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Background: It is unclear whether some patients with high-risk breast cancer do not warrant adjuvant dose-dense chemotherapy due to small expected absolute benefit., Methods: The phase 3 PANTHER trial (NCT00798070) compared adjuvant sequential epirubicin/cyclophosphamide (EC) and docetaxel (D) administered in either tailored dose-dense (tDD EC/D) or standard interval schedule (FEC/D) to patients with high-risk resected early breast cancer (n = 2003). We compared outcomes across key subgroups of interest, evaluated the performance of the online prognostication and treatment benefit estimation tool PREDICT and conducted a subpopulation treatment effect pattern plot (STEPP) analysis. Primary endpoint was breast cancer recurrence free survival (BCRFS)., Findings: Median follow-up was 10.3 years. Treatment with tDD EC/D improved 10-year BCRFS across all subgroups including according to menopausal status, with an absolute benefit of 2% or more, as well as in luminal (Hazard Ratio [HR] = 0.83, 95% Confidence Interval [CI] 0.65-1.05) and Human Epidermal Growth Factor Receptor 2 (HER2) positive (HR = 0.53, 95% CI 0.30-0.93), but not triple negative breast cancer patients (HR = 1.02, 95% CI 0.66-1.57). PREDICT underestimated overall survival in the entire population and across all subgroups. In STEPP analysis, absolute benefit from tDD EC/D in BCRFS was stable across risk-defined subpopulations, from 3.8% in the lowest risk patients to 3.6% in the highest risk ones. There was no differential treatment effect over time., Interpretation: We could not reliably identify any subgroup not benefiting from dose-dense treatment, which should be considered for patients with primary resected high-risk breast cancer., Funding: Cancerfonden, Bröstcancerförbundet, Radiumhemmets Forskningsfonder, Amgen, Roche, sanofi-aventis., Competing Interests: Alexios Matikas: speaker/consultancy (no personal fees) to Veracyte, Roche, Seagen; research funding paid to institution by Merck, AstraZeneca, Novartis, Veracyte. Sibylle Loibl: employment as Chief Executive Officer (CEO) at German Breast Group (GBG) Forschungs GmbH; institutional fees for advisory board membership for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb (BMS), Celgene, DSI, EirGenix, Gilead, GSK, Lilly, Merck, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi and Seagen; institutional fees as an invited speaker for AstraZeneca, DSI, Gilead, Medscape, Novartis, Pfizer, Roche, Seagen and Stemline-Menarini; institutional research grants from AbbVie, AstraZeneca, BMS/Celgene, Daiichi Sankyo, Immunomedics/Gilead, Molecular Health, Stemline-Menarini, Novartis, Pfizer and Roche; institutional funding from Greenwich Life Sciences; institutional licensing fees from VMscope GmbH; a role as a steering committee member (non-financial interest) for AstraZeneca, Daiichi Sankyo, Immunomedics/Gilead, Novartis, Pfizer, Roche and Seagen; a role as a Principal Investigator (PI) for Pfizer, AstraZeneca (non-financial interest). Günther Steger: personal fees and non-financial support from Roche, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Novartis, personal fees from Lilly, non-financial support from TEVA, personal fees and non-financial support from Pfizer. Michael Untch: personal fees for lectures and/or consultancy from Agendia, AstraZeneca, Daiichi Sankyo, Eisai Gilead, Lilly Deutschland, MSD, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi Aventis, Seagen, Stemline Richard Greil: institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. Michael Gnant: personal fees for advisory board membership for Eli Lilly, MSD, Novartis and Menarini-Stemline; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, EPQ Health, Novartis and Pierre Fabre; personal fees for an expert testimony for Veracyte; membership of the Board of Directors at Austrian Breast and Colorectal Cancer Study Group (ABCSG) GmbH and ABCSG Research Services GmbH; a role as a steering committee member for AstraZeneca (non-financial interest) and Eli Lilly (non-financial interest); a role as trial Chair for Pfizer (non-financial interest); and spouse employment at Sandoz. Theodoros Foukakis: institutional fees for consultancy to AstraZeneca, Daiichi Sankyo, Gilead and Roche; personal fees for consultancy to Affibody, Pfizer, Novartis, Veracyte, Exact Sciences; honoraria from UpToDate; research funding to institution from Pfizer, AstraZeneca, Novartis and Veracyte. Jonas Bergh: research funding to institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche and Sanofi; honoraria from UpToDate paid to Asklepios Cancer Research AB; head of advisory board at Stratipath AB; Coronis and Asklepios Cancer Research AB hold shares of Stratipath AB; honoraria for lectures/educational conferences for postgraduates courses from AstraZeneca paid to Coronis and Asklepios Cancer Research AB. All the other authors had no potential conflicts of interest to disclos, (© 2024 The Author(s).)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported .Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

Purpose: Ki-67 is recommended by international/national guidelines for risk stratification in early breast cancer (EBC), particularly for defining "intermediate risk," despite inter-laboratory/inter-observer variability and cutoff uncertainty. We investigated Ki-67 (> 10%- < 40%, determined locally) as a prognostic marker for intermediate/high risk in EBC, pN0-1 patients., Methods: This prospective, non-interventional, real-world study included females ≥ 18 years, with pN0/pN1mi/pN1, HR+ , HER2-negative EBC, and locally determined Ki-67 ranging 10%-40%. The primary outcome was changes in treatment recommendations after disclosing the Oncotype DX Breast Recurrence Score ® (RS) assay result., Results: The analysis included 567 patients (median age, 57 [range, 29-83] years; 70%/1%/29%/ with pN0/pN1mi/pN1 disease; 81% and 19% with RS results 0-25 and 26-100, respectively). The correlations between local and central Ki-67, local Ki-67, and the RS, and central Ki-67 and the RS results were weak (r = 0.35, r = 0.3, and r = 0.46, respectively), and discrepancies were noted in both directions (e.g., local Ki-67 was lower or higher than central Ki-67). After disclosing the RS, treatment recommendations changed for 190 patients (34%). Changes were observed in pN0 and pN1mi/pN1 patients and in patients with centrally determined Ki-67 ≤ 10% and > 10%. Treatment changes were aligned with RS results (adding chemotherapy for patients with higher RS results, omitting it for lower RS results), and their net result was 8% reduction in adjuvant chemotherapy use (from 32% pre-RS results to 24% post-RS results)., Conclusion: The Oncotype DX ® assay is a tool for individualizing treatments that adds to classic treatment decision factors. The RS result and Ki-67 are not interchangeable, and Ki-67, as well as nodal status, should not be used as gatekeepers for testing eligibility, to avoid under and overtreatment., (© 2024. The Author(s).)

GAIN-2 trial evaluated the optimal intense dose-dense (idd) strategy for high-risk early breast cancer. This study reports the secondary endpoints pathological complete response (pCR) and overall survival (OS). Patients (n = 2887) were randomized 1:1 between idd epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) versus leukocyte nadir-based tailored regimen of dose-dense EC and docetaxel (dtEC-dtD) as adjuvant therapy, with neoadjuvant therapy allowed after amendment. At median follow-up of 6.5 years (overall cohort) and 5.7 years (neoadjuvant cohort, N = 593), both regimens showed comparable 5-year OS rates (iddEnPC 90.8%, dtEC-dtD 90.0%, p = 0.320). In the neoadjuvant setting, iddEnPC yielded a higher pCR rate than dtEC-dtD (51.2% vs. 42.6%, p = 0.045). Patients achieving pCR had significantly improved 5-year iDFS (88.7% vs. 70.1%, HR 0.33, p < 0.001) and OS rates (93.9% vs. 83.1%, HR 0.32, p < 0.001), but OS outcomes were comparable regardless of pCR status. Thus, iddEnPC demonstrates superior pCR rates compared to dtEC-dtD, yet with comparable survival outcomes., (© 2024. The Author(s).)

Introduction: The presence of axillary lymph node involvement is an important prognostic factor and has a major impact on treatment decisions in early breast cancer patients. This study aimed to determine the role of cortical thickness in axillary ultrasound (AUS) as an indicator of lymph node metastasis., Methods: 766 patients with primary breast cancer who received AUS during clinical work-up were selected for this retrospective study. Lymph nodes were defined as suspicious if they showed a cortical thickness of >3.0 mm at 11-15 MHz harmonic imaging ultrasound. Lymph node involvement was assessed by core needle biopsy ( n = 150), sentinel node dissection or axillary dissection. Extensive axillary spread (EAS) was diagnosed if more than two lymph nodes showed metastatic disease in histology., Results: AUS for detecting all lymph node metastases had a sensitivity of 62.27%, a specificity of 93.15% and a negative predictive value of 81.74%. However, the resulting negative predictive value for transcapsular growth was 93.97%, and for EAS 97.52%., Conclusion: EAS - in contrast to non-palpable involvement of 1 or 2 lymph nodes - contributes relevantly to the individualization of breast cancer treatment. In combination with SNB, AUS using cortical thickness as the main distinctive parameter seems to be an easily available, robust tool of diagnosing extensive axillary metastases. If AUS proves negative, it helps to reduce the number of classic axillary dissections., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)

Background: Trastuzumab given intravenously in combination with chemotherapy is standard of care for patients with early HER2-positive breast cancer (BC). Different randomised studies have shown equivalent efficacy of a subcutaneous injection into the thigh compared to the intravenous formulation. Other body regions for injection have not been investigated but might be more convenient for patients., Methods: After surgery, patients were randomised to receive either subcutaneous trastuzumab into the thigh or into the abdominal wall (AW). Patient preferences were evaluated using validated questionnaires (PINT). Primary objectives of this multicentre, non-blinded, randomised substudy of the GAIN-2 study were to investigate pharmacokinetics of the injection into the thigh versus AW and to determine patients' preferences of either administration site versus the previously received intravenous application., Results: 226 patients were randomised and 219 patients (thigh: N = 110; AW: N = 109) formed the modified intent-to-treat (mITT). Overall, 83.5% (out of N = 182 with information about patients' preference) preferred subcutaneous over previous intravenous application or had no preference. Preference was similar between both administration sites (thigh: 80.6%; AW: 86.5; p = 0.322). Pharmacokinetic analysis included 30 patients. Geometric means of C max and AUC 0-21d were higher in thigh than in AW group (geometric mean ratio with body weight adjustment: C max : 1.291, 90%-CI 1.052-1.584; AUC 0-21d : 1.291, 90%-CI 1.026-1.626). Safety profile was in line with previous reports of subcutaneous trastuzumab., Conclusion: Subcutaneous trastuzumab into the thigh showed an approximately 30% higher bioavailability. Injections were well tolerated and preferred over intravenous administration. The subcutaneous injection into the thigh should remain the standard of care., Competing Interests: Declaration of competing interest MR reports travel support from AstraZeneca, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Seagen, Somatex and Roche. MU reports personal fees for lectures and/or consultancy from Abbvie, Amgen, Astra Zeneca, BMS, Celgene, Daiji Sankyo, Gilead, GSK, Lilly, MSD Merck, Mundipharma, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi Aventis, Saegen. MS reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Roche, and SeaGen outside the submitted work. Institutional research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre, and SeaGen; has a patent for EP2390370 B1 issued and a patent for EP2951317 B1issued. SL reports other from Amgen, other from BMS, grants and other from Celgene, grants, non-financial support and other from Roche, during the conduct of the study; grants and other from Abbvie, grants and other from AstraZeneca, other from Eirgenix, other from GSK, grants, non-financial support and other from Gilead, other from Lilly, other from Merck, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, non-financial support and other from Seagen, grants, non-financial support and other from Daiichi-Sankyo, other from Sanofi, outside the submitted work; In addition; has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid. ES reports honoraria from Pfizer, Roche, AstraZeneca, MSD, Gilead, Daiichi-Sankyo, Novartis, Seagen, Lilly, Pierre Fabre. SaS reports grants and non-financial support from F. Hoffman-La Roche, grants from BMS (Celgene), Amgen, during the conduct of the study; personal fees from Abbvie, outside the submitted work. CJ reports Honoraria from Amgen, AstraZeneca, Roche, Lilly, Novartis, Pfizer, Exact Sciences, Pierre-Fabré, Molecular Health. FM reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, EISAI outside the submitted work. CD reports stock and other ownership interest from Sividon Diagnostics (until 2016); consulting or advisor role from MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Merck, Roche, Lilly; research funding from Myriad Genetics, Roche; patents, royalties or other intellectual property from VMScope digital pathology software, patent applications WO2015114146A1 and WO2010076322A1-therapy response, patent application WO2020109570A1-immunotherapy. No other potential conflict of interest relevant to this article was reported., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite the large number of patients with early breast cancer (EBC) who have been treated with capecitabine in randomised trials, no individual patient data meta-analysis has been conducted. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS), and the secondary objectives were to analyse distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and the interaction between capecitabine-related toxicity and treatment effect., Methods: www., Clinicaltrials: gov and www.pubmed.ncbi.nlm.nih.gov were searched using the following criteria: use of capecitabine for EBC as adjuvant or neoadjuvant therapy; multicentre randomised trial with >100 patients; recruitment completed, and outcomes available. Required data were available for 13 trials., Results: Individual data from 15,993 patients were collected. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared with treatment without capecitabine (hazard ratio [HR] 0.952; 95% CI 0.895-1.012; P value = 0.115). There was also no effect on DFS in the subset of studies where capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; P = 0.455). However, capecitabine administered in addition to the standard systemic treatment improved DFS (HR 0.888; 95% CI 0.817-0.965; P = 0.005). An OS improvement was observed in the entire cohort (HR 0.892; 95% CI 0.824-0.965, P = 0.005) and in the subset of capecitabine addition (HR 0.837; 95% CI 0.751, 0.933, P = 0.001). Subgroup analyses revealed that triple-negative breast cancer (TNBC) patients benefitted from treatment with capecitabine overall and in addition to other systemic treatments in terms of DFS and OS., Conclusion: Capecitabine was able to improve DFS and OS in patients with TNBC and in all patients with EBC when administered in addition to systemic treatment., Competing Interests: Conflict of interest statement M.v.M. reports personal fees from AstraZeneca, personal fees from Amgen, personal fees from Novartis, personal fees from Genomic Health, personal fees from Gilead, personal fees from GSK, personal fees from Lilly, personal fees from Molecular Health, personal fees from Mylan, personal fees from Pfizer, personal fees from Roche, personal fees from Pierre Fabre, personal fees from Seagen, outside the submitted work; V.M. reports speaker honoraria from Amgen, AstraZeneca, Celgene, Roche, Teva, consultancy honoraria from Roche, Amgen, TESARO and Myelo Therapeutics; J.O.S. reports personal fees from AbbVie, personal fees from Agendia, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Celgene, personal fees from Eisai, personal fees from Genentech, personal fees from Immunomedics, personal fees from Ipsen, personal fees from Jounce, personal fees from Lilly, personal fees from Merck, personal fees from Myriad, personal fees from Novartis, personal fees from Ondonate Therapeutics, personal fees from Pfizer, personal fees from Puma, personal fees from Roche, personal fees from Seattle Genetics, personal fees from Prime Oncology, outside the submitted work; M.M. has received research grants from Roche, PUMA and Novartis, consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, Daiichi Sankyo and Pfizer and speakers' honoraria from AstraZeneca, Lilly, Amgen, Roche/Genentech, Novartis and Pfizer, outside the submitted work. H.J. reports personal fees from Orion Pharma, personal fees from Neutron Therapeutics, other from Orion Pharma, other from Sartar Therapeutics, outside the submitted work. M.U. reports personal fees and non-financial support from AbbVie, personal fees and non-financial support from Amgen GmbH, personal fees and non-financial support from Astra Zeneca, personal fees from BMS, personal fees and non-financial support from Celgene GmbH, personal fees and non-financial support from Daiichi Sankyo, personal fees and non-financial support from Eisai GmbH, personal fees from Lilly Deutschland, personal fees and non-financial support from Lilly Int., personal fees and non-financial support from MSD Merck, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Myriad Genetics, personal fees and non-financial support from Odonate, personal fees and non-financial support from Pfizer GmbH, personal fees from PUMA Biotechnology, personal fees and non-financial support from Roche Pharma AG, personal fees and non-financial support from Sanofi Aventis Deutschland GmbH, personal fees and non-financial support from TEVA Pharmaceuticals Ind Ltd, personal fees and non-financial support from Novartis, personal fees from Pierre Fabre, personal fees and non-financial support from Clovis Oncology, personal fees from Seattle Genetics, outside the submitted work; U.N. reports grants and personal fees from Agendia, grants and personal fees from Amgen, grants and personal fees from Celgene, grants, personal fees and other from Genomic Health, grants and personal fees from NanoString Technologies, personal fees from Novartis, personal fees and other from Pfizer, grants, personal fees and other from Roche/Genentech, personal fees from Teva, grants from Sanofi, outside the submitted work. G.S. reports personal fees and non-financial support from Roche, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Novartis, personal fees from Lilly, non-financial support from TEVA, personal fees and non-financial support from Pfizer, outside the submitted work. C.H.B. reports grants/research support from (to the institution) Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, BioMarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMar; Advisory boards and consulting: Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, Astra Zeneca, Zodiac, Lilly, Sanofi. HDB reports other from Merck, other from Pfizer, other from AbbVie, outside the submitted work. M.T. reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa-Hakko-Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Astra Zeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. H.M. reports grants from NCI grant to Alliance/CALGB, during the conduct of the study. T.R. reports personal fees from Roche, during the conduct of the study. S.L. reports grants and other from Roche, during the conduct of the study; grants and other from AbbVie, grants and other from Celgene, other from Seattle Genetics, other from PriME/Medscape, personal fees from Chugai, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from BMS, other from Puma, grants from Immunomedics, grants and other from AstraZeneca, other from Pierre Fabre, other from Merck, other from GlaxoSmithKline, other from EirGenix, grants and other from Bayer, grants and other from Amgen, grants and other from Novartis, grants and other from Pfizer, outside the submitted work; In addition, S.L. has a patent EP14153692.0 pending. All remaining authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Estrogen receptor-positive breast cancer is a highly prevalent but heterogeneous disease among women. Advanced molecular stratification is required to enable individually most efficient treatments based on relevant prognostic and predictive biomarkers. First objective of our study was the hypothesis-driven discovery of biomarkers involved in tumor progression upon xenotransplantation of Luminal breast cancer into humanized mice. The second objective was the marker validation and correlation with the clinical outcome of Luminal breast cancer disease within the GeparTrio trial. An elevated mdm2 gene copy number was associated with enhanced tumor growth and lung metastasis in humanized tumor mice. The viability, proliferation and migration capacity of inherently mdm2 positive breast cancer cells in vitro were significantly reduced upon mdm2 knockdown or anti-mdm2 targeting. An mdm2 gain significantly correlated with a worse DFS and OS of Luminal breast cancer patients, albeit it was also associated with an enhanced preoperative pathological response rate. We provide evidence for an enhanced Luminal breast cancer stratification based on mdm2. Moreover, mdm2 can potentially be utilized as a therapeutic target in the Luminal subtype., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS)., Methods: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial., Results: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23-0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor., Conclusions: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.

Background: GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points., Patients and Methods: Patients were randomised to receive 18 weeks of E (150 mg/m 2 ) followed by P (225 mg/m 2 ) followed by C (2000 mg/m 2 ), each q2w or weekly P (80 mg/m 2 ) plus M (20 mg/m 2 ) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles., Results: 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029)., Conclusion: While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS., Gov Identifier: NCT02125344., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work; CD reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, during the conduct of the study; personal fees from Novartis, personal fees from Roche, personal fees from MSD Oncology, personal fees from Daiichi Sankyo, personal fees from AstraZeneca, from Molecular Health, grants from Myriad, personal fees from Merck, other from Sividon diagnostics, outside the submitted work; In addition, Dr. Denkert has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1-cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1-therapy response issued; CH reports a consulting or advisory role for Roche, AstraZeneca, Novartis, Lilly-Pharma, Celgene; CJ reports personal fees from Roche, personal fees from Celgene, personal fees from AstraZeneca, during the conduct of the study; CS reports a consulting or advisory role for Hologicm, MSD; reports travel, accommodations, or expenses from Pfizer, MSD, AstraZeneca, Roche; EH reports honoraria and a consulting or advisory role from AstraZeneca; HT reports other from Pierre Fabre, other from Pfizer Pharma, other from Mundipharma, other from ClinSol, other from Novartis, other from Lilly, other from AMGEN, other from Grünenthal, other from Vifor, other from AstraZeneca, other from Mylan, other from BMS, during the conduct of the study; JH reports personal fees from Lilly, personal fees from Novartis, personal fees from Pfizer, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from MSD, personal fees from Celgene, personal fees from Roche, other from Daichii, other from Roche, other from Pfizer, grants from Novartis, grants from Hexal, outside the submitted work; JUB reports honoraria, travel support and unrestricted grants from AMGEN, AstraZeneca, Lilly, Molecular Health, MSD, Novartis, Pfizer, Pierre-Fabre, Roche; KK reports other from MSD Sharpe amd Dome GmBH, personal fees from Roche, personal fees from Pfizer, personal fees from Astra Zeneca, outside the submitted work; KL reports a consulting or advisory role for Roche, Novartis, Pfizer, Lilly, Exact Science Eisai, MSD; reports travel, accommodations, or expenses from Roche; KR reports personal fees from AstraZeneca, personal fees from Pfizer, personal fees from MSD, outside the submitted work; LM reports honoraria from Pfizer, Eisai, AstraZeneca, Roche, Lilly; reports a consulting or advisory role for Pfizer, Roche, Eisai, AstraZeneca; reports travel, accommodations, or expenses from Eisai, Pfizer, AstraZeneca, Lilly, and Roche; MU reports honoraria to the employer/institution from Amgen, Astra Zeneca, Celgene, Daiichi Sankyo, Lilly, Roche, Pfizer, Pierre Fabre, Sanofi-Aventis, MSD; reports research funding to the employer/institution from Amgen, Astra Zeneca, Celgene, Daiichi Sankyo, Lilly, Pfizer, Roche, Sanofi Aventis, Pierre Fabre; PAF reports honoraria from Roche, Novartis, Pfizer, Daiichi-Sankyo, Eisai, Merck Sharp & Dohme, Astra Zeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Cepheid, BionTech; reports a consulting or advisory role for Roche, Novartis, Pfizer, Daiichi-Sankyo, Eisai, Merck Sharp & Dohme, Astra Zeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Lilly; reports research funding from Novartis, BioNTech AG, Cepheid; SL reports honoraria from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Celgene, DSI, Eirgenix, GSK, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Puma, Roche, Samsung, and Seagen; reports a consulting or advisory role for Abbvie, Amgen, AstraZeneca, Bayer, BMS, Celgene, DSI, Eirgenix, GSK, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Puma, Roche, and Seagen; reports a speaker's bureau for AstraZeneca, DSI, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Roche, and Samsung; reports research funding from Abbvie, Amgen, AstraZeneca, Celgene, Cepheid, DSI, Immunomedics, Novartis, Pfizer, and Roche; reports a patent or intellectual property interest with VM Scope GmbH; reports another relationship with Roche; TL reports honoraria from Amgen, Roche, Clovis, MSD, Novartis, Pfizer, Lilly; reports a consulting or advisory role from Tesaro, Amgen, MSD, Roche, Pfizer, Lilly, Myriad, Esai, GSK; reports travel, accommodations, or expenses from MSD, Celgen, Clovis; VM reports and Speaker honoraria received from Amgen, AstraZeneca, Celgene, Roche, Teva. Consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics; No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed., Patients and Methods: GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m 2 , nab-paclitaxel (nP) 330 mg/m 2 and cyclophosphamide (C) 2000 mg/m 2 (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD)., Results: The duration of median follow-up was 45.8 (range 0.0-88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0-86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%., Conclusions: iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work; CD reports personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, grants from Myriad Genetics, other from Sividon Diagnostics/Myriad, outside the submitted work and has a patent EP18209672 pending, a patent EP20150702464 pending and a patent Software (VMscope digital pathology) pending. CJ reports honoraria from Roche, Celgene, Novartis, Genomic Health and Amgen; compensation for consulting and advisory role from Roche, Novartis and Pfizer; travel expenses from Roche, Astra Zeneca and Genomic Health; CS reports compensation for consulting and advisory role from Olympus, Hologic; and travel expenses from imed, MedConcept, Medtronic, Diaglog Service, Mentor, mylan, GBG and Pfizer; ES reports honoraria from Roche, Astra Zeneca, Novartis, Pfizer, ESAI, Tesaro and MSD; compensation for consulting and advisory role from Roche and Tesaro; and travel expenses from Roche and Pfizer; FM reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, EISAI, Celgene, Clovis, Janssen-Cilag, Immunomedics, GSK, MSD, Seagen and Lilly outside the submitted work; JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees and other from Pfizer, personal fees and other from Roche, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from Eisai, other from Daichii, grants, personal fees and other from Celgene, personal fees from MSD, grants and personal fees from Hexal, outside the submitted work; JUB reports personal fees from AMGEN, personal fees from ASTRA Zeneca, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from SonoScape, from Sysmex, outside the submitted work; MR reports honoraria from MSD, Astra Zeneca, Lilly, Novartis and SOMATEX; compensation for consulting and advisory role from Roche, Novartis, MSD, Astra Zeneca and Lilly; and travel expenses from Pfizer, Novartis and Celgene; MU reports honoraria paid to his employer by Amgen, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Pfizer, Novartis, Roche, Sanofi Aventis and PUMA Biotechnology; compensation for consulting and advisory role to the employer from Amgen, Abbvie, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Roche, PUMA Biotechnology, Sanofi Aventis and Teva; SL reports grants and other from Roche during the conduct of the study; grants and other from Abbvie, grants and other from Amgen, grants and other from Celgene, grants and non-financial support from Immunomedics, grants and other from Novartis, grants and other from Pfizer, other from Seattle Genetics, other from PriME/Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from EirGenix, other from BMS, other from Puma, other from MSD and grants and other from AstraZeneca outside the submitted work; In addition, SL has a patent EP14153692.0 pending. TL reports honoraria from Lilly, Teva, Tesaro, Roche, Novartis, Pfizer, MSD, Amgen and Clovis; compensation for consulting and advisory role from Lilly, Roche, Tesaro, Amgen and MSD; travel expenses from Roche, Pfizer and Celgene; VM reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics; WJ reports grants and personal fees from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai and AstraZeneca during the conduct of the study; No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

For many decades, the standard procedure to treat breast cancer included complete dissection of the axillary lymph nodes. The aim was to determine histological node status, which was then used as the basis for adjuvant therapy, and to ensure locoregional tumour control. In addition to the debate on how to optimise the therapeutic strategies of systemic treatment and radiotherapy, the current discussion focuses on improving surgical procedures to treat breast cancer. As neoadjuvant chemotherapy is becoming increasingly important, the surgical procedures used to treat breast cancer, whether they are breast surgery or axillary dissection, are changing. Based on the currently available data, carrying out SLNE prior to neoadjuvant chemotherapy is not recommended. In contrast, surgical axillary management after neoadjuvant chemotherapy is considered the procedure of choice for axillary staging and can range from SLNE to TAD and ALND. To reduce the rate of false negatives during surgical staging of the axilla in pN+ CNB stage before NACT and ycN0 after NACT, targeted axillary dissection (TAD), the removal of > 2 SLNs (SLNE, no untargeted axillary sampling), immunohistochemistry to detect isolated tumour cells and micro-metastases, and marking positive lymph nodes before NACT should be the standard approach. This most recent update on surgical axillary management describes the significance of isolated tumour cells and micro-metastasis after neoadjuvant chemotherapy and the clinical consequences of low volume residual disease diagnosed using SLNE and TAD and provides an overview of this year's AGO recommendations for surgical management of the axilla during primary surgery and in relation to neoadjuvant chemotherapy., Competing Interests: Conflict of Interest/Interessenkonflikt PD DR Banys-Paluchowski: Honoraria for lectures and advisory role from Lilly, Pfizer, Roche, Amgen, Eisai, Astra Zeneca, Daiichi Sankyo, Novartis, GSK and study support from Endomag, Merit Medical and Mammotome. Prof. Dr. V. Müller: VM received speaker honoraria from Amgen, Astra Zeneca, Daiichi Sankyo, Eisai, GSK, Pfizer, MSD, Novartis, Roche, Teva, Seagen and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Seagen. Institutional research support from Novartis, Roche, Seagen, Genentech. Travel grants: Roche, Pfizer, Daiichi Sankyo./ Vortragshonorare: Amgen, Astra Zeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics, GSK, Seagen. Beratertätigkeit: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, GSK, Tesaro, Seagen und Nektar. Forschungsuntersützung an den Arbeitgeber: Novartis, Roche, Seattle Genetics, Genentech. Reisekosten: Roche, Pfizer, Daiichi Sankyo., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest., Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM)., Results: We found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59-0.95], log-rank p = 0.019) and overall survival (OS: HR 0.69 [95%CI 0.50-0.94], log-rank p = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51-1.16]; p = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51-0.91]; log-rank p = 0.009, interaction p = 0.130; OS: HR 0.60 [95%CI 0.41-0.88], log-rank p = 0.008, interaction p = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50-0.88], log-rank p = 0.004, interaction p = 0.034; OS: HR 0.57 [95%CI 0.40-0.81], log-rank p = 0.002, interaction p = 0.015)., Conclusions: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer., Trial Registration: This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 ., (© 2021. The Author(s).)

The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m 2 PO daily d1-14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

Importance: The extent of changes in estradiol levels in male patients with hormone receptor-positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated., Objective: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy., Design, Setting, and Participants: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor-positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018., Interventions: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months., Main Outcomes and Measures: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months., Results: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients' median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (-23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (-18.5 ng/L) with AI plus GnRHa (P < .001). After 6 months, median estradiol levels increased by 41% (a change of +12 ng/L) with tamoxifen, decreased by 61% (-19.5 ng/L) with tamoxifen plus GnRHa, and decreased by 64% (-17.0 ng/L) with AI plus GnRHa (P < .001). Sexual function and quality of life decreased when GnRHa was added but were unchanged with tamoxifen alone., Conclusions and Relevance: This phase 2 randomized clinical trial found that AI or tamoxifen plus GnRHa vs tamoxifen alone led to a sustained decrease of estradiol levels. The decreased hormonal parameters were associated with impaired sexual function and quality of life., Trial Registration: ClinicalTrials.gov Identifier: NCT01638247.

Background: BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities., Methods: Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored., Results: Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies., Conclusions: gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research., Competing Interests: Conflict of interest statement The authors declare the following conflicts of interest: A.S. reports receiving grants from Celgene, Roche, AbbVie; personal fees from Roche, AstraZeneca, Celgene, Roche, Pfizer, Novartis, MSD, Tesaro, Lilly, and others from Roche, outside the submitted work; C.H. reports receiving personal fees from Roche, Novartis, Lilliy, MSD, Astra Zeneca, and Pfizer; C.J. reports personal fees from Roche, AsraZeneca, Celgene, Pfizer, Novartis, and Amgen; F.J.C. reports receiving personal fees from AstraZeneca; receiving grants from GRAIL, others from Qiagen and Ambry Genetics, outside the submitted work; H.T. reports receiving personal fees from Novartis, Pfizer, AstraZeneca, Roche, Eisai, and Lilly, outside the submitted work; J.H. reports receiving grants and personal fees from Novartis, personal fees from Lilly, Astra Zeneca, Eisai, MSD, and Abbvie, personal fees and other from Pfizer and Roche, other from Daichii; receiving grants, personal fees and other from Celgene; receiving grants and personal fees from Hexal, outside the submitted work; J.U.B. reports receiving personal fees from AMGEN, ASTRA Zeneca, Novartis, Pfizer, Roche, SonoScape, and Sysmex, outside the submitted work; K.L. reports personal fees and non-financial support from Roche, Lilly, personal fees from Novartis and Genomic Health, outside the submitted work; K.R. reports personal fees from AstraZeneca, Tesaro and Pfizer, outside the submitted work; M.U. reports personal fees and non-financial support from Abbvie, Amgen GmbH, Eisai GmbH, Daiji Sankyo, Celgene GmbH, MSD Merck, Mundipharma, Roche Pharma AG, Odonate, TEVA Pharmaceuticals Ind Ltd., Sanofi Aventis Deutschland GmbH, Pfizer GmbH, Astra Zeneca and Lilly Int., Novartis, Clovis Oncology, and Myriad Genetics; personal fees from BMS, Lilly Deutschland, PUMA Biotechnology, Pierre Fabre, outside the submitted work; P.A.F. reports receiving personal fees from Novartis, Lilly, Pierre Fabre, and Seattle Genetics, Roche, Pfizer, Daiichi-Sankyo, Astra Zeneca, Eisai, Merck Sharp & Dohme; grants from Biontech, Cepheid. R.S. reports receiving grants from Cologne Furtune; S.L. reports receiving grants and other from AstraZeneca, Daiichi-Sankyo, Roche, Pfizer, Novartis, Abbvie, Amgen and Celgene during the conduct of the study; grants and non-financial support from Immunomedics; other from Seattle Genetics, PriME/Medscape, Lilly, Samsung, Eirgenix, BMS, Puma, MSD; personal fees from Chugai; grants from Teva and Vifor; outside the submitted work; In addition, S.L. has a patent EP14153692.0 pending. T.L. reports non-financial support from Pharma Mar, Celgene and Daiichi-Sankyo; personal fees and non-financial support from MSD, Pfizer, Roche, Clovis; personal fees from Amgen, Novartis, Teva, Tesaro, outside the submitted work; V.M. reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA, and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutic; No other potential conflict of interest relevant to this article was reported., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients ( n = 197) had triple-negative, 33.4% ( n = 295) luminal A like, 25.1% ( n = 221) luminal B/HER2-enriched like and 19.2% ( n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis ( p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.

Purpose: The aim of this study was to evaluate the feasibility and the accuracy of a secondary, metachronous ultrasound (US)-guided marking of the stereotactic vacuum-assisted breast biopsy (ST-VABB) area., Materials and Methods: The institutional ethics committee approved the study. The retrospective study included 98 patients. In ST-VABB of 45 women, no tissue markers were deployed at the biopsy site, even if no residual calcifications remained. After histology proved the necessity for a subsequent operation, the biopsy site was marked under US guidance using a coil marker. All interventions were technically successful. No complications occurred. Mammography was done to visualize the coil deployment. The distances from the center of the lesion and the biopsy cavity to the coil location were measured in both planes to evaluate the accuracy of the marking procedure., Results: In 24 of the 46 cases, the whole lesion was biopsied without residual elements. The mean time between ST-VABB and sonographic marking of the lesion was 9.7 days (median 6.5). The biopsy cavity could be detected in 40 (87%) cases and thus marked exactly. The mean time of US-guided marking was 12.5 min. The mean distance between the coil and the target lesion was 0.6 ± 1.5 cm in the craniocaudal (cc) view and 0.5 ± 1.5 cm in the mediolateral (ml) view for all markings. The mean delta value from the distance nipple-original lesion and from the distance nipple-coil was 0.85 ± 1.2 cm (median 0.5) in the cc view and 0.88 ± 1.2 cm (median 0.6) in the ml view for all cases. Clip migration was not observed., Conclusion: Our study demonstrates the feasibility and the technical success of secondary metachronous coil marking of the biopsy site under US guidance after receipt of histology. This approach seems to be a cost-effective alternative to the standard procedure of the primary coil marking especially in all completely removed lesions. It may offer advantages for allergic patients., Competing Interests: Prof. Markus Müller-Schimpfle receives a royalty of Cook Medical, Bloomington, IN, USA, for the co-development of the MReye® breast localization coil. The other authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Background : Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods : The aim of this analysis was to characterize patients with asymptomatic BM ( n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results : Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80-100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions : These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.

Importance: The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome., Objective: To determine treatment outcome for BC according to germline variant status., Design, Setting, and Participants: This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018., Main Outcomes and Measures: Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status., Results: In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). 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%; OR, 3.44; 95% CI, 1.22-9.72; P = .02)., Conclusions and Relevance: 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., Trial Registration: ClinicalTrials.gov Identifier: NCT02125344.

Purpose: To prospectively compare HRQoL effects of two modern adjuvant chemotherapy breast cancer treatment regimens at six time-points up to 16 months after random assignment., Methods: The open-label, randomized, Phase 3 "Panther trial" was conducted between February 2007 and September 2011. 760 women, aged 65 years and younger, after surgery for non-metastatic node-positive or high-risk node-negative breast cancer were randomized 1:1 to the experimental group (four cycles of tailored and dose-dense adjuvant epirubicin and cyclophosphamide/2 weeks followed by four cycles of tailored dose-dense docetaxel/2 weeks) or standard group (three cycles of fluorouracil and epirubicin-cyclophosphamide/3 weeks followed by three cycles of docetaxel/3 weeks). HRQoL was assessed at all Swedish centres using EORTC QLQ-C30 and EORTC QLQ-BR23 at six points during 16 months before randomization., Results: Response rates to questionnaires were highest at baseline 728/780 (93%) and lowest 16 months after randomization, 557/750 (74%). HRQoL declined during treatment in both groups. At the end of treatment, the experimental group reported statistically significantly lower HRQoL (P < 0.001) than the standard group on global health status, physical functioning, role functioning, social functioning, fatigue, sexual functioning, and systemic therapy effects. No differences were found for emotional functioning, body image, and arm and breast symptoms. There were no statistically significant differences between the groups at the first follow-up and at subsequent assessments. HRQoL levels at the 16-month follow-up were similar to baseline values., Conclusions: Negative HRQoL impact of the dose-dense and tailored strategy appears to be prominent during treatment, but HRQoL recover once treatment ends., Trial Registration: clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Background: Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials., Methods: Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies., Results: From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m 2 ; 65.9% 1-3 and 22.7% ≥ 4 comorbidities; 61.4% 1-2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline-taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients., Conclusions: Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.

Every year the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) , a group of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology, prepares and updates evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. Every update is performed according to a documented rule-fixed algorithm, by thoroughly reviewing and scoring the recent publications for their scientific validity and clinical relevance. This current publication presents the 2019 update on the recommendations for metastatic breast cancer., Competing Interests: The conflict of interest statements of all authors with conflicts of interest can be found in the supplementary material (see www.karger.com/doi/10.1159/000500999).

Competing Interests: The conflict of interest statements of all authors with conflicts of interest can be found in the supplementary material (see www.karger.com/doi/10.1159/000501000).

Background: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial., Patients and Methods: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested., Results: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome., Conclusions: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC., Clinical Trial: NCT00196872., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC)., Patients and Methods: Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m 2 ) followed by P (225 mg/m 2 ) followed by C (2000 mg/m 2 ), each q2w for 3 cycles or weekly P (80 mg/m 2 ) plus M (20 mg/m 2 ) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344., Results: 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77-1.28, P = 0.979) with 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; two patients on PM(Cb) died., Conclusions: 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Method The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.

Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Methods The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure. Recommendations Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.

Background: The management of intraductal papilloma without atypia (IDP) in breast needle biopsy remains controversial. This study investigates the upgrade rate of IDP to carcinoma and clinical and radiologic features predictive of an upgrade., Methods: Patients with a diagnosis of IDP on image-guided (mammography, ultrasound, magnetic resonance imaging) core needle or vacuum-assisted biopsy and surgical excision of this lesion at a certified breast center between 2007 and 2017 were included in this institutional review board-approved retrospective study. Appropriate statistical tests were performed to assess clinical and radiologic characteristics associated with an upgrade to malignancy at excision., Results: For 60 women with 62 surgically removed IDPs, the upgrade rate to malignancy was 16.1% (10 upgrades, 4 invasive ductal carcinoma, 6 ductal carcinoma in situ). IDPs with upgrade to carcinoma showed a significantly greater distance to the nipple (63.5 vs. 36.8 mm; p = 0.012). No significant associations were found between upgrade to carcinoma and age, menopausal status, lesion size, microcalcifications, BI-RADS descriptors, initial BI-RADS category, and biopsy modality., Conclusion: The upgrade rate at excision for IDPs diagnosed with needle biopsy was higher than expected according to some guideline recommendations. Observation only might not be appropriate for all patients with IDP, particularly for those with peripheral IDP.

Background: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited., Methods: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions., Results: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001)., Conclusions: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy., Methods: The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy., Results: 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%., Conclusions: The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.

Background: Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis., Patients and Methods: Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC → P) q3w. Event-free survival (EFS) was the primary end point., Results: A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC → P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63-0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60-0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC → P arm, respectively., Conclusion: The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC → P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The BRCA1-like profile identifies tumors with a defect in homologous recombination due to inactivation of BRCA1. This profile has been shown to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break-inducing chemotherapy. We tested the predictive potential of the BRCA1-like profile for adjuvant non-myeloablative, intensified dose-dense chemotherapy in the GAIN trial., Methods: Lymph node positive breast cancer patients were randomized to 3 × 3 dose-dense cycles of intensified epirubicin, paclitaxel, and cyclophosphamide (ETC) or 4 cycles concurrent epirubicin and cyclophosphamide followed by 10 cycles of weekly paclitaxel combined with 4 cycles capecitabine (EC-TX). Only triple negative breast cancer patients (TNBC) for whom tissue was available were included in these planned analyses. BRCA1-like or non-BRCA1-like copy number profiles were derived from low coverage sequencing data., Results: 119 out of 163 TNBC patients (73%) had a BRCA1-like profile. After median follow-up of 83 months, disease free survival (DFS) was not significantly different between BRCA1-like and non-BRCA1-like patients [adjusted hazard ratio (adj.HR) 1.02; 95% confidence interval (CI) 0.55-1.86], neither was overall survival (OS; adj.HR 1.26; 95% CI 0.58-2.71). When split by BRCA1-like status, DFS and OS were not significantly different between treatments. However, EC-TX seemed to result in a trend to an improvement in DFS in patients with a BRCA1-like tumor, while the reverse accounted for ETC treatment in patients with a non-BRCA1-like tumor (p for interaction = 0.094)., Conclusions: The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

Oncologic therapy is currently undergoing significant changes. A number of innovative targeted medications currently in clinical development have raised high expectations. With that in mind, discussions about terms such as "clinical benefit" and "clinical relevance" are highly topical. This also applies to further developments in the field of adjuvant systemic therapies for early-stage breast cancer. As the treatment aim is curative, assessment of the clinical benefit of adjuvant therapies must be largely based on efficacy outcomes. The focus must be on improving disease-free survival rates and lowering the risk of recurrence. Because of the current low mortality rates, statements about overall survival rates are only possible after very long observation periods. Consequently, new drugs in adjuvant therapies should be considered as offering a clinical benefit, if they reduce the risk of recurrence below current low levels of risk. The evidence for established adjuvant therapy standards in early-stage breast cancer can be used as objective criteria for comparison. This review article considers the requirements for clinical benefit of new adjuvant therapies for early breast cancer, based on examples from adjuvant endocrine therapy, adjuvant polychemotherapy and adjuvant anti-HER2 therapy.

Background: Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine., Patients and Methods: Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4., Results: From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10)., Conclusion: Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The St. Gallen International Consensus Conference on the treatment of patients with primary breast cancer has been held regularly (every second year in the last six years) for more than 30 years. This year, the findings of the International St. Gallen Consensus Panel and their implications for clinical practice were again discussed by a German working group of leading breast cancer specialists. Five of the breast cancer specialists from Germany were also members of this year's St. Gallen panel. A comparison between the St. Gallen recommendations and the annually updated treatment guidelines of the Gynecologic Oncology Group (AGO 2017) and the S3-guideline agreed upon in 2017 is useful. The recommendations of the St. Gallen panel represent an international cross-section of opinions of experts from different countries and different disciplines, while the S3-guideline and AGO guidelines are evidence-based. The motto of this year's 15th St. Gallen Conference was "Escalating and De-Escalating". The rationale behind this concept was to promote more individualized treatment and thereby reduce overtreatment as well as undertreatment.

Objective: The purpose of this retrospective analysis was to evaluate the likelihood of malignancy in prospectively categorized BI-RADS 4 and BI-RADS 5 calcifications., Material and Methods: This analysis included 849 women who underwent vacuum biopsy for BI-RADS 4 (with the subgroups 4A, 4B and 4C) or BI-RADS 5 calcifications between February 2007 and May 2015. Calcifications were classified according to the morphology and distribution descriptors of the BI-RADS lexicon (BI-RADS 4th edition lexicon). A standardized scheme (matrix) was used to combine the characteristics of the grouped calcifications with the BI-RADS assessment category., Results: Overall, 275/849 (32%) lesions were found to be malignant. 285/327/208/29 calcified lesions were prospectively classified as BI-RADS 4A/4B/4C/5 indicating a risk for malignancy of 16%/27%/55%/90%, respectively. The morphology descriptors predicted the risk for malignancy as follows: typically benign (n=55): 2%; indeterminate (n=676): 27%; typically malignant (n=118): 80%. The distribution descriptors correlated with a malignant histology as follows: diffuse (n=0); round or oval (n=261): 22%; regional (n=398): 33%; segmental (n=106): 42%; linear or branching (n=85): 55%. There was a significant difference between the descriptor categories (p<0.0001)., Conclusion: A standard scheme combining the morphology and distribution characteristics proved to be a helpful tool in diagnosis of calcifications, bridging the gap between description and classification of these lesions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Importance: Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy., Objective: To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule., Design, Setting, and Participants: A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011., Interventions: Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks., Main Outcomes and Measures: The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects., Results: Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group., Conclusions and Relevance: 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., Trial Registration: clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Background: In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m 2 or adjusted to an ideal weight for obese patients due to safety reasons., Materials and Methods: Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome., Results: Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m 2 . A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]., Conclusion: Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment., Competing Interests: The authors declare no conflict of interest.

Introduction: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC)., Methods: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459)., Results: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients., Conclusion: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone., Trial Registration: The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types., Methods: Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition., Results: VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5., Conclusions: Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites. These patients may benefit from therapeutic VEGF inhibition.

Meta-analyses persistently confirm the superiority of dose-dense chemotherapy in comparison with standard chemotherapy. In contrast, individual studies have shown conflicting results. These may be explained by different risk profiles of the treated patient populations. Some trials show a significant advantage in disease-free survival (DFS) and overall survival (OS) in the estrogen receptor (ER)-negative population only, whereas trials with high-risk populations like GIM-2 (Gruppo Italiano Mammella) and AGO-iddETC (Arbeitsgemeinschaft Gynäkologische Onkologie, intense dose-dense epirubicin, paclitaxel, and cyclophosphamide) show a significant superiority in DFS and OS for both, ER-negative and ER-positive patients even after 7 and 10 years, respectively, of follow-up. In contrast, the 10-year follow-up data of the E1199/Intergroup trial no longer showed any superiority of weekly paclitaxel for ER-positive/HER2-negative patients; superiority was observed in the triple-negative subgroup only. Although a direct head-to-head comparison is missing, iddETC or 4 cycles each of dose-dense epirubicin/cyclophosphamide followed by paclitaxel are the preferred adjuvant regimens for patients at risk. Patients with ≥ 4 positive lymph nodes should preferentially be treated with iddETC.

Background: Although greater than 40% of breast cancers occur in patients aged ≥65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients., Methods: Patients aged ≥65 years with a Charlson comorbidity index ≤2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m(2) and cyclophosphamide at a dose of 600 mg/m(2) intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m(2), methotrexate at a dose of 40 mg/m(2), and 5-fluorouracil at a dose of 600 mg/m(2) iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m(2) iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m(2) orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events., Results: Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P<.001) with 1 and 5 deaths observed during treatment, respectively. Grade 3 to 5 adverse events were more frequent among patients treated with EC/CMF (90.9%) than among those treated with nPX (64.8%) (P<.001), with hematological toxicities being more frequent with EC/CMF (88.4% vs 22.3%; P<.001), but nonhematological toxicities (hand-foot syndrome, diarrhea, mucositis, fatigue, sensory neuropathy, thromboembolisms, and metabolic disorders) being more frequent with nPX (58.5% vs 18.7%; P<.001). None of the geriatric scores (Charlson comorbidity index, Vulnerable Elders Survey [VES-13], Instrumental Activities of Daily Living [IADL], and G8) independently predicted grade 3 to 5 toxic events or treatment discontinuations. No differences in survival between the treatment groups were observed after 22.8 months., Conclusions: Compared with EC/CMF, treatment with nPX led to more treatment discontinuations and nonhematological toxicities in elderly patients with moderate or high-risk breast cancer., (© 2015 American Cancer Society.)