation and treatment resistance. Chemotherapy and radiotherapy also upregulate HER2 in HER2-low BC cells, through the activation of the NF-κB pathway. Although preclinical models implicate HER2 as a mechanism of response to several stress stimuli, its oncogenic role in HER2-low BC is still unclear. Thus, evidence to date is insufficient to support defining HER2-low BC as an individual BC subtype with well-characterized features associated with prognosis and responsiveness to therapy. No solid evidence supports HER2-low status as an independent prognostic factor. As a predictive factor and integral biomarker for trial eligibility, patients with centrally determined HER2-low tumors gained no benefit from adjuvant trastuzumab in the phase III NSABP-B47 trial.Another still-underestimated issue of HER2 expression or overexpression in BC is the clinical implication of intratumoral heterogeneity. Besides HER2 overexpression, additional HER2 aberrations have been proved actionable. In particular, approximately 2% of BCs harbor HER2 mutations, which appear to be enriched in HER2-low tumors.
Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER)	Lancet Oncol	2020		2	metastatic BC	HR positive and HER2 positive	who had previously received at least two HER2-targeted therapies for advanced disease	endocrine therapy + targeted therapy	abemaciclib, trastuzumab +- fulvestrant	metastatic	chemotherapy + targeted therapy	chemotherapy + trastuzumab	metastatic	8.3m with fulvestrant, 5.7m without	5.7m		yes with fulvestrant, no without							The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer.		Using genetically engineered mouse models, cell lines, and patient-derived xenografts of HER2-therapy resistant breast cancer, the CDK4 and CDK6 pathway can mediate resistance to HER2-targeted therapies and that this can be overcome by abemaciclib. 237 patients randomized. The confirmed overall responses in both the intention-to-treat population and the subset with measurable disease were more than doubled in group A versus group C. There was no significant improvement in progression-free survival for group B (abemaciclib and trastuzumab) compared with group C (standard-of-care chemotherapy and trastuzumab). Notably, the abemaciclib–trastuzumab doublet (group B) showed similar benefit to that of chemotherapy–trastuzumab (group C), indicating activity for abemaciclib in this patient population. It is reasonable to suppose the superiority of group A compared with group C is owing to the synergism rather than the addition of fulvestrant alone. Abemaciclib was generally well tolerated; however, the incidence of thrombocytopenia was higher than that previously reported in MONARCH 1 and MONARCH 2. Significant detriments in group A compared with group C were reported for nausea and vomiting, and diarrhoea. The detriment reported in diarrhoea was also clinically meaningful and consistent with the adverse event profile.
Expanding the Role for Immunotherapy in Triple-Negative Breast Cancer : discussion about the KEYNOTE-522 pembrolizumab trial	Cancer Cell	2020		editorial	early BC	triple negative		chemotherapy + immunotherapy	pembrolizumab-carbo-taxol followed by EC	neoadjuvant														PD-1 axis blockade, in combination with chemotherapy, improves outcomes in advanced triple-negative breast cancer that is PD-L1 positive. The phase 3 KEYNOTE-522 trial now shows that the addition of pembrolizumab to chemotherapy improves pathological complete response rates regardless of PD-L1 status and appears to improve survival.		discussion about neoadjuvant immunotherapy for early stage TNBC. Mature survival data are awaited to assess the true significance of KEYNOTE- 522, as demonstration of broad efficacy regardless of PD-L1 status would likely cement PD-(L)1 blockade as part of the therapy backbone for early-stage TNBC. Nevertheless, it does not seem premature to conclude that KEYNOTE- 522 and related studies are redefining the treatment of stage II and III TNBC.
Randomized Trial of Text Messaging to Reduce Early Discontinuation of Adjuvant Aromatase Inhibitor Therapy in Women With Early-Stage Breast Cancer: SWOG S1105	JCO	2020		3	early BC	RH pos	postmenopausal women on AI	motivational intervention	text messaging															first large, long-term, randomized trial of an intervention directed at improving AI adherence. We found high rates of AI AF. Twice-weekly text reminders did not improve adherence to AIs. Improving long-term adherence will likely require personalized and sustained behavioral interventions.		Test messages were sent twice a week over 36 months. Content themes focused on overcoming barriers to medication adherence and included cues to action, statements related to medication efficacy, and reinforcements of the recommendation to take AIs. The primary outcome was time to adherence failure (AF), where AF was defined as urine AI metabolite assay results satisfying one of the following: < 10 ng/mL, undetectable, or no submitted specimen. Observed adherence at 36 months was 55.5% for TM and 55.4% for No-TM. A predetermined set of 40 text messages was developed from focus groups and a review of the literature; these messages had multiple formats, each with 160 characters or less. Content themes focused on overcoming potential barriers to medication adherence and included cues to action, statements related to the efficacy of the medication, reinforcements of the physician’s recommendation to take this medication, and words of support and encouragement. The primary analysis showed no difference in time to AF by arm (3-year AF: 81.9% TM v 85.6% No-TM; HR, 0.89 [95% CI, 0.76 to 1.05]; P = .18). the simple receipt of text messages represents a passive experience for patients, and the messages themselves may become repetitive. Thus, the unidirectional text-messaging intervention used in this study that did not actively engage the patient may have been insufficient to produce behavioral change. A review of interventional trials to improve medication adherence stressed that reminders are most effective when personalized and interactive. In addition, it has been reported that the primary reason for AI discontinuation is musculoskeletal symptoms. Although the text messages directed patients to inform their provider if they developed adverse effects, the current treatments for AI arthralgias are limited.
Avoiding Peg-Filgrastim Prophylaxis During the Paclitaxel Portion of the Dose-Dense Doxorubicin-Cyclophosphamide and Paclitaxel Regimen: A Prospective Study	JCO	2020		2	early BC		stage I to III	omission of G-CSF support during paclitaxel	4x epirubicine-cyclophosphamide dose dense with peg-filgastrim - paclitaxel (175 mg/m² 1x/2 weeks) without peg-filgastrim	neoadjuvant or adjuvant				90% completed dose-dense paclitaxel within 7 weeks. 6.4% received peg-filgrastim during the trial.										Omission of routine peg-filgrastim during dose-dense paclitaxel according to a prespecified algorithm seems to be safe and feasible and was associated with a 95.7% reduction in the use of peg-filgrastim relative to the current standard of care. Omission of peg-filgrastim was not causally related to noncompletion of paclitaxel in any patients. The most common reasons for dose reduction or delays were nonhematologic. Implementation of the algorithm tested in this prospective study has the potential to reduce health care costs in the setting of dose-dense paclitaxel.		CALGB) 9741 clinical trial established the superiority of a dose-dense, every-2-week schedule of 4 cycles of AC followed by 4 cycles of paclitaxel, compared with an every-3-week schedule of the same drugs, in the adjuvant treatment of patients with node-positive breast cancer, and filgrastim support was administered routinely on days 3-10 in all cycles, to allow for every-2-week chemotherapy administration (both AC and paclitaxel). G-CSF adds a considerable (up to 20-fold) increase in the costs of the dose-dense AC-paclitaxel regimen compared to the once-weekly paclitaxel regimen. CALGB 40101 trial showed that the incidence of any grade 3 or higher hematologic toxicity was considerably higher in the AC arms compared with the paclitaxel arms. This trial prospectively tested the feasibility and safety of omitting the routine use of prophylactic peg-filgrastim during the paclitaxel portion of the dose-dense AC-paclitaxel regimen for stage I-III breast cancer. OF NOTE, patients with a history of previous chemotherapy, receiving immunosuppressive medications, with abnormal liver or renal function and individuals older than 65 years were excluded given a higher risk of neutropenia.
Who Benefits from Herceptin and Other Anti-HER2 Cancer Therapies?	The Scientist	2020		review		HER2 positive			anti HER2															HER2-positive breast cancer may be a misnomer, according to a growing body of evidence that one of the most widely recognized oncogenes, HER2, may not be the primary driver of the disease. The research, which comes from several groups including Genentech, makers of the prevailing anti-HER2 treatment, has researchers questioning whether current clinical guidelines for classifying and treating breast cancer may be off the mark. New classification schemes may better identify those patients more likely to benefit from anti-HER2 treatment, or point to therapies that might be more effective.
Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients	Annals of Oncology	2020		cohort study	metastatic BC			MSK-IMPACT targeted DNAseq and MSK-Fusion targeted RNAseq																Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.		27 of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit. Kinase fusions occur in both ductal and lobular tumors and are not mutually exclusive with common BC mutations such as PIK3CA or AKT1 mutations. kinase fusions may represent another mechanism of MAPK pathway-mediated resistance separate from direct reactivation of ER activity. Typically, kinase fusions like other strong MAPK pathway drivers such as KRAS exon 2 and BRAF p.V600E mutations are thought to be present early and clonally in a malignancy as ‘drivers’. The current paper highlights a unique scenario in which kinase fusions develop later in the course of disease, likely under selective pressure during ET.
Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer	Ann Oncol	2020		3	metastatic BC	HR pos HER2 neg	previously treated with endocrine therapy	endocrine therapy + targeted therapy	fulvestrant + alpelisib	metastatic	endocrine therapy	fulvestrant	metastatic											Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management.		initial occurrences of both higher-grade hyperglycemia and rash were observed within the first 2 weeks of therapy, whereas diarrhea was seen over the course of the treatment. Iinsulin sensitizers (e.g. metformin) may be preferable to insulin secretagogues (e.g. sulfonylurea, meglitinides) to manage hyperglycemia in patients treated with alpelisib due to the insulin spikes and relative resistance noted with PI3K inhibitors. The decrease in incidence of grade 3/4 hyperglycemia and rash may be attributed to the protocol amendment, as well as other factors, such as earlier identification and appropriate management of AESIs. Prophylactic management (antihistamines, steroids) also had a positive impact on the incidence and severity of rash. The previously reported PFS benefit of alpelisib plus fulvestrant over placebo was evident even at lower median dose intensities of alpelisib. However, higher dose intensities resulted in relatively longer benefits, supporting the need for optimal AE management in the effort to maintain the highest possible dose intensities. A gradual increase in HbA1c was observed with alpelisib, irrespective of baseline glycemic status, and remained slightly elevated throughout study treatment. All patients who developed hyperglycemia had grade 0 or 1 hyperglycemia following discontinuation of alpelisib. Among the patients with prediabetic baseline status randomly assigned to receive alpelisib plus fulvestrant, 74% experienced hyperglycemia during study treatment (grade 3, 43.4%; grade 4, 5.0%) compared with 52% of the patients with normal baseline glycemic status (grade 3, 16.8%; grade 4, 1.8%).
Eliminating the breast cancer surgery paradigm after neoadjuvant systemic therapy: current evidence and future challenges	Ann Oncol	2020		review	early BC		neoadjuvant chemotherapy																	Our goal is to do no harm to patients while continuing to de-escalate surgery and increase quality of life, but achieving this goal can be challenging in breast surgical management after NST. We believe that there may exist a subgroup of breast cancer patients who derive no benefit from breast surgery after NST. However, at present, no definitive evidence is available with which to resolve our questions, and it remains a worthy challenge to conduct high-quality clinical trials necessary to develop such evidence. In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about ‘response-adjusted’ surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?		To quantify the sampling error to rule out residual disease (i.e. to predict pCR), we propose the false-negative rate (1-sensitivity) as the primary outcome measure of such a diagnostic tool. It may not be necessary to be 100% certain that no residual disease remains at all, particularly if adjuvant radiation treatment and/or further systemic treatment will be delivered. In the sentinel node trials, an FNR of 10% did not translate into a worse local and overall survival. Specificity is also relevant when considering this new paradigm shift: the diagnostic tool should validly identify as many pCR patients as possible to be clinically relevant. Multiple small prospective and retrospective trials have yielded different but in sum mediocre results regarding the diagnostic accuracy of imaging (MRI, PET CT) in identifying residual disease after NST. Future trials might also consider the use of biomarkers besides image-guided biopsies to predict pCR without surgery as they could further improve the diagnostic accuracy. Diffuse cell loss is associated with a greater likelihood of in-breast tumor recurrence and makes the identification of residual disease after NST more difficult. Could a no-surgery strategy therefore be acceptable in breast cancer patients in whom all available evidence points toward a complete response after NST? It seems very unlikely that breast cancer patients with an apparent complete response to NST would experience distant relapses, but minimal residual disease could be missed and might lead to local recurrence or regrowth. The frequency and the effect of missed minimal residual disease in the breast on distant relapses and death are unknown but this scenario might be comparable to patients presenting with occult breast cancer (= reportedly equivalent to other breast cancer patients). Clinical trials to examine de-escalation of surgical management in breast cancer patients with an excellent response to NST may be very challenging with respect to sample size. The aim is to address one major question: whether breast surgery can be safely omitted after NST in patients with an excellent, image-guided biopsy–‘proven’ complete response. To answer this question, we should design a trial comparing two strategies after NST: (i) standard therapy being surgery plus radiation treatment, (ii) no breast surgery but standard radiation treatment.
Expanding the landscape of actionable genomic alterations in metastatic breast cancer: comprehensive genomic profiling for all?	Ann Oncol	2020		editorial	metastatic BC																			Based on the rarity and diversity of kinase fusions in BC, testing for individual fusions using immunohistochemistry or FISH is probably not justified apart from the ETV6-NTRK3 fusion in secretory carcinoma of the breast, and would lead to depletion of tumor material with the increasing number of assays. At this point in time, most therapies targeting kinase fusions are either still in clinical development or approved in tumor types other than BC and thus not available for routine clinical practice. Taken together, at this time, the clinical utility of NGS-based fusion gene testing might not yet be sufficiently convincing for reimbursement in Europe. It should, however, be noted that advancing techniques might soon allow for fusion gene detection in the context of already carried out gene panel sequencing at limited additional costs. Until that moment, large molecular screening programs providing comprehensive genomic profiling of breast tumors will be paramount for the enrollment of patients with tumors harboring rare genetic alterations in (‘basket’) trials, allowing us to advance knowledge and eventually impact clinical practice.		discussion about the paper " Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients"
Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial	JCO	2020		3	metastatic BC	HER2 pos	Patients with brain metastases, previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. patients who had received lapatinib more than 12 months before initiating a trial regimen were eligible.	chemotherapy + dual targeted therapy	capecitabine 1000 mg/m² + trastuzumab + tucatinib (300 mg po 2x/d continuously)	metastatic	chemotherapy + targeted therapy	capecitabine 1000 mg/m² + trastuzumab	metastatic	9.9m CNS-PFS	4.2m CNS-PFS	0.32	yes	18m	12m	0.58	yes			In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.		291 pts with BMs. Intracranial ORR was higher in the tucatinib arm (47.3% vs 20%). Small-molecule HER2 kinase inhibitors have the potential to penetrate the brain more effectively. Tucatinib is a small-molecule oral tyrosine kinase inhibitor (TKI) that is highly selective for HER2, with demonstrated antitumor activity alone and in combination with other HER2-targeting agents. A unique subset was the group of 66 patients with untreated BMs who elected to enter HER2CLIMB in lieu of radiation therapy. Although the overall numbers were small, median CNS-PFS was 8.1 months in the tucatinib arm, suggesting this strategy merits further exploration, because it may delay the need for radiation therapy. Patients with isolated progression in the brain could continue study-assigned, blinded therapy after local management with radiation therapy or surgery. Although only 30 patients continued on trial after local therapy, median time from progression in the brain to second progression (brain or body) or death in these patients was 4.5 months longer in the tucatinib arm compared with the control arm, suggesting that continuation of tucatinib after cranial radiation therapy may delay subsequent disease progression.
The link between kidney disease and cancer: complications and treatment	Lancet	2020		review																				Acute and chronic kidney disease encompasses a complex set of diseases that can both lead to, and result from, cancer. In particular, kidney disease can arise from the use of chemotherapeutic agents. Many of the current and newly developed cancer chemotherapeutic agents are nephrotoxic and can promote kidney dysfunction, which frequently manifests during the terminal stages of cancer. Given the link between kidney disease and cancer development and treatment, the aim of this Review is to highlight the importance of multidisciplinary collaboration between oncologists and nephrologists to predict and prevent chemotherapeutic-induced nephrotoxicity. As new therapies are introduced to treat cancer, new renal toxicities require proper diagnosis and management. We anticipate that multidisciplinary collaborations will lead to the development and implementation of guidelines for clinicians to improve the therapeutic management of patients with both cancer and renal impairment.
Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk	JCO	2020		cohort study	early BC	HR pos	premenopausal women																	Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.		Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (HR 2.3, p=0.03)
A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study	Ann Oncol	2019		2	early BC	triple negative	cT2-cT4a-d	chemotherapy + immunotherapy	nabpaclitaxel-durvalumab followed by EC	neoadjuvant	chemotherapy	nabpaclitaxel-placebo followed by EC	neoadjuvant	53% pCR, 61% in the window part	44% pCR, 41% in the window part		no (yes for the window part)							The addition of durvalumab to chemotherapy did numerically but not statistically significantly increase the pCR rate in the whole study population, with significance only in the subgroup of patients who received durvalumab alone 2 weeks before start of chemotherapy. Based on these results priming with durvalumab seems warranted for investigation in future trials. It supports further investigation of durvalumab as treatment of early TNBC patients with higher tumour load as pCR in small tumours is often achieved with chemotherapy alone.		Windows phase for part of study : durvalumab given 2 weeks before start of nab-paclitaxel. 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. In both arms, significantly increased pCR (P< 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P= 0.045) and for PD-L1-immune cell in placebo arm (P= 0.040). it is not clear if this effect is due to immunological interactions in the window-phase or due to different patient characteristics in the window and non-window cohort. The non-window cohort had fewer patients with stage IIA and higher as well as with lymph-node involvement. Only sTILs but not iTILs before therapy predicted a higher pCR rate overall and in both therapy groups. However, sTILs were not specifically predictive for durvalumab response. It should be noted that the sTIL rate was lower compare to other cohorts. An increase of iTILs in post-window samples compared with pre-therapeutic samples was predictive of pCR specifically in the durvalumab arm.
Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo	Ann Oncol	2020		2	early BC	triple negative	cT2-cT4a-d	chemotherapy + immunotherapy	nabpaclitaxel-durvalumab followed by EC	neoadjuvant	chemotherapy	nabpaclitaxel-placebo followed by EC	neoadjuvant											TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.		Median TMB was 1.52 mut/Mb (range 0.02–7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). Both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP.
Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial	Ann Oncol	2020		2	early BC	HER2 positive	after 1 year of trastuzumab	targeted therapy + diarrheal prophylaxis	neratinib + loperamide ; loperamide + budesonide ; loperamide + colestipol ; loperamide as needed + colestipol ; neratinib dose-escalation	adjuvant				G3 diarrhea 31% ; 28% ; 21% ; 32% ; 15%										Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period.		in ExteNET, 40% of patients developed grade 3 diarrhea. As most diarrhea events with neratinib occur early during treatment (median onset of grade ≥3 diarrhea 8 days), structured intensive prophylaxis with loperamide during months 1–2 of neratinib treatment has been used to ameliorate diarrhea. Preclinical studies suggest that neratinib-associated diarrhea may be caused by multiple factors with possible inflammatory and secretory etiologies. Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0–2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Nausea and constipation were the next most common treatment-emergent AEs in CONTROL. DE substantially lowered the rate of constipation, from 57% and 75% of patients in the L and BL cohorts, respectively, to 33% in the DE cohort.
Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases	Ann Oncol	2020		1	metastatic BC	HER2 positive	progressive, measurable HER2 positive brain metastases	targeted therapy	tucatinib + trastuzumab	metastatic														The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases.		Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). There was a modest rate of CNS objective response and notable rate of disease stabilization in a heavily pretreated population including in patients with prior exposure to lapatinib and/or neratinib. This complements the HER2CLIMB study in that it provides efficacy and safety data for the use of tucatinib and trastuzumab without capecitabine, including the intracranial activity of tucatinib in patients with active/progressive brain metastases. Because patients did not receive concomitant chemotherapy, we can attribute the observed intracranial responses to tucatinib.
Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients : RESPECT trial	JCO	2020			early BC	HER2 positive	stage I to IIIA , patients aged 70-80 years old	targeted therapy	trastuzumab monotherapy	adjuvant	chemotherapy + targeted therapy	trastuzumab + chemotherapy (taxane or EC or AC or CMF or TC or TCH)	adjuvant	89% at 3 years	93% at 3 years	1.36	no							The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients. In subgroup analysis, age > 75 years, PS1, and ER positivity had relatively small influences on the effects of chemotherapy.		275 patients. First randomized prospective adjuvant trial to compare trastuzumab monotherapy with trastuzumab + chemotherapy for HER2-positive breast cancer. Most patients (83.5%) had either stage I or IIA disease, and more than 92% had an ECOG of 0. Common AEs were anorexia (7.4% v 44.3%; P < .0001) and alopecia (2.2% v 71.7%; P < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% (P = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab + chemotherapy; P = .016) and at 1 year (19% v 38%; P = .009). Statistically, RESPECT is underpowered, but it provides clear evidence that eliminating chemotherapy is likely associated with a modest quantifiable increased risk of a DFS event for selected patients, but the risk within the first 3 to 5 years is low in both groups. Thus, a negative impact of monotherapy on survival in this population is likely to be modest.
Are We RESPECTing Older Patients With Breast Cancer?	JCO	2020		editorial	early BC	HER2 positive	stage I to IIIA , patients aged 70-80 years old	targeted therapy	trastuzumab monotherapy	adjuvant	chemotherapy + targeted therapy	trastuzumab + chemotherapy (taxane or EC or AC or CMF or TC or TCH)	adjuvant											On the basis of the results of the RESPECT trial, it is possible to consider that adjuvant trastuzumab monotherapy could be an option for a subset of patients, particularly those who may have a higher risk of toxicity with chemotherapy and those with a lower anatomic risk of disease recurrence (stages I or IIA). It is important to stress, however, that the choice of therapy in older patients should never be made on the basis of age alone. Comprehensive geriatric assessment is the standard of care for evaluation before chemotherapy and should generate a care plan to be implemented during treatment to minimize the risk of complications and maintain QoL and functionality.		discussion about the RESPECT trial and de-escalation HER2 trials (less chemo or shorter treatment duration). The SOFT and TEXT trials provide convincing evidence that clinicians are good at identifying patients who are at low risk of recurrence even without receiving chemotherapy. In the RESPECT trial, physicians enrolled a cohort of selected patients age 70 to 80 years with HER2-positive BC who had a risk of a DFS event that was one quarter of the rate anticipated in the study design. To properly apply findings from de-escalation trials to clinical practice, it is essential to pay attention to the characteristics of the patients who are actually enrolled instead of the eligibility criteria of the trial, as also shown in the APT trial.
A FDA analysis of survival outcomes comparing the Adjuvant Paclitaxel and Trastuzumab trial with an external control from historical clinical trials	Ann Oncol	2020		2	early BC	HER2 positive	cN- ; T < 3 cm	chemotherapy + targeted therapy	paclitaxel and trastuzumab	adjuvant	chemotherapy + targeted therapy	EC-TH or TCH or EC-T	adjuvant	96.5 % iDFS at 5 years	96.6 and 92.9 % iDFS at 5 years in EC-TH and TCH arms			99.3% at 5 years	99 and 97.4 % at 5 years in EC-TH and TCH arms					patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy. Our analysis further supports the benefit of addition of trastuzumab even in de-escalated fashion. Additional analyses were conducted in subgroups defined by primary tumor size (T1mi/T1a/T1b and T1c/T2), and the results were similar to those seen in overall population.		Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected ( n = 1770). Patients were matched (1:1) to patients treated in the APT trial using propensity scores (using covariates of age, tumor stage, estrogen receptor status, progesterone receptor status, and histological grade). The propensity score method is an alternative method for the analysis of nonrandomized cohorts, using existing data and adjusting for selection bias using measured confounders. By matching patient-level data, the balance of patients' baseline characteristics can be examined to provide a measure of similarity between patients in the treatment and control arms.
Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial : IMMU-132-01 basket study.	Ann Oncol	2020		1 - 2	metastatic BC	HR pos, HER2 neg	Progression on endocrine-based therapy and at least one prior chemotherapy for mBC	antibody drug conjugate	sacituzumab govitecan	metastatic				5.5m				12m						SG shows encouraging activity in patients with pretreated HR+/HER2− mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing. Clinical activity seen is encouraging in relation to current standard-of-care chemotherapies in this setting ((ORR ∼9%-32% and PFS ∼3-9 months).		Trop-2-directed ADC with a payload of SN-38, the active metabolite of irinotecan (a topoisomerase 1 inhibitor). SG has a high DAR, utilizing a camptothecin that is more toxic than its prodrug, irinotecan, and having a unique drug-release profile owing to its hydrolyzable linker, which has dual mechanism of action by cytotoxic activity after internalization and tumor kill via a bystander effect, suggesting extracellular release of SN-38 in the tumor microenvironment, which complements intracellular release from internalized SG. 54 women. ORR 31%, median DOR 8.5m. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Consistent with the toxicities expected of irinotecan and its metabolite SN-38, the major toxicities of SG were GI symptoms and hematologic suppression. However, the frequency of grade ≥3 GI toxicity with SG was low, with a reported frequency of nausea, vomiting, and diarrhea of 1.9%, 3.7%, and 7.4%, respectively. There were no grade 4 diarrhea events.
Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2−, Node-Positive, High-Risk, Early Breast Cancer : monarchE	JCO	2020		3	early BC	HR pos, HER2 neg	N2 or N1 with T3, G3 or Ki67 >= 20%	endocrine therapy + targeted therapy	ET 5-10 years + abemaciclib (150 mg bid) 2 years	adjuvant	endocrine therapy	ET 5-10 years	adjuvant	92.2% iDFS at 2 years	88.7% iDFS at 2 years	0.75	0.01							Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2− node-positive EBC at high risk of early recurrence.		5637 patients randomised. The goal in monarchE was to treat the patients with primary endocrine-resistant disease who were likely to experience recurrence earlier in the course of their disease, especially in the first 5 years. Despite 95% of patients having received prior chemotherapy and radiotherapy, the estimated 2-year IDFS rate in the monarchE control arm indicates that 11.3% of patients with high-risk clinicopathological features will develop an invasive disease event within 2 years. The treatment effect was observed in all prespecified subgroups. Among the 43.5% of patients who were premenopausal at diagnosis, there was a significant 37% reduction in the risk of recurrence relative to ET alone. Kaplan-Meier curves for both IDFS and DRFS separate at 9-12 months, which may indicate the need for early treatment of very-high-risk patients who may have subclinical micrometastatic disease at diagnosis. Arthralgia and hot flushes were significantly reduced in those treated with abemaciclib plus ET compared with ET alone (arthralgia, 20.5% v 31.3%; hot flush, 14.1% v 21.0%). This intriguing observation has been reported previously in the PALLET trial (underreporting due to CDK4/6 AEs ?). Two-thirds of participants required dose adjustments, approximately 17% discontinued abemaciclib, and approximately 6% of patients stopped both abemaciclib and endocrine therapy. Although serious adverse events were similarly reported in both arms, venous thromboembolic events and interstitial lung disease were observed in the abemaciclib arm at a 2.5% frequency each. Three-quarters of participants had stage III disease, and the others had stage II (approximately 12% stage IIa). Approximately 60% of participants had N2 disease, and approximately 40% had tumors that were high grade or had a high Ki67. Approximately 45% of monarchE participants were premenopausal. Approximately half of them also received some form of ovarian suppression added to tamoxifen or to an aromatase inhibitor, and adherence data to specific endocrine therapies and associated outcomes have not yet been reported. It is too early to understand the long-term impact from the adjuvant use of CDK4/6 inhibitors in this setting. The biology of early recurrence, such as currently assessed in monarchE, may be quite different from that of late recurrence. Longer follow-up of monarchE is therefore critical to confirm the persistence of the clinical benefit now reported and the proportionality of the annual hazards for recurrence. However undesirable, it is theoretically possible that the IDFS curves could converge with long-term follow-up.
Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors	JCO	2020		review																				We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients’ insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient’s perspectives, are presented in this consensus article.
Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer	JCO	2020			early BC	HER2 positive	stage II or stage III	chemotherapy + targeted therapy	paclitaxel + trastuzumab and lapatinib	neoadjuvant	chemotherapy + targeted therapy	paclitaxel + trastuzumab	neoadjuvant											Dual HER2 blockade with lapatinib added to trastuzumab and chemotherapy demonstrated a significant effect on RFS compared with trastuzumab plus chemotherapy alone, and patients who achieved pCR had significantly better outcomes than patients with RD. However, most patients with RD did not experience relapse, and some pCR patients did experience relapse. Our genomic data suggest that future escalation and de-escalation strategies may benefit from integrating the information provided by clinical parameters, intrinsic subtype, and immune signatures to predict not only response, but also survival.		women whose tumors had pCR to neoadjuvant chemotherapy plus HER2 targeting had significantly better RFS and OS than did women with RD, a finding consistent with many other neoadjuvant trials. Of interest, there was a significant improvement in RFS and OS at 7 years with dual therapy in this trial, a surprising finding given that a large adjuvant trial, ALTTO, which included a lower clinical risk but otherwise similar patient population, demonstrated only a modest and statistically nonsignificant effect (disease-free survival HR, 0.84) of adding lapatinib administered for a longer duration. A trial similar in population and intervention to CALGB 40601, NeoALTTO, found numerically higher but nonsignificant EFS differences with dual therapy (84% v 76%). Accumulating evidence supports the clinical validity of two prognostic biomarkers in HER2-positive breast cancer: intrinsic subtype and immune cell features. The HER2-Enriched subtype, a key and independent predictor of pCR, was also found to be an inverse predictor of RFS.
Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study	Lancet Oncol	2020		1 -2	metastatic BC	HER2 negative	germline BRCA1 or BRCA2 mutated, not more than 2 lines of chemotherapy in metastatic setting	targeted therapy + immunotherapy	olaparib + durvalumab	metastatic				80% disease control at 12 weeks										Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.		34 patients included. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. PD-L1 status did not have an effect on treatment benefit in this study. The median duration of response of 9·2 months and median progression-free survival of 8·2 months with the combination of durvalumab and olaparib were also similar to the median duration of response of 6·4 months and median progression-free survival of 7·0 months with olaparib monotherapy. Although median progression-free survival in the triple-negative breast cancer subgroup was only 4·9 months, which might have been driven by several non-responders with early disease progression, responses were mostly durable. The median duration of response in triple-negative breast cancer patients (ten responders) compares favourably to standard-of-care chemotherapy with or without the addition of immune checkpoint inhibitors. Overall survival was also similar between the triple-negative breast cancer and hormone receptor positive subgroups, despite the poorer prognosis expected for patients with triple-negative breast cancer.
Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial	Lancet Oncol	2020		3	metastatic BC	HER2 negative	BRCA germline mutation, up to two previous lines of chemotherapy for metastatic disease	chemotherapy + targeted therapy	carboplatin AUC6 + paclitaxel 80 mg/m² (3W/4) + veliparib (120 mg bid d-2 to d5) followed by veliparib maintenance (300 mg bid)	metastatic	chemotherapy	carboplatin AUC6 + paclitaxel 80 mg/m² (3W/4)	metastatic	14.5m	12.6m	0.71	yes							The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.		Veliparib selectively inhibits the polymerase activity of PARP without substantial trapping of PARP protein onto DNA damage repair intermediates. This mechanism of action makes veliparib more suitable than other PARP inhibitors to be administered in combination with platinum-based chemotherapy, since PARP trapping has been shown to be associated with myelosuppression. BROCADE3 is the first phase 3 trial to evaluate a PARP inhibitor with platinum doublet chemotherapy for BRCA mutation-associated breast cancer. In subgroup analyses, the progression-free survival benefit was similar in patients with triple-negative breast cancer (PFS 16m, OS 35m) and those with hormone receptor-positive breast cancer (PFS 13m, OS 32m). The most common grade 3 or worse adverse events were neutropenia (81 vs 84%), anemia (42 vs 40%) and thrombocytopenia (40 vs 28%). Discontinuation in fewer than 10% of patients. Dose reductions of veliparib were relatively infrequent; however, dose reductions of carboplatin and paclitaxel were frequent in both groups. During maintenance, the only grade 3 or worse adverse event that occurred more frequently with veliparib versus placebo was nausea, and the only serious adverse event that occurred more frequently was seizure. The clinical significance of the difference in seizure frequency between treatment groups is unclear.
Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial	Lancet Oncol	2020		2	metastatic BC	HER2 positive	previously treated with trastuzumab and a taxane	targeted therapy + immunotherapy	trastuzumab emtansine + durvalumab	metastatic	targeted therapy	trastuzumab emtansine	metastatic	8m	7m	0.82	no							Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer.		More thrombocytopenia, anemia, increased ALT and AST in the immunotherapy group. SAE 33 vs 19%. Too small sample size to analyze results based on PDL1 status. However, other studies in advanced HER2-positive breast cancer suggest that the benefit from PD-(L)1 inhibitors could be restricted to PD-L1-positive disease. Here, other results support the idea that the benefit from atezolizumab plus trastuzumab emtansine is probably dependent on pre-existing immunity.
Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial	Lancet Oncol	2020		3	early BC	HR pos	postmenopausal, operable women	endocrine therapy	letrozole for 14 days before and following surgery	neoadjuvant	placebo			91% at 5 years	90.4% at 5 years	0.92	no							Giving perioperative endocrine therapy with an aromatase inhibitor had no significant effect on long-term outcome. The trial also showed that using Ki67B and aromatase inhibitor on-treatment Ki672w could help guide adjuvant treatment decisions. First, we believe that we have identified a subgroup with a low baseline Ki67 who have a sufficiently good prognosis that the majority will do well on standard endocrine therapy alone (except perhaps for a minority as dictated by other clinical–pathological factors) and who do not require a repeat 2-week biopsy. Second, giving POAI to the subgroup with high baseline Ki67 can differentiate two groups of patients according to their 2-week Ki67 value: those who convert to a low Ki67 might not need anything beyond adjuvant endocrine therapy (taking consideration of other clinical-pathological factors), whereas those with a high Ki67 that has remained high, should be considered for further adjuvant treatments and trials.		POETIC showed no suggestion of long-term outcome improvement with POAI overall or in the node-positive subgroup. On a pragmatic note, it is common practice to start some patients on preoperative endocrine therapy if there has to be a significant delay in surgery for any reason. Despite not showing any statistical evidence of clinical benefit, our results provide reassurance that there is no detriment to this practice. Previously, IMPACT had shown that 2-week on-treatment Ki67 predicted outcome better than baseline and, unlike baseline, was significant in multivariable analysis. POETIC has provided evidence for the clinical validity of on-treatment aromatase inhibitor Ki672W in addition to Ki67B to predict those with high residual risk of recurrence in spite of standard-of-care therapy. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The HER2-positive subgroup was small (10%) with relatively few events. Previously, it had been shown that patients with a low Ki67B have a better prognosis than those with a high Ki67B value. POETIC confirmed this in a larger prospective population, dichotomising Ki67B at 10% with 5-year recurrence risk in HER2-negative patients in the POAI group of 4·4% for low Ki67B and 11·8% for high Ki67B. Patients whose tumours had a high baseline Ki67 in the POAI group, 73% had a low Ki672w 2 weeks after starting treatment; those patients had a better prognosis at 5 years than those who continued to have a high Ki672W (8·4% vs 21·5% 5-year recurrence risk). In the population of of patients non-confounded by chemotherapy, 21% with high Ki67B remained high at surgery (high–high) and those had 11·2% 5-year recurrence risk (arguably meriting chemotherapy in addition), compared with the low–low groups in which recurrence by 5 years was only 1·6% and the high–low group in which recurrence by 5 years was only 2·9% (indicating that additional chemotherapy would be of no clinically relevant benefit). This exploratory outcome must be interpreted with caution but further supports the prognostic value of measuring Ki67 at 2 weeks.
A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study of the Short-HER study with an external evaluation	Lancet Oncol	2020		retrospective	early BC	HER2 positive	node positive, or node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity)	chemotherapy + targeted therapy	anthracycline plus taxane-based combinations with 9 weeks of trastuzumab	adjuvant	chemotherapy + targeted therapy	anthracycline plus taxane-based combinations with 1 year of trastuzumab	adjuvant											The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.		The objective was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1%, 88·9% and 73·9%. In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77) and as group categories (low-risk vs high-risk HR 0·27). 5-year disease-free survival in the HER2DX low-risk group was 93·5% and in the high-risk group was 81·1%.
HER2DX: a tool that might inform treatment choices for HER2-positive breast cancer	Lancet Oncol	2020		editorial	early BC	HER2 positive	node positive, or node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity)	chemotherapy + targeted therapy	anthracycline plus taxane-based combinations with 9 weeks of trastuzumab	adjuvant	chemotherapy + targeted therapy	anthracycline plus taxane-based combinations with 1 year of trastuzumab	adjuvant											It is noteworthy that nearly three-quarters of samples used to develop HER2DX were hormone receptor-positive. Although hormone receptor status was not associated with risk category in the training set, PAM-50 subtype was associated with risk, with a higher proportion of luminal A or B tumours (typically hormone receptor-positive) in the low-risk category and a higher proportion of HER2-enriched tumours in the high-risk category. In the evaluation dataset, both hormone receptor status and PAM-50 subtype were associated with risk category. Evaluation of HER2DX in a larger set of hormone receptor-negative tumours is warranted. Additionally, given the potential cost associated with HER2DX and that the score seems heavily weighted for size, nodal status, and hormonally-related genes, it will also be important for studies to address whether this tool is significantly better than a calculation that incorporates information already clinically available. Finally, as the authors acknowledge, retrospective and prospective validation are clearly warranted before clinical use of the score. These initial results provide early hope for a tool that might help to reduce overtreatment for patients with HER2-positive breast cancer and intelligently refine how we choose specific treatments.		Although hormone receptor co-expression has been considered as a more indolent type of HER2-positive breast cancer, 10-year follow up from the N9831 and B-31 trials indicates a later onset of recurrences, but a similar benefit from the use of trastuzumab for hormone receptor-positive disease. Pathological response to neoadjuvant therapy has been shown to be prognostic and also predicts benefit from adjuvant trastuzumab emtansine. However, the question of whether all patients with HER2-positive breast cancer should be treated with a full course of multidrug therapy to evaluate the need for more therapy has continued the search for a tool, akin to the 21-gene recurrence score for HER2-negative disease, to guide therapy selection for HER2-positive breast cancer. HER2DX aims at predicting survival outcomes in patients with newly diagnosed, HER2-positive breast cancer. The variables comprising this score include nodal and tumour stage, the number of stromal tumour-infiltrating lymphocytes, PAM50 subtypes (HER2-enriched and basal-like vs rest), and 13 genes relating to proliferation and underlying subtype-related biology. The most heavily weighted factors were nodal stage and tumour size.
Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial	JCO	2020		2	metastatic		oligometastatic, all cancer types		standard of care + stereotactic radiotherapy	metastatic		standard of care	metastatic	14% at 4 years	3+ at 4 years		yes	42% at 5 years	18% at 5 years		yes			With extended follow-up, the impact of SABR on OS was larger in magnitude than in the initial analysis and durable over time. There were no new safety signals, and SABR had no detrimental impact on QOL.		99 patients. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16). Median follow-up was 51 months.
Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index : re-analysis of BIG 2-98	JCO	2020		retrospective	early BC		node positive	chemotherapy	docetaxel-containing	adjuvant	chemotherapy	non docetaxel-containing	adjuvant											This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition–based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.		The efficacy of most of the anticancer drugs has not yet been thoroughly and systematically evaluated according to patient adiposity. Therefore, it remains questionable whether the main results from randomized clinical trials for cancer treatment are applicable to the different BMI subgroups. There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Overweight (33% of patients) vs lean (47% of patients) : DFS HR 1.12 (NS) and OS HR 1.27 (S). Obese (19% of patients) vs Lean : DFS HR 1.32 (S) and OS HR 1.63 (S). Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS and OS. When exploring the groups of patients made by the different BMI and ER status categories, it appears that the benefit for docetaxel-based versus non-docetaxel–based treatment could be limited to lean and overweight patients with ER-positive tumors and, possibly, to lean patients with ER-negative tumors but that docetaxel-based treatment could even be detrimental for overweight patients with ER-negative tumors. These results, however, should be taken with caution, given the multiplicity of the tests. The present observations could be explained by the lipophilic nature of docetaxel, which results in a higher volume of distribution and a decreased efficacy at the distant level in patients with increased BMI. No other trial has compared the efficacy of taxane-based versus non-taxane–based regimens in the adjuvant setting without an upfront capping of the BSA in heavier patients to calculate the chemotherapeutic doses to be administered.
Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial	JCO	2020		2			medication-related osteonecrosis of the jaw	targeted therapy	teriparatide		placebo			45% resolution at 1 year	33% resolution at 1 year		yes							Teriparatide improves the rate of resolution of MRONJ lesions and represents an efficacious and safe treatment for it.		Teriparatide is a peptide corresponding to the first 34 amino acids of human parathyroid hormone. It has been approved for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture and in glucocorticoid-induced osteoporosis. The rationale for using PTH for osteoporosis comes from studies that show dual effects of this hormone, which has a negative effect if administrated continuously (as in hyperparathyroidism), whereas it acts as a bone anabolic if given intermittently at low doses. Teriparatide was also associated with reduced bony defects at week 52 (OR, 8.1; P = .017). The incidence of adverse events was balanced between groups, including nausea, anorexia, and musculoskeletal pain, most of mild severity. Data from this study may generate enthusiasm, but it should be balanced against the contraindications for the use of teriparatide in patients who have had previous skeleton irradiation or bone malignancies (potential carcinogenic effect?). Another potential concern is that the potent anabolic effect played by teriparatide may induce proliferation of dormant malignant cells within the bone, thus stimulating the occurrence of active malignant bone disease.
Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations	JCO	2020		retrospective	early BC		young (< 40) and BRCA1 or BRCA2 germline mutation																	Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.		811 patients with BRCA1 mutation, 430 with BRCA2 mutation. Pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). 8% of induced abortion and 10% of miscarriages. 77% gave birth, with 11% pf pregnancy complications and 1.8% of congenital anomalies, similar to what it seen in the general population. No difference in DFS were or OS were observed between the pregnancy and nonpregnancy cohorts, both by Cox modeling as by case-control analyses.
Long-term Safety of Pregnancy Following Breast Cancer According to Estrogen Receptor Status	JNCI	2018		retrospective case-control study	early BC																			This study provides reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those with ER-positive disease.		Women who had a pregnancy after breast cancer (pregnant cohort) were matched (1:3) to nonpregnant patients (nonpregnant cohort) according to ER status, nodal status, adjuvant treatments, age, and year of diagnosis. The median follow-up was 9.6 years from breast cancer diagnosis (7.2 years after pregnancy). No DFS difference was shown between the pregnant and nonpregnant cohorts in ER-positive or ER-negative patients. Similarly, there was no OS difference between the two cohorts in ER-positive patients. Yet, a better OS was observed in the pregnant cohort for ER-negative patients. As compared with matched women from the nonpregnant cohort, no difference in DFS was observed in patients who completed their pregnancy nor in those who had an abortion. Pregnancy should not be discouraged after breast cancer, even in women with history of ER-positive disease. Timing of pregnancy does not appear to have a major impact on outcomes. These findings suggest that an individualized approach should be adopted taking into account parameters including patient’s age, risk of recurrence, adjuvant therapy, and ovarian reserve. Physicians’ and patients’ fear toward a possible detrimental effect of pregnancy after breast cancer might partially explain the high rate of induced abortion observed in this study (approximately 30%) as well as others. However, these confirm that abortion does not influence patients’ survival, underscoring that it should not be promoted for therapeutic purposes. This remains the only report addressing the safety of breastfeeding after breast cancer. As compared with matched women from the nonpregnant cohort, no difference in DFS was observed in patients who breastfed their newborns or in those who did not.
Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial	JCO	2020		3	metastatic BC	HER2 positive	at least 2 previous HER2 directed therapies	chemotherapy + targeted therapy	capecitabine + neratinib	metastatic	chemotherapy + targeted therapy	capecitabine + lapatinib	metastatic	8.8m	6.6m	0.76	yes	24m	22m	0.88	no			N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.		2.2-month mean PFS improvement without a significant benefit in OS. Significantly fewer patients in N+C versus L+C required intervention for CNS disease, suggesting prevention of—or delayed time to development of—CNS disease. The largely indistinguishable PFS curves up until 24 weeks suggest a group of patients resistant to HER2-directed therapies, capecitabine, or both, with patients having received ≥ 2 lines of HER2-directed therapies in the metastatic setting. Patients in NALA who had hormone receptor–negative disease derived the greatest PFS benefit from N+C, consistent with the neoadjuvant I-SPY study, but in contrast to the extended adjuvant ExteNET trial, which showed a greater benefit in hormone receptor–positive disease : estrogen-receptor signaling may be activated with inhibition of HER2 alone. The ExteNET study in the early-disease setting permitted endocrine therapy in hormone receptor–positive patients, whereas NALA and I-SPY, which combined neratinib with a chemotherapeutic agent, did not include concomitant endocrine therapy for hormone receptor–positive disease, as this is not recommended in the advanced setting. Fewer patients in N+C versus L+C required intervention for CNS metastases (cumulative incidence of intervention, 22.8% v 29.2%, respectively). This is consistent with findings from NEfERT-T, which reported a benefit for neratinib in patients with CNS metastases and TBCRC 022, which showed activity against refractory HER2-positive breast cancer brain metastases. Diarrhea was managed with mandatory prophylaxis in cycle 1 and loperamide as needed thereafter and was less severe than observed previously (24% grade 3 diarrhea with N+C in NALA v 30% in NEfERT-T and 40% in ExteNET. The duration of grade 3 diarrhea and rate of diarrhea-related discontinuations (N+C 2.6% v L+C 2.3%) were similar between groups.
Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor–Positive, ERBB2-Negative Advanced Breast Cancer	JAMA Oncol	2021		2	metastatic BC	RH pos HER2 neg	first line	endocrine therapy + targeted therapy	letrozole + palbociclib	metastatic	endocrine therapy + targeted therapy	fulvestrant + palbociclib	metastatic	32.8	27.9	1.13	no							Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor–positive, ERBB2-negative advanced breast cancer.
Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer : I-SPY2	JAMA Oncol	2021		2	early BC		stage 2/3 breast cancer at high risk of early recurrence	chemotherapy + targeted therapy	paclitaxel + investigational agent followed by AC	neoadjuvant	chemotherapy	paclitaxel - AC	neoadjuvant											In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy.		Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (RH+ HER2- HR 1.75 ; RH+ HER2+ HR 1.55 ; RH- HER2+ HR 2.39 ; RH- HER2- HR 1.99). Prognostic information from RCB was similar from treatments that graduated or were control. Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis.
Impact of RxPONDER and monarchE on the Surgical Management of the Axilla in Patients With Breast Cancer	JCO	2022		editorial	early BC	RH pos HER2 neg																		RxPONDER and monarchE were important studies to define systemic therapy in patients with HR+/HER2– breast cancer. Although it is questioned whether one should know the absolute extent of nodal disease before implementing these trial data, it is important to recall that these were systemic therapy trials not surgical trials and should be interpreted in the context of nodal burden as determined by current surgical management of the axilla that has been defined by the conduct of prospective, randomized studies addressing that specific question. Although a minority of patients may be understaged by not having an ALND performed, the totality of the data suggests that this does not mean they are undertreated. Although ALND may be considered in individual patients being managed by a multidisciplinary team, we suggest that routine ALND is not indicated to safely apply the results of RxPONDER or monarchE to determine systemic therapy recommendations for patients with HR+/HER2– breast cancer.		On the basis of Z0011 and AMAROS demonstrating no benefit with respect to survival or local control, the majority of early stage, clinically node-negative HR+/HER2– patients undergo SLNB alone in the setting of 1-2 positive nodes. The RxPONDER and monarchE results have caused some to question whether ALND is necessary to quantify the exact number of positive nodes to appropriately tailor systemic therapy recommendations. On the basis of the findings from RxPONDER, chemotherapy is not indicated in postmenopausal patients with 1-3 positive node HR+/HER2– breast cancer and a RS of ≤ 25. For premenopausal patients, some have concluded that chemotherapy should be advised for patients with 1-3 positive nodes regardless of the RS. Our group at the Dana-Farber Brigham Cancer Center has interpreted the data to support consideration for either chemotherapy or ovarian suppression with an aromatase inhibitor (on the basis of the results of the SOFT and TEXT trials), with the decision being based on risk defined by the RS and clinical risk including tumor size, grade, and nodal burden. Additional data regarding the likelihood of axillary metastases in patients with a clinically negative examination come from Memorial Sloan Kettering. In a cohort of 5,142 patients, a positive SLN was identified in 25%: 19% with a macrometastasis and 6% with a micrometastasis. ALND was performed in 1,314 patients with a positive SLN and 84% had 1-3 positive nodes and 16% had ≥ 4 positive nodes. Investigators from Memorial have also shown that the likelihood of significant nodal disease varies with subtype; among 11,596 patients treated from 1998 to 2010, ≥ 4 positive nodes were identified in 9% with HR+/HER2– breast cancer compared with 16% with HR+/HER2+, 22% with HR–/HER2+, and 13% with HR–/HER2– disease. In MonarchE, patients with 1-3 positive nodes were required to meet additional criteria for high-risk disease. The role of abemaciclib in lower risk patients has not been studied. It could, therefore, be considered that ALND should be performed in any patient with 1-3 positive nodes that does not meet any of those additional criteria. At Dana-Farber, 887 patients with HR+/HER2– breast cancer who underwent up-front surgery or received neoadjuvant chemotherapy and had 1-3 positive SLNs treated between January 2016 and June 2021, 265 (29.8%) did not meet the definition of high-risk on the basis of tumor size or grade. An ALND was performed in 35 with eight having a total of ≥ 4 positive nodes.
Atezolizumab With Neoadjuvant Anti–Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial	JCO	2022		3	early BC	HER2 positive	T2-4, N1-3, M0	chemotherapy + targeted therapy + immunotherapy	atezolizumab with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel-trastuzumab-pertuzumab	neoadjuvant	chemotherapy + targeted therapy	dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel-trastuzumab-pertuzumab	neoadjuvant	62% pCR overall (72% in PDL1 pos)	62% pCR overall (64% in PDL1 pos)		no, also for PDL1 pos							Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide–paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1–positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.		After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. despite the use of ado-trastuzumab emtansine in patients with residual disease, > 10% experience relapse after approximately 3.5 years, emphasizing the need to improve pCR rates and outcomes for high-risk, HER2-positive EBC. Preclinical data provide a strong rationale for combining cancer immunotherapy with HER2-targeted therapy in HER2-positive BC. This is the first phase III study to report data on cancer immunotherapy in HER2-positive EBC. pCR rates with PH and chemotherapy were high and in accordance with study expectations. Although achieving a pCR has been associated with significantly improved long-term outcomes (eg, EFS, overall survival [OS]) in patients with HER2-positive EBC receiving neoadjuvant anti–HER2-based therapy, there may be a long-term impact of cancer immunotherapy even with no pCR improvement, given the time required for cancer immunotherapy to exert an antitumor immune response (GeparNuevo, Keynote 522 as seminal examples). As observed previously, patients with tumors either hormone receptor–positive, HER2 IHC 2+, or PIK3CA-mutated tended to have lower pCR rates in IMpassion050, compared with those with hormone receptor-negative, HER2 IHC 3+, or PIK3CA-wild-type tumors, respectively, potentially reflecting lower addiction to the HER2 pathway and/or intrinsic resistance to anti-HER2 therapies.
https://ascopubs.org/doi/abs/10.1200/PO.22.00009	JCO	2022		3	early BC		axillary node dissection	prophylactic compression sleeves		adjuvant							yes							Prophylactic use of compression sleeves compared with the control group reduced and delayed the occurrence of arm swelling in women at high risk for lymphedema in the first year after surgery for breast cancer.		The HR for developing arm swelling in the compression group relative to the control group was 0.61 (95% CI, 0.43 to 0.85; P = .004) on the basis of BIS and 0.56 (95% CI, 0.33 to 0.96; P = .034) on the basis of RAVI. The estimated cumulative incidence of arm swelling at 1 year was lower in the compression group than the control group on the basis of BIS (42% v 52%) and RAVI (14% v 25%). HRs for time from baseline to the first change of the minimally important difference were not statistically significant for any of the four scales of EORTC QLQ-30 and BR23 questionnaires.
Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice	JCO PO	2022		review	metastatic BC	RH pos HER2 neg																		there are a number of promising biomarkers at baseline and several dynamic biomarkers that might predict response to CDK4/6 inhibitors. Validation of these findings and assessment of clinical utility are crucial to make the final translation to clinical practice. Better understanding of disease heterogeneity and further elucidation of resistance mechanisms could inform future studies of rationally selected biomarkers. Retinoblastoma protein status and cyclin E1 mRNA expression were promising baseline biomarkers, whereas PIK3CA circulating tumor DNA ratio on treatment relative to baseline, change in plasma thymidine kinase activity, and circulating tumor cell count were potential dynamic biomarkers of response. A number of biomarkers were unsuccessful, despite a strong mechanistic rationale, and others are still being explored.
Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer	JCO PO	2022		translational	metastatic BC																			We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests (n= 300 patients). Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame.
Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results	JCO	2022		3	metastatic BC	HER2 positive		chemotherapy + targeted therapy	margetuximab + chemotherapy	metastatic	chemotherapy + targeted therapy	trastuzumab + chemotherapy	metastatic	5.8	4.9	0.76	yes	21.6m	21.9m	0.95	no			the final OS analysis after 385 deaths in the ITT population did not demonstrate a survival advantage for margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy in patients with pretreated HER2+ advanced BC.		Margetuximab-cmkb is an Fc-engineered anti–human epidermal growth factor receptor 2 (anti-HER2) immunoglobulin G monoclonal antibody that targets the same epitope as trastuzumab. Compared with trastuzumab, margetuximab was designed to increase binding affinity (in vitro) for activating Fcγ receptor (FcγR) CD16A (FcγRIIIa) and decrease binding affinity for inhibitory FcγR CD32B (FcγRIIb). Margetuximab has improved binding affinity for both polymorphic allelic variants (158V or 158F) of CD16A, binds CD16A-158F with higher affinity than trastuzumab binds CD16A-158V, and enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. The prespecified non–α-allocated evaluation of FcγR allelic variation on efficacy including an analysis of CD16A genotypes (FF, FV, and VV) suggested a possible improvement in OS in favor of margetuximab in the CD16A-158FF patients, along with a possible improvement in OS in favor of trastuzumab in the CD16A-158VV patients. Of note, there was an imbalance in poor prognostic characteristics between the two treatment groups in the CD16A-158VV patients.
Smartphone Psychotherapy Reduces Fear of Cancer Recurrence Among Breast Cancer Survivors: A Fully Decentralized Randomized Controlled Clinical Trial (J-SUPPORT 1703 Study)	JCO	2022		2	early BC		disease free patients aged 20-49 years	smartphone app		adjuvant	control		adjuvant											Novel smartphone psychotherapy offers a promising way to reduce fear of cancer recurrence given the large number of survivors and a limited number of therapists to competently conduct psychotherapy.		Participants were disease-free breast cancer survivors age 20-49 years who were randomly assigned to the smartphone-based intervention or waitlist control. Both groups received treatment as usual. The control group could access the smartphone apps during weeks 8-24. The intervention comprised smartphone problem-solving therapy and behavioral activation apps. The intervention group had statistically greater improvements than controls at week 8 on the Concerns About Recurrence Scale (difference –1.39; 95% CI, –1.93 to –0.85; P < .001), FCRI-SF (difference –1.65; 95% CI, –2.41 to –0.89; P < .001), HADS depression (difference –0.49; 95% CI, –0.98 to 0; P < .05), and SCNS-SF34 psychological domain (difference –1.49; 95% CI, –2.67 to –0.32; P < .05). These scores at week 24 were not statistically significant compared with week 8 although the HADS depression score at week 24 was significantly reduced (P = .03).
Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials	JCO	2022		3	early BC	RH pos		endocrine therapy	OFS + exemestane	adjuvant	endocrine therapy	OFS + tamoxifen	adjuvant	80.5% at 12 years	75.9% at 12 years	0.79	yes	90.8% at 12 years for HER2 neg subgroup	88.8% at 12 years for HER2 neg subgroup	0.85	yes for HER2 neg subgroup			In conclusion, with a 13-year MFU, a reduction not only in recurrences but also in mortality emerged for exemestane + OFS versus tamoxifen + OFS in women with HER2-negative disease, most clinically meaningful for those at higher risk of relapse. No overall survival benefit with exemestane + OFS was evident in women at lower risk of relapse not receiving chemotherapy. Given the burden of treatment intensification on quality of life, proper selection of women most likely to benefit is paramount.		In the ITT population, absolute improvements were retained in both 12-year DFS (+4.6%) and DRFI (+1.8%). Treatment effects on recurrence tended to attenuate over time, being strongest in years 0-5 with no further improvement after ≥ 10 years. Overall survival was excellent with both treatments, not improved by exemestane + OFS (90.1% v 89.1% in patients assigned tamoxifen + OFS); the lack of survival benefit from exemestane + OFS is at least in part attributable to early emergent, persistent favorable outcomes with tamoxifen + OFS in the HER2-positive subgroup. The EBCTCG meta-analysis showed that in premenopausal women receiving OFS, AIs versus tamoxifen reduced the relative risk of recurrence by 21% and of distant recurrence by 17%; no significant difference in breast cancer mortality or overall survival was found, but follow-up beyond 10 years was extremely limited. Meaningful 12-year overall survival improvements in the predominant HER2-negative subgroup were now observed after a 13-year MFU, as high as 3.3% in both chemotherapy cohorts; Women with HER2-negative tumors with high-risk clinicopathologic characteristics experienced the greatest absolute improvements in 12-year overall survival when treated with exemestane + OFS compared with tamoxifen + OFS, ranging 4.0% to 5.5%. Distinct outcomes persisted long term according to the baseline risk of recurrence and the choice to administer chemotherapy or not. The 12-year overall survival > 95% in women selected not to receive adjuvant chemotherapy confirmed that premenopausal patients at lower risk of relapse have excellent long-term outcomes with risk-adapted endocrine therapy even in the presence of node-positive disease (8.3% in SOFT and 20.7% in TEXT).
Clinicopathologic Characteristics and Prognosis of ERBB2-Low Breast Cancer Among Patients in the National Cancer Database	JAMA Oncol	2023		RWE		HER2 negative																		This large-scale retrospective cohort analysis found minimal prognostic differences between ERBB2-low and ERBB2-negative breast cancer. These findings suggest that, moving forward, outcomes in ERBB2-low breast cancer will be driven by ERBB2-directed antibody-drug conjugates, rather than intrinsic differences in biological characteristics associated with low-level ERBB2 expression. These findings do not support the classification of ERBB2-low breast cancer as a unique disease entity.		1 136 016 patients in the US diagnosed with invasive breast cancer from January 1, 2010, to December 31, 2019. A slightly lower rate of pathologic complete response was seen in patients with ERBB2-low disease vs patients with ERBB2-negative disease on multivariable analysis (aOR, 0.89; 95% CI, 0.86-0.92; P < .001). ERBB2-low status was also associated with small improvements in OS for stage III (aHR, 0.92; 95% CI, 0.89-0.96; P < .001) and stage IV (aHR, 0.91; 95% CI, 0.87-0.96; P < .001) triple-negative breast cancer, although this amounted to only a 2.0% (stage III) and 0.4% (stage IV) increase in 5-year OS. Higher estrogen receptor expression was associated with increased rates of ERBB2-low disease (aOR, 1.15 per 10% increase). In contrast to prior work, ERBB2-low disease was associated with lower rates of brain metastasis. Our data suggest that ERBB2-low status alone should not influence neoadjuvant treatment decisions with currently approved regimens in this setting but could perhaps provide an incremental improvement in multivariable or multiomic models for pCR. Whether there is a molecular basis that could explain these subtle differences in survival and chemotherapy responsiveness in ERBB2-low breast cancer remains to be ascertained. Prior studies have found that ERBB2-low cancers have an overrepresentation of the luminal A molecular subtype, which is known to have lower rates of pCR but maintains an excellent prognosis.5,23 Furthermore, ERBB2-low cases may be associated with the luminal androgen receptor (LAR) subtype of TNBC, given higher rates of androgen receptor positivity among ERBB2-low cases28 and high rates of ERBB2-enriched disease by 50-gene signature assay (PAM50) among patients with LAR TNBC.31 Because androgen receptor–positive TNBC has a better prognosis but worse response to chemotherapy, further study is needed to examine how much of the prognostic association of ERBB2-low TNBC is attributable to enrichment for the LAR subtype.
Back to the Beginning: The Role of Ovarian Suppression in Management of Hormone Sensitive Breast Cancer in Premenopausal Women	JCO	2023		editorial																				In the articles that accompany this editorial, SOFT and TEXT investigators report a sustained improvement in long-term outcomes (disease-free survival) and for the first time an improvement in overall survival for premenopausal women with estrogen receptor–positive breast cancer through incorporation of ovarian suppression as a component of endocrine therapy. Based on these data, ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk (ie, grade 3, T2, and age < 35 years) estrogen receptor–positive breast cancer.		Long-term follow-up of trials in premenopausal women with ER-positive breast cancer remains critical because of both propensity for late recurrence and cumulative risk of late toxicities from early menopause. In the articles that accompany this editorial, Pagani et al9 and Francis et al10 report a sustained improvement in DFS at 12 years and, for the first time to our knowledge, an improvement in OS with incorporation of ovarian suppression as a component of endocrine therapy. Not surprisingly, the survival benefit was greatest in patients with a higher risk of recurrence including those with grade 3 tumors (5.5%), tumors > 2 cm (4.5%), diagnosis age < 35 years (4.0%), or prior adjuvant chemotherapy (3.3%). Despite the improvements in DFS, adoption of ovarian suppression as a standard component of adjuvant therapy has been modest. The improvements in OS reported in the SOFT trial, similar in magnitude to the benefit of adjuvant cytotoxic therapy, highlight the profound benefit of optimal hormone therapy. Ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk (ie, grade 3, T2, and age < 35 years) ER-positive breast cancer. We favor a stepwise approach, first initiating and evaluating toxicity with ovarian suppression alone and then adding an aromatase inhibitor. Should toxicity be intolerable, reversion to tamoxifen alone, or with continued ovarian suppression remains an option and is certainly preferable to discontinuation of all antiestrogen therapies. Ovarian suppression should not be considered a mandate for patients with lower risk disease where the long-term toxicities outweigh the benefits.
Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT	JCO	2023		3	early BC	RH pos		endocrine therapy	OFS + tamoxifen	adjuvant	endocrine therapy	tamoxifen	adjuvant	76.1% at 12 years	71.9 % at 12 years	0.82	yes	89% at 12 years	86.8% at 12 years	0.78	yes			after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.		Among those who received prior chemotherapy for human epidermal growth factor receptor-2–negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. Compared with patients assigned tamoxifen, patients assigned tamoxifen plus OFS showed a greater early mortality reduction in the first 5 years, while those assigned exemestane plus OFS showed a later emergence of improved survival. The overall intention-to-treat analysis population was 3,047 women. The median age was 40 years in the cohort who were premenopausal after prior chemotherapy (53.4%), and 46 years in the no-chemotherapy cohort. Most patients (84.9%) had HER2-negative tumors. In the no-chemotherapy cohort, 12-year OS exceeded 95% in all three treatment groups. In patients with grade 3 tumors (n = 642), 12-year OS was 76.4% with tamoxifen alone, 80.8% with tamoxifen plus OFS, and 84.0% with exemestane plus OFS. There continued to be heterogeneity of treatment effect in subgroups defined by HER2 status that suggested greater benefit from the addition of OFS to tamoxifen in HER2-positive tumors. Although overall SOFT did not enroll particularly high-risk patients, there are high-risk subgroups. More than half of the patients who received neoadjuvant chemotherapy experienced recurrence when assigned tamoxifen alone. Almost one in four patients with grade 3 tumors assigned tamoxifen have died. Currently there is no indication of excess noncancer deaths in patients assigned 5 years of OFS in SOFT, notwithstanding quality-of-life effects.
Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials	JCO	2023		3	early BC	RH pos		endocrine therapy	OFS + exemestane	adjuvant	endocrine therapy	OFS + tamoxifen	adjuvant	80.5% at 12 years	75.9% at 12 years	0.79	yes	90.1% at 12 years	89.1% at 12 years	0.93	no			Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS. Women with HER2-negative tumors with high-risk clinicopathologic characteristics experienced the greatest absolute improvements in 12-year overall survival when treated with exemestane + OFS compared with tamoxifen + OFS, ranging 4.0% to 5.5%. with a 13-year MFU, a reduction not only in recurrences but also in mortality emerged for exemestane + OFS versus tamoxifen + OFS in women with HER2-negative disease, most clinically meaningful for those at higher risk of relapse. No overall survival benefit with exemestane + OFS was evident in women at lower risk of relapse not receiving chemotherapy.		4,690 premenopausal women. Most patients (86.0%) had HER2-negative tumors. Deaths without breast cancer or second (nonbreast) cancer (Data Supplement) were rare and not higher with exemestane. Similar findings, reported in the postmenopausal meta-analysis of adjuvant AIs versus tamoxifen,4 contrast data of increased cardiovascular deaths in premenopausal women undergoing oophorectomy7,8 and are reassuring for the safety of 5-year AI + OFS in premenopausal patients. The EBCTCG meta-analysis9 showed that in premenopausal women receiving OFS, AIs versus tamoxifen reduced the relative risk of recurrence by 21% and of distant recurrence by 17%; no significant difference in breast cancer mortality or overall survival was found, but follow-up beyond 10 years was extremely limited. Distinct outcomes persisted long term according to the baseline risk of recurrence and the choice to administer chemotherapy or not. The 12-year overall survival > 95% in women selected not to receive adjuvant chemotherapy confirmed that premenopausal patients at lower risk of relapse have excellent long-term outcomes with risk-adapted endocrine therapy even in the presence of node-positive disease (8.3% in SOFT and 20.7% in TEXT). Meaningful 12-year overall survival improvements in the predominant HER2-negative subgroup were now observed after a 13-year MFU, as high as 3.3% in both chemotherapy cohorts; ongoing follow-up will provide a better assessment of any additional survival benefit.
ESMO Expert Consensus Statements on the management of breast cancer during pregnancy	Ann Onc	2023		guidelines			pregnant women
Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort	Lancet	2010		3	early	HER2 positive AND parallel cohort of HER2 negative	locally advanced or inflammatory breast cancer. Parallel cohort of 99 patients with HER2-negative disease	chemotherapy + anti-HER2	doxorubicin-paclitaxel, then paclitaxel, followed by CMF, + concomitant trastuzumab	neoadjuvant	chemotherapy	doxorubicin-paclitaxel, then paclitaxel, followed by CMF	neoadjuvant	71% at 3 years in HER2 positive	56% at 3 years in HER2 positive	0.59	yes	87% at 3 years in HER2 positive	79% at 3 years in HER2 positive	0.62	no			in patients with HER2-positive locally advanced or inflammatory breast cancer, addition of 1 year of trastuzumab (starting as neoadjuvant and continuing as adjuvant therapy) to neoadjuvant chemotherapy improved overall response rates, almost doubled rates of pathological complete response, and reduced risk of relapse, progression, or death compared with patients who did not receive trastuzumab. We recorded a benefit of trastuzumab in all subgroups tested, including women with inflammatory disease (27% of HER2-positive patients) who benefited substantially from trastuzumab.		Trastuzumab significantly improved rates of pathological complete response in patients with HER2-positive disease (38% vs 19%). Importantly, we did not compare a neoadjuvant plus adjuvant approach with adjuvant treatment alone. Therefore, we cannot conclude that the neoadjuvant component of trastuzumab treatment led to the improvement in event-free survival—the same improvement might have been seen with 1 year of adjuvant trastuzumab alone. Nevertheless, the encouraging improvements in pathological complete response rate seen when neoadjuvant trastuzumab was given in combination with neoadjuvant chemotherapy suggest that this approach has other advantages.