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Background: Human epidermal growth factor receptor 2 positive (HER2+, also referred to as ERBB2+) breast cancer is a subtype, historically associated with a particularly poor prognosis. Research into biological and molecular pathomechanisms of breast cancer has resulted in the development and adoption of several therapies targeting HER2. In parallel, various escalation/de-escalation strategies have been examined to further optimize patient outcomes and care., Summary: In this review, we highlighted the landmark trials in the evolution of treatment and management of HER2+ early breast cancer (eBC)., Key Messages: Continuous research over the last two decades has gradually prolonged survival in patients with early HER2+ eBC. Incorporation of post-neoadjuvant setting into clinical practice improved long-term outcomes in high-risk patients with residual disease after neoadjuvant therapy. In parallel, use of modern anti-HER2 agents may potentially allow omission of chemotherapy without compromising the survival in a significant number of selected patients. Current research focused on exploring the molecular heterogeneity of HER2+ breast cancer resulted in identification of new prognostic and predictive biomarkers which could pave the way toward the development of truly personalized therapy., Competing Interests: M.G. received consulting fees from AstraZeneca and travel support from Daiichi Sankyo, all outside of the submitted work. O.G. received consulting fees from Celgene, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, and Molecular Health; honoraria from Genomic Health/Exact Sciences, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, and AstraZeneca; payment for expert testimony from Genomic Health; and travel support from Roche, all outside of the submitted work; and co-director position at West German Study Group., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Oral cancer medications offer advantages but also pose challenges for therapy management and adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the patient's quality of life (QoL) continuously throughout the course of treatment., Material and Methods: AGO-B WSG PreCycle (NCT03220178) is a multicenter, randomized phase IV intergroup trial evaluating the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1) to CANKADO-active arm (supported by CANKADO PRO-React) or CANKADO-inform arm (drug intake documentation only) This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account., Results: While distributions of adverse events (AEs) were similar by arm overall, patients in the CANKADO-active arm had a favorable hazard ratio of 0.67 (95%CI 0.46-0.97; p = 0.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. At 24 months, 22.9% [17.9%-27.8%] of patients in CANKADO-active had suffered an SAE vs. 30.3% [22.6%-38.0%] in CANKADO-inform. AE-related dose reductions affected approximately 20% of patients (CANKADO-active: 18.2%, CANKADO-inform: 21.1%)., Conclusion: Exploratory safety analysis of PreCycle demonstrates for the first time in a randomized prospective trial that interactive autonomous eHealth-based support has a substantial favorable impact on the risk of SAEs and mitigates their severity for patients with advanced HR+/HER2- breast cancer on oral tumor therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [NH reported support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from palleos healthcare; consulting fees from Gilead, Pfizer, Sanofi, Sandoz, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, EPG Communication, Lilly, MSD, Pierre Fabre, Roche, Seagen, Viatris, Daiichi Sankyo, Gilead, MEDSCAPE, Novartis, Pfizer, Sanofi, Springer, Zuelligpharma; and co-director position at WSG – West German Study Group. REK reported consulting fees to an immediate family member from Roche/Genentech, Novartis, BMS, Pfizer, Lilly, Sandoz, Daiichi Sankyo, Agendia, AstraZeneca, Merck Sharp & Dohne, Ondonate Therapeutics, Sattle Genetics, and palleos healthcare; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to an immediate family member from Roche, Novartis, BMS, Amgen, Pfizer, Genomic Health, and NanoString Technologies. TS reported stock or stock options from CANKADO GmbH; other financial or non-financial interests from CANKADO GmbH. RW reported consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel from Agendia, Aristo, BMS, Daiichi Sankyo, Exact Sciences, Glaxo Smith Kline, Lilly, MSD, Mylan, Novartis, Paxman, Pfizer, PINK, Sandoz/Hexal, Riemser, Seattle Genetics/Seagen, Tesaro Bio, Veracyte, Amgen, AstraZeneca, Clovis Oncology, Eisai, Gilead, Hexal, Medstrom Medical, Mundipharma, Nanostring, Ondonate, palleos healthcare, Perre Fabre, PumyBiotechnology, Roche, Sanofi Genzyme, Stemline, Teva, Viatris; other financial or non-financial interests from FOMF, Pomme Med, MCI, Aurikamed, medconcept and Breast Center, Department of Obstetrics and Gynecology and Comprehensive Center (CCC) Munich, LMU University Hospital, Munich Germany. DL reported consulting fees from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; honoraria from Astra Zeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; payment for expert testimony from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; support for attending meetings and/or travel from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; Board or Advisory Board from AstraZeneca, Novartis, Daiichi Sankyo, Amgen, Loreal, High5md, Eli Lilly, Pfizer, Gilead, GSK, Onkowissen; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Deutsche Stiftung für junge Erwachsene mit Krebs. OH reported consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from Roche, MSD, Gilead, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, Amgen, Eisai; from Roche, MSD, Gilead, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, Amgen, Eisai. TDecker reported personal fees from Adboards, Novartis and iOMEDICO. MR reported consulting fees from Roche, Daiichi Sankyo, Somatex; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, AstraZeneca, Novartis, Daiichi Sankyo, Gilead, Somatex, Pfizer, Lilly; support for attending meetings and/or travel from Novartis, Pfizer, Gilead and Astra Zeneca. PS reported honoraria from Abbvie, Amgen, AstraZeneca, BMS, MSD Oncology, Pfizer, Merck Serono, Roche, Novartis; consulting or advisory role from Abbvie, Amgen, AstraZeneca, BMS; speakers' bureau from Abbvie, Amgen, AstraZeneca, BMS, Roche, Pfizer; research funding from Abbvie, BMS, Novartis, Roche; travel, accommodations, expenses from Abbvie, AstraZeneca; other from Abbvie, Amgen, BMS, Eisai, Incyte, Ipsen, Gilead Sciences, AstraZeneca, Janssen Oncology, Lilly Medical, Merck Serono, MSD Oncology, Pfizer, Roche, Novartis, Takeda. OG reported consulting fees from Daiichi Sankyo, BMS, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, Molecular Health; honoraria from Genomic Health/Exact Sciences, Eisai, Roche, BMS, Pfizer, Novartis, NanoString Technologies, Agendia, AstraZeneca; travel support from Roche, Daiichi Sankyo, all outside of the submitted work; co-director position at West German Study Group (WSG). PAF reported personal fees for advisory board from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Hexal, Lilly, Merck, Sharp&Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi Aventis, Seagen; personal fees for invited speaker from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, Merck, Sharp&Dohme, Novartis, Seagen; personal fees for medical writing support from Roche; non-financial support to the Institution from BioNTech, Cepheid; non-financial interests: member for Arbeitsgemeinschaft für Gynäkologische Onkologie, ASCO, Deutsche Gesellschaft für Senologie, Translational Research in Oncology. MS reported grants or contracts paid to the Institution from from AstraZeneca, BioNTech, Eisai, German Breast Group, Genentech, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche; consulting fees from AstraZeneca, BioNTech, Eisai, Daiichi Sankyo, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Novartis, Pfizer, Roche, Seagen; support for attending meetings and/or travel from Pfizer, Roche; patents planned, issued or pending EP 2951317 B1, EP 2390370 B1; participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seagen. All other authors have declared no conflicts of interest.]., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer., Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023., Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter., Competing Interests: Prof. Dr. Tjoung-Won Park-Simon. Honoraria for lectures and/or consulting: Roche, AstraZeneca, GSK, Pfizer, Lilly, MSD, Exact Sciences, Daiichi Sankyo, Seagen, Novartis, Gilead Science, NCO, Onkowissen, Exact Sciences, Seagen. Travel compensation: Roche, AstraZeneca, Pfizer. Prof. Dr. med. Ute-Susann Albert. Lectures: Pfizer, Novartis, AstraZeneca. Advisory board: Daiichi Sankyo. PD. Dr. Malgorzata Banys-Paluchowski. M.B. has received honoraria for lectures and advisory from Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre and ExactSciences, study support from EndoMag, Mammotome, MeritMedical, Gilead, Hologic, ExactSciences, and travel/congress support from Eli Lilly, ExactSciences, Pierre Fabre, Pfizer, Daiichi Sankyo and Roche. Dr. med. Ingo Bauerfeind. Honoraria for lectures: Pfizer, Roche, Seagen. Prof. Dr. med. Jens-Uwe Blohmer. Honoraria for advisory boards and lectures: Astrazeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Seagen Prof. Dr. med. Wilfried Budach. Lecture: Merck, BMS, Jörg Eickeler Veranstaltungen, medpublico GmbH, BVDST. Prof. Dr. med. Peter Dall, Honoraria for lectures and advisory boards: Novartis, Pierre Fabre, Gilead, MSD, Daiichi Sankyo, Lilly, AstraZeneca, Pfizer, Roche. Prof. Dr. Nina Ditsch. Advisory Boards and speakers bureaus. AstraZeneca, Aurikamed, BGGF, Daiichi-Sankyo, Elsevier Verlag, ESO, Exact Sciences, Gilead, GSK, if-Kongress, KelCon, Leopoldina Schweinfurt, Lilly, Lukon, Molekular Health, MSD, Novartis, onkowissen, Pfizer, RG-Ärztefortbildungen, Roche, Seagen Prof. Dr. med. Eva Maria Fallenberg. Research grant: DFG. Speaker honorarium: GE Healthcare, Bayer Healthcare, Guerbet, Siemens, BD, Roche, EUSOBI, ESOR, ESMO. Prof. Dr. med. Peter A. Fasching. Advisory board: Pfizer, Novartis, Roche, Daiichi Sankyo, Eisai, AstraZeneca, Lilly, MSD, Seagen, Agendia, Pierre Fabre, Sanofi Aventis, Gilead Science. Lecture: Pfizer, Novartis, Roche, Daiichi Sankyo, Eisai, AstraZeneca, Lilly, MSD, Seagen, Gilead Sciences. Other: Onkowissen, art tempi. Prof. Dr. med. Tanja N. Fehm. Onkowissen Prof. Dr. med. Michael Friedrich. Advisory Board: Gilead Sciences. Other honoraria: Roche, MSD. Prof. Dr. med. Bernd Gerber. Lecture honoraria: Roche, AstraZeneca, Seagen, Novartis, Pfizer, MedConcept. Others: Pfizer. PD Dr. med. Oleg Gluz. Honoraria for lectures and/or consulting: Amgen, AstraZeneca, Daiichi Sanyko, Gilead Science, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Exact Sciences, Agendia. Minority share holder: Westdeutsche Studiengruppe (WSG). Prof. Dr. med. Nadia Harbeck. Honoraria for lectures and/or consulting: Amgen, AstraZeneca, Daiichi Sanyko, Gilead, Lilly, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Viatris, Zuelligpharma Minority share holder: Westdeutsche Studiengruppe (WSG). Prof. Dr. med. Andreas Hartkopf. Honoraria for consulting and speaking engagements from AstraZeneca, Agendia, Amgen, Clovis, DaichiiSankyo, Eisai, ExactScience, Gilead, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Pfizer, Roche, Pierre-Fabre, Seagen, Stemline and Verazyte. Prof. Dr. med. Jörg Heil. None. Prof. Dr. med. Jens Huober. Trial funding: Novartis, Lilly. Honoraria for lectures: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene; Abbvie, Seagen, Gilead, Daiichi. Honoraria for consulting/advisory board: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Abbvie, Daiichi, Gilead. Travel grants: Roche, Pfizer, Daiichi, Gilead. Prof. Dr. med. Christian Jackisch. Advisory board: Astra Zeneca, Novartis, Lilly, Gilead, Exact Sciences, Pfizer, Roche, GSK, Pierre-Fabre, Roche, Seagen; Lecture: Art tempi, AstraZeneca, Lilly, Novartis, Roche, Amgen, Pierre-Fabre, Exact Sciences, MSD, GynUpdate, StreamedUp. Prof. Dr. med. Cornelia Kolberg-Liedtke. Advisory board: SeaGen, Exact Sciences, Pfizer, Novartis, AstraZeneca, Lilly, SeaGen, Daiichi Sankyo, Agendia, Gilead, Onkowissen; Lecture: Novartis Ireland, NOGGO, CECOG, PINK, Pfizer, Roche, AstraZeneca, Carl Zeiss Meditec, Lilly, SeaGen, Daiichi Sankyo. Other: Gilead Science, POMME. Stockholding: Phaon Scientific, Theraclion SA. Trial Funding: Gilead Science. Prof. Dr. med. Hans-Heinrich Kreipe. Advisory board: Lilly. Lecture: AstraZeneca, Roche, Daiichi Sankyo, Pfizer. PD Dr. David Krug. Lecture: Merck Sharp & Dohme, onkowissen, Pfizer. Research funding: Merck KGaA. Advisory Board: Gilead. Prof. Dr.med. Thorsten Kühn. Advisory Board: Sysmex, Neodynamics. Trial funding: Merit Medical, Endomag, Mammotome. Lecture: Pfizer. Prof. Dr. med. Sherko Kümmel. Lecture: Roche, Lilly, Exact Sciences, Novartis, Amgen, Daiichi Sankyo, AstraZeneca, Somatex, MSD, Pfizer, pfm medical, Seagen, Gilead Science, Agendia. Other honoraria: Roche, Daiichi Sankyo, Sonoscape Advisory board: Lilly, MSD, Roche. Prof. Dr. med. Sibylle Loibl. Advisory Board, institutional: Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, Eirgenix, GSK, Gilead Science, Lilly, Merck, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeuticas, Puma, Roche, Samsung, Sanofi, Seagen Invited speaker, institutional: Astra Zeneca, DSI, Gilead, Novartis, Pfizer, Pierre Fabre, Roche, Seagen Invited speaker, personal: Medscape, Stemline-Menarini. Trial funding/others: Astra Zeneca, Abbvie, Celgene, Daiichi-Sankyo, Greenwich Life Sciences, Immunomedics/Gilead, Molecular Health, Novartis, Pfizer, Roche, Seagen, VM Scope GmbH. Prof. Dr. med. Diana Lüftner. Lecture: Lilly, Roche, MSD, Onkowissen, Novartis, Pfizer, Daiichi Sankyo, Gilead, AstraZeneca, Loreal, high4md. Advisory board: Lilly, Roche, MSD, Novartis, Pfizer, Daiichi Sankyo, Gilead, AstraZeneca, Other: Novartis. Prof. Dr. med. Michael Patrick Lux. M.P.L. has participated on advisory boards for AstraZeneca, Lilly, MSD, Novartis, Pfizer, Eisai, Gilead, Exact Sciences, Pierre Fabre, Grünenthal, Daiichi-Sankyo, PharmaMar, Roche, SamanTree, Sysmex and Hexal and has received honoraria for lectures from MSD, Lilly, Roche, Novartis, Pfizer, Exact Sciences, Daiichi-Sankyo, Grünenthal, pfm, Gilead, AstraZeneca, and Eisai. Prof. Dr. med. Nicolai Maass. Advisory board: Amgen, AstraZeneca, Clovis, Daiichi Sankyo, GSK, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen Lecture: AstraZeneca, Daiichi Sankyo, GSK, Lilly, Novartis, Pfizer, Roche. Prof. Dr. med. Christoph Mundhenke. Advisory board: AstraZeneca, Pfizer, Daiichi Sankyo, Seagen, Novartis. Lecture: Pfizer, Novartis. Prof. Dr. med. Toralf Reimer. Trial funding: German Cancer Aid and Else Kroener-Fresenius-Stiftung. Advisory board: MSD, Novartis, Myriad. Lecture: Pfizer, Novartis, Roche, AstraZeneca. Prof. Dr. med. Kerstin Rhiem. Lecture: AstraZeneca, Amgen, Roche. Prof. Dr. med. Achim Rody. Advisory board: AstraZeneca, Novartis, Roche, Exact Sciences, Pierre Fabre, Lilly, Seagen, Amgen, MSD. Lecture: Pfizer, Celgene, Eisai. Trial funding: Eisai. Prof. Dr. med. Marcus Schmidt. MS reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, and SeaGen, His institution has received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre, and SeaGen. In addition, he has a patent for EP 2390370 B1 and a patent for EP 2951317 B1 issued. Prof. Dr. med. Andreas Schneeweiss. Lecture: Amgen, AstraZeneca, Aurikamed, Clinsol, ConnectMedica, Gilead Science, GSK, I-Med, Lilly, MSD, Nanostring, Novartis, Onkowissen, Promedicis, Pfizer, Pierre Fabre, Roche, Seagen, StreamedUp. Other: Thieme. Prof. Dr. med. Florian Schütz. Lecture: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, ExactSciences, Gilead, Pfizer, MSD, Novartis, Onkowissen, Roche Pharma. Advisory board: Lilly, MSD, Atheneum Partners. Travel expanses: Lilly, Daiichi-Sankyo, Amgen, Prof. Dr. med. Hans-Peter Sinn. Advisory board: Exact Sciences, Daiichi Sankyo. Lecture: AstraZeneca. Trial Funding: AstraZeneca. Prof. Dr. med. Christine Solbach. Lecture: DiaLog Service GmbH, Jörg Eickeler, Pfizer, MedConcept, Medicultus, GBG, Dt. Röntgengesellschaft, BVF Akademie, LÄK Hessen Akademie, Meet the Expert Academy. Advisory board: MSD, Roche. Prof. Dr. med. Erich-Franz Solomayer. Roche, Amgen, Celgen, Tesaro, Astra Zeneca, Pfizer, Storz, Erbe, Gedeon Richter, Eisai, Medac, MSD, Vifor, Teva, Ethikon, Johnson Johnson, Daiichi-Sankyo, Gilead, Exact Sciences, GSK, Pierre Fabre. Prof. Dr. med. Elmar Stickeler. Advisory boards: Gilead, Iomedico, Lilly, MSD, Seagen Lecture: Pfizer, Bsh Düsseldorf, Gilead, Iomedico, PharmaMar, Onkowissen, Roche. Prof. Dr. med. Christoph Thomssen. Compensation for advisory boards, lectures or publications. Amgen, AstraZeneca, Aurikamed, Daiichi-Sankyo, Forum Sanitas, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, Nanostring, Novartis, Onkowissen, Pfizer, Roche, Seagen, Vifor Prof. Dr. med. Michael Untch. M.U. has received honoraria for lectures and consulting or advisory role from AstraZeneca, Art tempi, Amgen, Daiji Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Novartis, Gilead, Stemline, Genzyme, Agendia, Onkowissen, Eisai, All honoraria and fees to the employer/institution. Prof. Dr. Isabell Witzel. Lecture: Daiichi Sankyo, Pfizer, Roche, MSD, Lilly, Seagen, AstraZeneca, Gilead. Other: Onkowissen Prof. Dr. med. Achim Wöckel. Advisory board: Amgen, AstraZeneca, Aurikamed, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Genomic Health, Pierre Fabre, Clovis, Organon. PD. Dr. Rachel Würstlein. Agendia, Amgen, Aristo, Astra Zeneca, Aurikamed, Celgene, Clinsol, Clovis Oncology, Daiichi-Sankyo, Eisai, Exact Sciences, FOMF, Gilead, Glaxo Smith Kline, Hexal, Lilly, MCI, medconcept, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, Pomme Med, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Stemline, Tesaro Bio, Teva, Veracyte, Viatris Prof. Dr. med. Volkmar Müller. V.M. received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics, Genomic Health, Hexal, Roche, Pierre Fabre, ClinSol, Daiichi-Sankyo, Eisai, Lilly, Tesaro, Seattle Genetics and Nektar. Institutional research support from Novartis, Roche, Seattle Genetics, Genentech. Travel grants: Roche, Pfizer, Daiichi Sankyo. Prof. Dr. med. Wolfgang Janni. Lecture: Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Gilead Science. Trial Funding: Amgen, AstraZeneca, Lilly, Novartis, Roche. Prof. Dr. med. Marc Thill. M.T. received personal fees for consulting from Agendia, Amgen, AstraZeneca, Aurikamed, Becton/Dickinson, Biom‘Up, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Lilly, MSD, Norgine, Neodynamics, Novartis, Onkowissen, Organon, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Seagen, Sirius Pintuition, Sysmex, for manuscript support from Amgen, ClearCut, Clovis, pfm medical, Roche, Servier, for travel expenses from Amgen, Art Tempi, AstraZeneca, Clearcut, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Neodynamics, Norgine, Novartis, Pfizer, pfm Medical, Roche, RTI Surgical, Seagen, for congress support Amgen, AstraZeneca, Celgene, Daiichi Sanyko, Hexal, Neodynamics, Novartis, Pfizer, Roche, Sirius Medical, for lectures from Amgen, Art Tempi, AstraZeneca, Clovis, Connect Medica, Eisai, Exact Sciences, Gedeon Richter, Gilead Science, GSK, Hexal, I-Med-Institute, Jörg Eickeler, Laborarztpraxis Walther et al. Lilly, MCI, Medscape, MSD, Medtronic, Novartis, Onkowissen, Pfizer, pfm medical, Roche, Seagen, StreamedUp, Sysmex, Vifor, Viatris, for trial funding from Endomag, Exact Sciences and institutional fees from AstraZeneca, Biom’Up, Celgene, Clearcut, Neodynamics, Novartis, pfm medical, Roche, RTI Surgical., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy., Patients and Methods: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant., Results: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; P log-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; P log-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; P log-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy., Conclusion: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2023 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer (mBC)., Competing Interests: The authors have the following conflicts of interest: Prof. Dr. Med. Marc Thill: MT received personal fees for consulting from Agendia, Amgen, AstraZeneca, Aurikamed, Becton/Dickinson, Biom‘Up, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Science, Grünenthal, GSK, Lilly, MSD, Norgine, NeoDynamics, Novartis, Onkowissen, Organon, Pfizer, pfm Medical, Pierre Fabre, Roche, RTI Surgical, Seagen, Sirius Pintuition, and Sysmex; for manuscript support from Amgen, ClearCut, Clovis, pfm medical, Roche, and Servier; for travel expenses from Amgen, Art Tempi, AstraZeneca, ClearCut, Clovis, ConnectMedica, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, NeoDynamics, Norgine, Novartis, Pfizer, pfm Medical, Roche, RTI Surgical, and Seagen; for congress support Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Hexal, NeoDynamics, Novartis, Pfizer, Roche, and Sirius Medical; for lectures from Amgen, Art Tempi, AstraZeneca, Clovis, ConnectMedica, Eisai, Exact Sciences, Gedeon Richter, Gilead Science, GSK, Hexal, I-Med-Institute, Jörg Eickeler, Laborarztpraxis Walther, Lilly, MCI, Medscape, MSD, Medtronic, Novartis, Onkowissen, Pfizer, pfm medical, Roche, Seagen, STREAMED UP, Sysmex, Vifor, and Viatris; for trial funding from Endomag, Exact Sciences; and institutional fees from AstraZeneca, Biom’Up, Celgene, ClearCut, NeoDynamics, Novartis, pfm medical, Roche, and RTI Surgical. Prof. Dr. Med. Ute-Susann Albert, lectures: Pfizer, Novartis, and AstraZeneca; advisory board: Daiichi Sankyo. PD Dr. Malgorzata Banys-Paluchowski: M.B. has received honoraria for lectures and advisory from Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre, and Exact Sciences; study support from Endomag, Mammotome, Merit Medical, Gilead, Hologic, and Exact Sciences; and travel/congress support from Eli Lilly, Exact Sciences, Pierre Fabre, Pfizer, Daiichi Sankyo, and Roche. Dr. Med. Ingo Bauerfeind, honoraria for lectures: Pfizer, Roche, and Seagen. Prof. Dr. Med. Jens-Uwe Blohmer, honoraria for advisory boards and lectures: AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen. Prof. Dr. Med. Wilfried Budach, lecture: Merck, BMS, Jörg Eickeler Veranstaltungen, medpublico GmbH, and BVDST. Prof. Dr. Med. Peter Dall, honoraria for lectures and advisory boards: Novartis, Pierre Fabre, Gilead, MSD, Daiichi Sankyo, Lilly, AstraZeneca, Pfizer, and Roche. Prof. Dr. Nina Ditsch, advisory boards and speakers bureaus advisory boards and speakers bureaus: AstraZeneca, Aurikamed, BGGF, Daiichi Sankyo, Elsevier Verlag, ESO, Exact Sciences, Gilead, GSK, if-Kongress, KelCon, Leopoldina Schweinfurt, Lilly, Lukon, Molecular Health, MSD, Novartis, Onkowissen, Pfizer, RG-Ärztefortbildungen, Roche, and Seagen. Prof. Dr. Med. Eva Maria Fallenberg, research grant: DFG; speaker honorarium: GE Healthcare, Bayer Healthcare, Guerbet, Siemens, BD, Roche, EUSOBI, ESOR, ESMO. Prof. Dr. Med. Peter A. Fasching, advisory board: Pfizer, Novartis, Roche, Daiichi Sankyo, Eisai, AstraZeneca, Lilly, MSD, Seagen, Agendia, Pierre Fabre, Sanofi-Aventis, and Gilead Science; lecture: Pfizer, Novartis, Roche, Daiichi Sankyo, Eisai, AstraZeneca, Lilly, MSD, Seagen, and Gilead Sciences; and other: Onkowissen, art tempi. Prof. Dr. Med. Tanja N. Fehm, Onkowissen. Prof. Dr. Med. Michael Friedrich, advisory board: Gilead Sciences; other honoraria: Roche and MSD. Prof. Dr. Med. Bernd Gerber, lecture honoraria: Roche, AstraZeneca, Seagen, Novartis, Pfizer, and MedConcept; and others: Pfizer. PD Dr. Med. Oleg Gluz, honoraria for lectures and/or consulting: Amgen, AstraZeneca, Daiichi Sankyo, Gilead Science, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Exact Sciences, and Agendia; and minority share holder: Westdeutsche Studiengruppe (WSG)mmc1. Prof. Dr. Med. Nadia Harbeck, honoraria for lectures and/or consulting: Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Viatris, and Zuellig Pharma; minority share holder: Westdeutsche Studiengruppe (WSG). Prof. Dr. Med. Andreas Hartkopf, honoraria for consulting and speaking engagements from AstraZeneca, Agendia, Amgen, Clovis, Daiichi Sankyo, Eisai, Exact Science, Gilead, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Pfizer, Roche, Pierre Fabre, Seagen, Stemline, and Verazyte. Prof. Dr. Med. Jörg Heil, none. Prof. Dr. Med. Jens Huober, trial funding: Novartis and Lilly; honoraria for lectures: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene; AbbVie, Seagen, Gilead, and Daiichi; honoraria for consulting/advisory board: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, AbbVie, Daiichi, and Gilead; and travel grants: Roche, Pfizer, Daiichi, and Gilead. Prof. Dr. Med. Christian Jackisch, advisory board: AstraZeneca, Novartis, Lilly, Gilead, Exact Sciences, Pfizer, Roche, GSK, Pierre Fabre, Roche, and Seagen; lecture: Art tempi, AstraZeneca, Lilly, Novartis, Roche, Amgen, Pierre Fabre, Exact Sciences, MSD, Gyn Update, and STREAMED UP. Prof. Dr. Med. Cornelia Kolberg-Liedtke, advisory board: SeaGen, Exact Sciences, Pfizer, Novartis, AstraZeneca, Lilly, SeaGen, Daiichi Sankyo, Agendia, Gilead, and Onkowissen; and lecture: Novartis Ireland, NOGGO, CECOG, PINK, Pfizer, Roche, AstraZeneca, Carl Zeiss Meditec, Lilly, SeaGen, and Daiichi Sankyo; other: Gilead Science and POMME; stockholding: Phaon Scientific and Theraclion SA; and trial Funding: Gilead Science. Prof. Dr. Med. Hans-Heinrich Kreipe, advisory board: Lilly; lecture: AstraZeneca, Roche, Daiichi Sankyo, and Pfizer. PD Dr. David Krug, lecture: Merck Sharp and Dohme, Onkowissen, and Pfizer; research funding: Merck KGaA; and advisory board: Gilead. Prof. Dr. med. Thorsten Kühn, advisory board: Sysmex and NeoDynamics; trial funding: Merit Medical, Endomag, and Mammotome; and lecture: Pfizer. Prof. Dr. Med. Sherko Kümmel, lecture: Roche, Lilly, Exact Sciences, Novartis, Amgen, Daiichi Sankyo, AstraZeneca, Somatex, MSD, Pfizer, pfm medical, Seagen, Gilead Science, and Agendia; other honoraria: Roche, Daiichi Sankyo, and Sonoscape; and advisory board: Lilly, MSD, and Roche. Prof. Dr. Med. Sibylle Loibl, board, advisory board, institutional: AbbVie, Amgen, AstraZeneca, BMS, Celgene, DSI, EirGenix, GSK, Gilead Science, Lilly, Merck, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Puma, Roche, Samsung, Sanofi, and Seagen; invited speaker, institutional: AstraZeneca, DSI, Gilead, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen; invited speaker, personal: Medscape and Stemline-Menarini; trial funding/others: AstraZeneca, AbbVie, Celgene, Daiichi Sankyo, Greenwich Life Sciences, Immunomedics/Gilead, Molecular Health, Novartis, Pfizer, Roche, Seagen, VM Scope Gmbp. Prof. Dr. Med. Diana Lüftner, lecture: Lilly, Roche, MSD, Onkowissen, Novartis, Pfizer, Daiichi Sankyo, Gilead, AstraZeneca, Loreal, and high4md; advisory board: Lilly, Advisory board: Lilly, Roche, MSD, Novartis, Pfizer, Daiichi Sankyo, Gilead, and AstraZeneca; and other: Novartis. Prof. Dr. Med. Michael Patrick Lux: M.P.L. has participated on advisory boards for AstraZeneca, Lilly, MSD, Novartis, Pfizer, Eisai, Gilead, Exact Sciences, Pierre Fabre, Grünenthal, Daiichi Sankyo, PharmaMar, Roche, SamanTree, Sysmex, and Hexal; and has received honoraria for lectures from MSD, Lilly, Roche, Novartis, Pfizer, Exact Sciences, Daiichi Sankyo, Grünenthal, pfm, Gilead, AstraZeneca, and Eisai. Prof. Dr. Med. Nicolai Maass, advisory board: Amgen, AstraZeneca, Clovis, Daiichi Sankyo, GSK, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, and Seagen; and lecture: AstraZeneca, Daiichi Sankyo, GSK, Lilly, Novartis, Pfizer, and Roche. Prof. Dr. Med. Christoph Mundhenke, advisory board: AstraZeneca, Pfizer, Daiichi Sankyo, Seagen, and Novartis; and lecture: Pfizer and Novartis. Prof. Dr. Med. Toralf Reimer; trial funding: German Cancer Aid and Else Kroener-Fresenius-Stiftung; advisory board: MSD, Novartis, and Myriad; and lecture: Pfizer, Novartis, Roche, and AstraZeneca. Prof. Dr. Med. Kerstin Rhiem, lecture: AstraZeneca, Amgen, and Roche. Prof. Dr. Med. Achim Rody, advisory board: AstraZeneca, Novartis, Roche, Exact Sciences, Pierre Fabre, Lilly, Seagen, Amgen, and MSD; lecture: Pfizer, Celgene, and Eisai; and trial funding: Eisai. Prof. Dr. Med. Marcus Schmidt: MS reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, and SeaGen; his institution has received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre, and SeaGen. In addition, he has a patent for EP 2390370 B1 and a patent for EP 2951317 B1 issued. Prof. Dr. Med. Andreas Schneeweiss, lecture: Amgen, AstraZeneca, Aurikamed, Clinsol, ConnectMedica, Gilead Science, GSK, I-Med, Lilly, MSD, NanoString, Novartis, Onkowissen, Promedicis, Pfizer, Pierre Fabre, Roche, Seagen, and STREAMED UP; and other: Thieme. Prof. Dr. Med. Florian Schütz, lecture: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Pfizer, MSD, Novartis, Onkowissen, and Roche Pharma; and advisory board: Lilly, MSD, and Atheneum Partners; and travel expenses: Lilly, Daiichi Sankyo, and Amgen. Prof. Dr. Med. Hans-Peter Sinn, advisory board: Exact Sciences and Daiichi Sankyo; lecture: AstraZeneca; and trial Funding: AstraZeneca. Prof. Dr. Med. Christine Solbach, lecture: DiaLog Service GmbH, Jörg Eickeler, Pfizer, MedConcept, Medicultus, GBG, Dt. Röntgengesellschaft, BVF Akademie, LÄK Hessen Akademie, Meet the Expert Academy; advisory board: MSD and Roche. Prof. Dr. Med. Erich-Franz Solomayer, Roche, Amgen, Celgen, Tesaro, AstraZeneca, Pfizer, Storz, Erbe, Gedeon Richter, Eisai, Medac, MSD, Vifor, Teva, Ethikon, Johnson & Johnson, Daiichi Sankyo, Gilead, Exact Sciences, GSK, and Pierre Fabre. Prof. Dr. Med. Elmar Stickeler, advisory boards: Gilead, Iomedico, Lilly, MSD, and Seagen; and lecture: Pfizer, Bsh Düsseldorf, Gilead, Iomedico, PharmaMar, Onkowissen, and Roche. Prof. Dr. Med. Christoph Thomssen, compensation for advisory boards, lectures or publications: Amgen, AstraZeneca, Aurikamed, Daiichi Sankyo, Forum Sanitas, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, NanoString, Novartis, Onkowissen, Pfizer, Roche, Seagen, and Vifor. Prof. Dr. Med. Michael Untch: M. U. has received honoraria for lectures and consulting or advisory role from AstraZeneca, Art tempi, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Novartis, Gilead, Stemline, Genzyme, Agendia, Onkowissen, Eisai; all honoraria and fees to the employer/institution. Prof. Dr. Isabell Witzel, lecture: Daiichi Sankyo, Pfizer, Roche, MSD, Lilly, Seagen, AstraZeneca, and Gilead; other: Onkowissen. Prof. Dr. Med. Achim Wöckel; advisory board: Amgen, AstraZeneca, Aurikamed, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Genomic Health, Pierre Fabre, Clovis, and Organon. PD. Dr. Rachel Würstlein, Agendia, Amgen, Aristo, AstraZeneca, Aurikamed, Celgene, Clinsol, Clovis Oncology, Daiichi Sankyo, Eisai, Exact Sciences, FOMF, Gilead, Glaxo Smith Kline, Hexal, Lilly, MCI, medconcept, Medstrom Medical, MSD, Mundipharma, Mylan, NanoString, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, Pomme-med, Puma Biotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Stemline, Tesaro Bio, Teva, Veracyte, and Viatris. Prof. Dr. Med. Volkmar Müller: VM received speaker honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics, Genomic Health, Hexal, Roche, Pierre Fabre, Clinsol, Daiichi Sankyo, Eisai, Lilly, Tesaro, Seattle Genetics, and Nektar; institutional research support from Novartis, Roche, Seattle Genetics, and Genentech; and travel grants: Roche, Pfizer, and Daiichi Sankyo. Prof. Dr. Med. Wolfgang Janni, lecture: Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, and Gilead Science; trial Funding: Amgen, AstraZeneca, Lilly, Novartis, and Roche. Prof. Dr. Tjoung-Won Park-Simon, honoraria for lectures and/or consulting: Roche, AstraZeneca, GSK, Pfizer, Lilly, MSD, Exact Sciences, Daiichi Sankyo, Seagen, Novartis, Gilead Science, NCO, Onkowissen, Exact Sciences, and Seagen; and travel compensation: Roche, AstraZeneca, and Pfizer., (© 2023 S. Karger AG, Basel.)

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed., Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC., Design, Setting, and Participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level)., Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days., Main Outcomes and Measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies., Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm., Conclusions and Relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab., Trial Registration: ClinicalTrials.gov Identifier: NCT03272477.

The utility of multigene expression assays in advanced (≥ 4 positive lymph nodes) early breast cancer (EBC) is limited. We conducted exploratory transcriptomic analysis of 758 genes (Breast Cancer 360 panel, nCounter ® platform; NanoString) in primary tumor samples collected during a phase 3 trial comparing adjuvant taxane-containing dose-dense chemotherapy (ddCTX) versus standard-dosed chemotherapy (stCTX) in resected EBC with ≥ 4 positive lymph nodes. Prognostic and predictive associations with disease-free survival (DFS) and overall survival (OS) were evaluated by Cox regression with false discovery rate (FDR) adjustment. Data were available from tumor samples of 141/226 patients (median follow-up: 14 years). Several genes/signatures, including immune markers, showed prognostic relevance in unadjusted analyses. Of these, two remained significant after multiplicity adjustment: a positive effect on DFS of programmed cell death 1 ligand-2 (PD-L2) in the ddCTX arm (univariate HR: 0.53, FDR-adjusted P = 0.036) and a negative effect on OS of HER2-enriched (HER2-E) signature in the stCTX arm (univariate HR: 5.40, FDR-adjusted P = 0.036). Predictive analyses showed greater DFS benefit of ddCTX in tumors with high antigen processing machinery (APM) expression (multivariate interaction P = 0.024). Multigene expression assays have a prognostic and predictive potential in advanced EBC, and further investigation is warranted in order to identify candidates for de-escalated treatment. In addition, intrinsic subtype and immune gene expression have predictive potential., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose of Review: Clinical decisions for (neo)adjuvant treatment in early breast cancer (eBC) have been based mostly on clinical factors over the last decades. We have reviewed development and validation of such assays in the HR + /HER2 eBC and discuss possible future directions in this field., Recent Findings: Increasing knowledge about the biology of hormone-sensitive eBC, based on the precise and reproducible multigene expression analysis, has led to a significant change in the treatment pathways and reduction of overtreatment in particular by chemotherapy in HR + /HER2 eBC with up to 3 positive lymph nodes based on results from several retrospective-prospective trials used several genomic assays and in particular prospective trials (TAILORx, RxPonder, MINDACT, and ADAPT used OncotypeDX® and Mammaprint®). Precise evaluation of tumor biology together with endocrine responsiveness assessment appears as promising tools for individualized treatment decisions together with clinical factors and menopausal status in early hormone-sensitive/HER2-negative breast cancer., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

TP53 mutation is associated with primary endocrine resistance in luminal breast cancer (BC). Nuclear accumulation of p53, as determined by immunohistochemistry (IHC), is a surrogate marker for TP53 mutation. The immunohistochemical p53 index that defines a p53-positive status is not well established. This study determined the optimal p53 index cutoff to identify luminal BCs harboring TP53 mutations. In total, 364 luminal BCs from the West German Study Group ADAPT trial (NCT01779206) were analyzed for TP53 mutations by next-generation sequencing and for p53 expression by IHC (DO-7 antibody). P53 indices were determined by automated image analysis. All tumors were from patients treated with short-term preoperative endocrine therapy (pET; tamoxifen or aromatase inhibitor) before tumor resection. IHC evaluation included needle biopsies before therapy (baseline) and resections specimens after therapy (post-pET). Optimal p53 index cutoffs were defined with Youden statistics. TP53 mutations were detected in 16.3% of BC cases. The median p53 indices were significantly higher in TP53-mutated BCs compared to BCs harboring wild-type TP53 (baseline: 47.0% vs 6.4%, P < .001; post-pET: 50.1% vs 1.1%, P < .001). Short-term pET decreased p53 indices in BCs harboring wild-type TP53 (P < .001) but not in TP53-mutated BCs (P = .102). For baseline biopsies, the optimal p53 index cutoff was ≥34.6% (specificity 0.92, sensitivity 0.63, Youden index 0.54, accuracy: 0.87). For post-pET specimens, the optimal cutoff was ≥25.3% (specificity 0.95, sensitivity 0.65, Youden index 0.60, accuracy: 0.90). Using these cutoffs to define the p53 status, p53-positive BCs were >2-fold more common in pET nonresponders compared to pET responders (baseline: 37/162, 22.8% vs 18/162, 11.1%, P = .007; post-pET: 36/179, 20.1% vs 16/179, 8.9%, P = .004). In summary, IHC for p53 identifies TP53-mutated luminal BCs with high specificity and accuracy. Optimal cutoffs are ≥35% and ≥25% for treatment-naïve and endocrine-pretreated patients, respectively., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452)., Experimental Design: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression., Results: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures., Conclusions: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Bevacizumab (BV) plus paclitaxel (PTX) is a treatment option in patients with HER2-negative metastatic breast cancer (mBC). We conducted an international pooled analysis with individual patient data to evaluate the effectiveness of BV + PTX as a first-line treatment for HER2-negative mBC patients under routine practice., Methods: A total of 2,474 mBC patients treated with BV + PTX from four prospective observational studies were analyzed. The primary endpoint was overall survival (OS). The other endpoints including identifying independent prognostic factors and validation of the modified Prognostic Factor Index (PFI) developed in the ATHENA trial., Results: Median follow-up time was 10.9 months (M). Median OS were 21.4 M (95% confidential interval 19.8-22.7 M). The seven independent prognostic factors (tumor subtype, age, ECOG performance status (PS), disease-free interval (DFI), liver metastases, number of metastatic organs, and prior anthracycline and/or taxane treatment) for OS found in this analysis included the five risk factors (RFs [DFI < 24 months, ECOG PS 2, liver metastases and/or > 3 metastasis organ sites, TNBC, prior anthracycline and/or taxane therapy]). High- (> 3 RFs [median OS 12.6 M]) and intermediate-risk groups (2 RFs [median OS 18.0 M]) had a significantly worse prognosis than the low-risk group (< 1 RF [median OS 27.4 M]), (p < 0.0001)., Conclusions: This international pooled analysis showed the effectiveness of first-line BV + PTX for HER2-negative mBC patients identifying seven independent prognostic factors as real-world evidence. The usefulness of the modified PFI developed in the ATHENA trial in predicting OS among patients receiving BV + PTX was also verified., (© 2022. The Author(s).)

Invasive lobular breast cancer (ILC) is a special breast cancer (BC) subtype and is mostly hormone receptor (HR)-positive and ERBB2 non-amplified. Endocrine therapy restrains tumor proliferation and is the mainstay of lobular BC treatment. Mutation of ERBB2 has been associated with recurrent ILC. However, it is unknown whether ERBB2 mutation impacts on the otherwise exquisite responsiveness of early ILC to endocrine therapy. We have recently profiled n = 622 HR-positive early BCs from the ADAPT trial for mutations in candidate genes involved in endocrine resistance, including ERBB2. All patients were treated with short-term preoperative endocrine therapy (pET, tamoxifen or aromatase inhibitors) before tumor resection. Tumor proliferation after endocrine therapy (post-pET Ki67 index) was determined prospectively by standardized central pathology assessment supported by computer-assisted image analysis. Sustained or suppressed proliferation were defined as post-pET Ki67 ≥10% or <10%. Here, we report a subgroup analysis pertaining to ILCs in this cohort. ILCs accounted for 179/622 (28.8%) cases. ILCs were enriched in mutations in CDH1 (124/179, 69.3%, P < 0.0001) and ERBB2 (14/179, 7.8%, P < 0.0001), but showed fewer mutations in TP53 (7/179, 3.9%, P = 0.0048) and GATA3 (11/179, 6.1%, P < 0.0001). Considering all BCs irrespective of subtypes, ERBB2 mutation was not associated with proliferation. In ILCs, however, ERBB2 mutations were 3.5-fold more common in cases with sustained post-pET proliferation compared to cases with suppressed post-pET proliferation (10/75, 13.3% versus 4/104, 3.8%, P = 0.0248). Moreover, ERBB2 mutation was associated with high Oncotype DX recurrence scores (P = 0.0087). In summary, our findings support that ERBB2 mutation influences endocrine responsiveness in early lobular BC., (© 2022. The Author(s).)

The recommendations of the AGO Breast Committee on the surgical therapy of breast cancer were last updated in March 2022 (www.ago-online.de). Since surgical therapy is one of several partial steps in the treatment of breast cancer, extensive diagnostic and oncological expertise of a breast surgeon and good interdisciplinary cooperation with diagnostic radiologists is of great importance. The most important changes concern localization techniques, resection margins, axillary management in the neoadjuvant setting and the evaluation of the meshes in reconstructive surgery. Based on meta-analyses of randomized studies, the level of recommendation of an intraoperative breast ultrasound for the localization of non-palpable lesions was elevated to "++". Thus, the technique is considered to be equivalent to wire localization, provided that it is a lesion which can be well represented by sonography, the surgeon has extensive experience in breast ultrasound and has access to a suitable ultrasound device during the operation. In invasive breast cancer, the aim is to reach negative resection margins ("no tumor on ink"), regardless of whether an extensive intraductal component is present or not. Oncoplastic operations can also replace a mastectomy in selected cases due to the large number of existing techniques, and are equivalent to segmental resection in terms of oncological safety at comparable rates of complications. Sentinel node excision is recommended for patients with cN0 status receiving neoadjuvant chemotherapy after completion of chemotherapy. Minimally invasive biopsy is recommended for initially suspect lymph nodes. After neoadjuvant chemotherapy, patients with initially 1 - 3 suspicious lymph nodes and a good response (ycN0) can receive the targeted axillary dissection and the axillary dissection as equivalent options., Competing Interests: Conflict of Interest/Interessenkonflikt Maggie Banys-Paluchowski received fees for lectures and consultancy activities from Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, AstraZeneca, Amgen, Samsung, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre and study support from EndoMag, Mammotome, MeritMedical. Marcus Schmidt reports that he received personal fees for lectures and consulting activities from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Roche and SeaGen, which are not related to this publication. Jens Huober: Research support: Celgene, Novartis, Hexal, Lilly. Lecture activity: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene; Eisai, Abbvie, Seagen, Gilead. Consultancy: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie. Travel expenses: Roche, Pfizer, Novartis, Celgene, Daiichi Sankyo. Peter Dall: Lecture fees: Novartis, Pfizer, AstraZeneca, Roche, Lilly. Ad Boards: Novartis, Seagen, Daiichi Sankyo, AstraZeneca, Roche, Gilead. David Krug: honoraria from Merck Sharp & Dohme and Pfizer as well as research funding from Merck KGaA. Other authors do not indicate any conflicts of interest./ Maggie Banys-Paluchowski erhielt Honorare für Vorträge und beratende Tätigkeiten von Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, AstraZeneca, Amgen, Samsung, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre und Studienunterstützung von EndoMag, Mammotome, MeritMedical. Marcus Schmidt berichtet, persönliche Honorare für Vorträge und Beratungstätigkeiten von AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Roche und SeaGen erhalten zu haben, die nicht im Zusammenhang mit der vorliegenden Publikation stehen. Jens Huober: Forschungsunterstützung: Celgene, Novartis, Hexal, Lilly. Vortragstätigkeit: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene; Eisai, Abbvie, Seagen, Gilead. Beratertätigkeit: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie. Reisekosten: Roche, Pfizer, Novartis, Celgene, Daiichi Sankyo. Peter Dall: Vortragshonorare: Novartis, Pfizer, AstraZeneca, Roche, Lilly. Ad-Boards: Novartis, Seagen, Daiichi Sankyo, AstraZeneca, Roche, Gilead. David Krug: honoraria from Merck Sharp & Dohme and Pfizer as well as research funding from Merck KGaA. Weitere AutorInnen geben keine Interessenkonflikte an., (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: Higher density of stromal tumor-infiltrating lymphocytes (sTILs) at baseline has been associated with increased rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC). While evidence supports favorable association of pCR with survival in TNBC, an independent impact of sTILs (after adjustment for pCR) on survival is not yet established. Moreover, the impact of sTIL dynamics during NACT on pCR and survival in TNBC is unknown., Methods: The randomized WSG-ADAPT TN phase II trial compared efficacy of 12-week nab-paclitaxel with gemcitabine versus carboplatin. This preplanned translational analysis assessed impacts of sTIL measurements at baseline (sTIL-0) and after 3 weeks of chemotherapy (sTIL-3) on pCR and invasive disease-free survival (iDFS). Predictive performance of sTIL-0 and sTIL-3 for pCR was quantified by ROC analysis and logistic regression; Kaplan-Meier estimation and Cox regression (with mediation analysis) were used to determine their impact on iDFS., Results: For prediction of pCR, the AUC statistics for sTIL-0 and sTIL-3 were 0.60 and 0.63, respectively, in all patients; AUC for sTIL-3 was higher in NP/G. The positive predictive value (PPV) of "lymphocyte-predominant" status (sTIL-0 ≥ 60%) at baseline was 59.3%, though only 13.0% of patients had this status. To predict non-pCR, the cut point sTIL-0 ≤ 10% yielded PPV = 69.5% while addressing 33.8% of patients. Higher sTIL levels (particularly at 3 weeks) were independently and favorably associated with better iDFS, even after adjusting for pCR. For example, the adjusted hazard ratio for 3-week sTILs ≥ 60% (vs. < 60%) was 0.48 [0.23-0.99]. Low cellularity in 3-week biopsies was the strongest individual predictor for pCR (in both therapy arms), but not for iDFS., Conclusion: The independent impact of sTILs on iDFS suggests that favorable immune response can influence key tumor biological processes for long-term survival. The results suggest that the reliability of pCR following neoadjuvant therapy as a surrogate for survival could vary among subgroups in TNBC defined by immune response or other factors. Dynamic measurements of sTILs under NACT could support immune response-guided patient selection for individualized therapy approaches for both very low levels (more effective therapies) and very high levels (de-escalation concepts)., Trial Registration: Clinical trials No: NCT01815242, retrospectively registered January 25, 2013., (© 2022. The Author(s).)

Purpose: To our knowledge, WSG-ADAPT-HR+/HER2- (ClinicalTrials.gov identifier: NCT01779206; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer., Materials and Methods: Baseline and postendocrine Ki67 (Ki67 post ) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67 post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental ( v control) arm; secondary end points included distant DFS, overall survival, and translational research., Results: Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was -3.3%, establishing prespecified noninferiority ( P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% ( P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001)., Conclusion: WSG-ADAPT-HR+/HER2- demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.

Background: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy., Methods: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models., Results: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology., Conclusion: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy., (© 2022. The Author(s).)

Background: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype., Methods: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m 2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment., Findings: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group)., Interpretation: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing., Funding: Roche, Bayer., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests UN reports research funding paid to their institution from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, and Sanofi; consulting fees from Genomic Health and Roche; honoraria from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis, Pfizer, Roche/Genentech, and Teva; payment for expert testimony from Genomic Health; travel support from Genomic Health, Pfizer, and Roche; participation on a data safety monitoring board or advisory board at Roche, Seagen, and Exact Sciences (all outside the submitted work); and a co-director position at the West German Study Group. OG reports consulting fees from Celgene, Genomic Health/Exact Sciences, Lilly, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, and Molecular Health; honoraria from Genomic Health/Exact Sciences, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, and AstraZeneca; payment for expert testimony from Genomic Health; and travel support from Roche (all outside the submitted work); and a co-director position at the West German Study Group. MG reports consulting fees from AstraZeneca and travel support from Daiichi Sankyo, all outside of the submitted work. SK reports research funding from Roche and Novartis; consulting fees from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health/Exact Science, Lilly, MSD, Novartis, Seagen, Pfizer, pfm Medical, Roche, Somatex, and Gilead; travel support from Roche and Daiichi Sankyo; and other financial or non-financial interests for non-continuing medical education services from Somatex, Roche, Novartis, and Lilly (all outside of the submitted work); and a co-director position at the West German Study Group. MB reports consulting fees from AstraZeneca, Exact Sciences, Novartis, Puma, and Roche; honoraria from AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva, and MSD; and travel support from AstraZeneca, Celgene, Medac, Novartis, Roche, and Daiichi Sankyo (all outside the submitted work). KK reports honoraria from Roche, RG Gesellschaft für Information und Organisation, Reuter Medico Consulting, and bsh medical communications (all outside the submitted work). HF reports honoraria from Roche and iOMEDICO (lecture); and travel support from Celgene and Amgen (all outside of the submitted work). TR reports research funding from Else Kröner-Fresenius-Stiftung and German Cancer Aid; consulting fees from Pfizer; honoraria from Pfizer, AstraZeneca, Novartis, Lilly, and Roche; and other financial or non-financial interests from Pfizer (all outside the submitted work). HHF reports consulting fees and honoraria from Roche Pharma, AstraZeneca, Pfizer, and Genomic Health (all outside of the submitted work). RK reports consulting fees from AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Sandoz, and Seattle Genetics; and honoraria from Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Zodiac Pharma (all paid to immediate family members and outside the submitted work); and a co-director position at the West German Study Group. RW reports consulting fees, honoraria, and travel support from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Eisai, Exact Sciences/Genomic Health, Gilead, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Tesaro Bio, Teva, Veracyte and Viatris; and other financial or non-financial interests from FomF (Forum for medical education in Germany), Aurikamed, Clinsol, and Pomme Med (all outside the submitted work). HHK reports honoraria for lectures from Roche Pharma, Novartis, Genomic Health, AstraZeneca, Lilly, and Pfizer; and participation in a data safety monitoring board or advisory board at Roche Pharma, Genomic Health, and AstraZeneca (all outside the submitted work). NH reports research funding paid to institution from Lilly, MSD, Novartis, Pfizer, and Roche/Genentech; honoraria for lectures or consulting from Amgen, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Sandoz, and Seagen (all outside the submitted work). All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A substantial minority of early breast cancer (EBC) patients relapse despite their tumors achieving pathologic complete response (pCR) after neoadjuvant therapy. We compared gene expression (BC360; nCounter ® platform; NanoString) between primary tumors of patients with post-pCR relapse (N = 14) with: (i) matched recurrent tumors from same patient (intraindividual analysis); and (ii) primary tumors from matched controls with pCR and no relapse (N = 41; interindividual analysis). Intraindividual analysis showed lower estrogen receptor signaling signature expression in recurrent tumors versus primaries (logFC = -0.595; P = 0.022). Recurrent tumors in patients with distant metastases also exhibited reduced expression of immune-related expression parameters. In interindividual analyses, primary tumor major histocompatibility complex class II expression was lower versus controls in patients with any relapse (logFC = -0.819; P = 0.030) or distant relapse (logFC = -1.151; P = 0.013). Primaries with later distant relapse also had greater homologous recombination deficiency than controls (logFC = 0.649; P = 0.026). Although no associations remained statistically significant following adjustment for false discovery rate, our results show that transcriptomic analyses have potential for prognostic value and may help in selecting optimal treatment regimens for EBC at risk of relapse and warrant further investigation., (© 2022. The Author(s).)

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

Background: Whereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer., Methods: In this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization., Results: ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each)., Conclusion: We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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/ ).)

Introduction: Tumor biological factors of breast cancer (BC) such as hormone receptor (HR) status, HER2 status, and grade can differ in the metastatic cascade from primary to lymph node (LN) metastasis and to distant metastatic tissue. Systematic data regarding therapeutic consequences are yet limited., Methods: We conducted a prospectively planned, retrospective cohort study comparing BC phenotype in tissue from primary tumors (PTs), locoregional LN metastases, and disease recurrence (DR). HR and HER2 as well as tumor grade in PTs and DR were obtained by a database search. No centralized biomarker testing was performed. The impact of changes in tumor biological factors on post-recurrence survival (PRS) and overall survival was analyzed., Results: PriMet comprises 635 patients (LN tissue in 142 patients). Discrepancies for HR or HER2 status between PT and DR were observed in 18.7 and 21.6% of cases, respectively. For HR status, positivity of PT and negativity of DR was seen more often (13.2%) than vice versa (5.5%). For HER2 status, negativity of the primary and positivity of DR was seen more often (14.9%) than vice versa (6.7%). Discordance was more often observed between PT and LN metastasis compared to LN versus DR. However, numbers were small. Compared to concordant non-triple-negative (TN) disease, concordant TN disease showed significantly inferior PRS., Conclusion: We demonstrate receptor discordance to occur relatively frequently between PT, LN metastasis, and DR and to impact patient prognosis. However, clinical consequences of receptor discordance need to be drawn with caution considering clinical aspects as well as tumor biology., Competing Interests: C. Kolberg-Liedtke has received honoraria/travel support by Phaon Scientific, Novartis, Pfizer, Celgene, Roche, AstraZeneca, Lilly, HEXAL, Amgen, Eisai, and SonoScape and has received research funding by Roche, Novartis, and Pfizer (CKL). O. Gluz has received lecture/consultancy fees from Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, and MSD, and assistance with travel costs from Celgene, Roche, and Daiichi-Sankyo. N. Harbeck has received honoraria for lectures and/or consulting from Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. R. Wuerstlein, M. Freudenberger, E. Bensmann, A. du Bois, U. Nitz, E. Pelz, M. Warm, M. Ortmann, E. Sultova, S.Y. Brucker, R.E. Kates, and T. Fehm state that they have no conflict of interest regarding the paper., (Copyright © 2020 by S. Karger AG, Basel.)

Objective: We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials., Methods: US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders., Results: pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45-5.29, and OR 4.17, 95%CI 2.26-7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08-1.24, and OR 1.25, 95%CI 1.16-1.35, respectively) as parameters associated with pCR., Conclusions: Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria., Competing Interests: Declaration of competing interest Dr. Graeser reports personal fees from AstraZeneca, non-financial support from Daiichi Sanyko, outside the submitted work. Dr. Harbeck reports ownership interest for WSG Study Group, personal fees from Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Zodiac Pharma, consulting/advisory role for Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, Seattle Genetics, West German Study Group (Institution), grants from Lilly (Institution), Merck Sharp & Dohme (Institution), Novartis (Institution), Pfizer (Institution), Roche/Genentech (Institution), outside the submitted work. Dr. Gluz reports ownership interest for WSG Study Group, personal fees from Genomic Health, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, AstraZeneca, consulting/advisory role for Celgene, Exact Sciences, Lilly, MSD Brazil, Novartis pharma SAS, Pfizer Pharmaceuticals Israel, Roche, grants from Roche, outside the submitted work. Dr. Wuerstlein reports non-financial support and consulting/advisory role for Agendia, Amgen, Aristo, Astra Zeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Esai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva, outside the submitted work. Dr. zu Eulenburg has nothing to disclose. Dr. Schumacher reports grants from Roche (Institution), Novartis (Institution), Boehringer (Institution), outside the submitted work. Dr. Grischke has nothing to disclose. Dr. Forstbauer reports personal fees, non-financial support and consulting/advisory role for Roche, Celgene, Amgen, outside the submitted work. Dr. Dimpfl has nothing to disclose. Dr. Braun reports personal fees from AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva, consulting/advisory role for AstraZeneca, Exact Sciences, Novartis, Puma, Roche, non-financial support from AstraZeneca, Celgene, Medac, Novartis, Roche, outside the submitted work. Dr. Christgen has nothing to disclose. Dr. Kreipe reports personal fees from Roche, Novartis, AstraZeneca, Genomic Health, consulting/advisory role for AstraZeneca, Genomic Health, Novartis pharma SAS, Roche Pharma AG, non-financial support from AstraZeneca, Genomic Health, Novartis pharma SAS, Roche Pharma AG, outside the submitted work. Dr. Potenberg has nothing to disclose. Dr. von Schumann has nothing to disclose. Dr. Aktas reports personal fees from Pfizer, Roche Pharma, Novartis Pharma, AstraZeneca, Amgen, Tesaro Bio Germany, PharmaMar, Eisei, consulting/advisory role for Novartis Pharma, Roche Pharma, Pfizer, Tesaro Bio, non-financial support from AstraZeneca, Amgen, Roche Pharma, Pfizer, Novartis Pharma, Tesaro Bio Germany, PharmaMar, Eisei, outside the submitted work. Dr. Kolberg-Liedtke reports ownership interest for Theraklion (Institution), Phaon Scientific (Institution), personal fees from Roche, AstraZeneca, Celgene, Novartis, Pfizer, Lilly, Hexal, Amgen, SonoScape, Pfizer (Institution), Novartis (Institution), Roche (Institution), Genomic Health (Institution), Amgen (Institution), AstraZeneca (Institution), Riemser (Institution), Carl Zeiss MediTec (Institution), TEVA Pharmaceuticals Industries (Institution), Theraklion (Institution), Janssen-Cilag (Institution), GlaxoSmithKline (Institution), LIV Pharma (Institution), consulting/advisory role for Roche, Novartis, Pfizer, Celgene, Phaon Scientific, Pfizer (Institution), Novartis (Institution), SurgVision (Institution), CarlZeissMeditec (Institution), Amgen (Institution), Onkowissen (Institution), grants from Roche, Novartis, Pfizer, non-financial support from Roche, Daiichi Sankyo, Novartis, Carl Zeiss Meditec (Institution), LIV Pharma (Institution), Novartis (Institution), Amgen (Institution), Pfizer (Institution), Daiichi Sankyo (Institution), outside the submitted work. Dr. Kümmel reports ownership interest for West German Study Group, consulting/advisory role for Roche, Genomic Health, Novartis, AstraZeneca, Amgen, Celgene, SOMATEX Medical Technologies, Daiichi Sankyo, pfm medical, Pfizer, MSD, Lilly, Sonoscape, non-financial support from Roche, Daiichi Sankyo, Sonoscope, outside the submitted work. Dr. Nitz reports other from West German Study Group, personal fees from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis pharma SAS, Pfizer Pharmaceuticals Israel, Roche/Genentech, Teva, other from Genomic Health, Roche, grants from Agendia (Institution), Amgen (Institution), Celgene (Institution), Genomic Health (Institution), NanoString Technologies (Institution), Roche (Institution), Sanofi (Institution), non-financial support from Genomic Health, Pfizer Pharmaceuticals Israel, Roche, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA -mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.

Competing Interests: N. Ditsch: MSD, Novartis, Pfizer, Roche, AstraZeneca, Teva, Mentor, MCI. M. Untch: Presentations and travel grants, all paid to his institution by Abbvie, Amgen GmbH München, AstraZeneca, BMS, Celgene GmbH München, Daiichi Sankyo, Eisai GmbH München, Janssen Cilag, Johnson & Johnson, Lilly Deutschland, Lilly Int., MSD, Mundipharma, Myriad Genetics GmbH Zürich, Odonate, Pfizer GmbH Berlin, PUMA Biotechnology, Riemser, Roche Pharma AG Grenzach-Wyhlen, Sanofi Aventis Deutschland GmbH, Sividon Diagnostics Köln, Teva Pharmaceuticals Ind. Ltd. Berlin. C. Kolberg-Liedtke: Advisory boards: Phaon Scientific, Novartis, Pfizer, SurgVision, Carl Zeiss Meditec, Amgen, Onkowissen. Lectures: Roche, Novartis, Pfizer, Lilly, Genomic Health, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, Teva, Theraclion Janssen-Cilag, GSK, LIV Pharma, Theramex. Travel expenses: Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo. D. Krug: MSD. M. Friedrich: Roche, Pfizer, AstraZeneca, Novartis. W. Janni: Research grants and/or honoraria: Sanofi-Aventis, Novartis, Roche, Pfizer, AstraZeneca, Chugai, GSK, Eisai, Celgene, Lilly, Janssen, Menarini. V. Müller: Speaker honoraria: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics. Consultancy honoraria: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Nektar. Institutional research support: Novartis, Roche, Seattle Genetics, Genentech. U.-S. Albert: Lectures and/or consulting: Medexo GmbH, Institut für Versiche­rungsmedizin, Pfizer. M. Banys-Paluchowski: Advisory board: Eisai. Lectures: AstraZeneca. Study support: Mammotome, EndoMag, MeritMedical. I. Bauerfeind: No conflicts of interest. J.-U. Blohmer: Honoraria: Amgen, AstraZeneca, Genomic Health, MSD Oncology, Myriad Genetics, Novartis, Pfizer, Roche, Sonoscape. Travel and accommodation expenses: Pfizer, Roche. W. Budach: No conflicts of interest. P. Dall: Advisory boards: Olympus, Roche, Novartis, Tesaro. Congress support: Roche. Lectures: Amgen, Roche. E.M. Fallenberg: GE Healthcare, Siemens, ECR, EUSOBI, ESOR, KCR, DFG. P.A. Fasching: Grants: Novartis, BioNTech, Cepheid. Personal fees: Novartis, Roche, Pfizer, Celgene, Daiichi Sankyo, AstraZeneca, MSD, Myelo Therapeutics, Macrogenics, Eisai, Puma, Lilly. T. Fehm: AstraZeneca, Celgene, Pfizer, Novartis, Roche, Teva, Daiichi Sankyo. B. Gerber: No conflicts of interest. O. Gluz: Lecture and consulting fees: Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, MSD. Travel expenses: Celgene, Roche, Daiichi Sankyo. N. Harbeck: Lecture and/or consulting fees: Agendia, Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. Minority share holder: Westdeutsche Studiengruppe. J. Heil: No conflicts of interest. J. Huober: Research support: Celgene, Novartis, Hexal. Lectures: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie. Consulting: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie. Travel expenses: Roche, Pfizer, Novartis, Celgene, Daiichi Sankyo. C. Jackisch: Advisory boards: Amgen, AstraZeneca, Novartis, Pierre Fabre, Exact Sciences, Roche, Lilly, Pfizer. Travel grants: Roche, Novartis, Pfizer, Exact Sciences, Amgen. Lectures: Amgen, AstraZeneca, Daiichi Sankyo, Novartis, Pierre Fabre, Exact Sciences, Roche, Lilly, Pfizer. H.-H. Kreipe: Reimbursement for attending symposia: Ventana. Other expenses (advisory boards, lectures): Amgen, AstraZeneca, Genomic Health, Lilly, Roche Pharma. T. Kühn: Celgene, Roche, Pfizer. S. Kümmel: Roche, Genentech, Novartis, AstraZeneca, Amgen, Celgene, SOMATEX, Daiichi Sankyo, Puma Biotechnology, pfm medical, Pfizer, MSD Oncology. S. Loibl: Advisory boards/lectures: Abbvie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Seattle Genetics, PriME/Medscape, Daiichi Sankyo, Lilly, Samsung, Eirgenix, BMS, Puma, MSD, Merck, Pierre Fabre. D. Lüftner: Advisory boards/oral presentations: Amgen, AstraZeneca, GSK, Eli Lilly, L'Oréal, MSD, Mundipharma, Mylan, Novartis, Pfizer, Roche, Teva. M.P. Lux: Advisory boards, lectures, travel support: Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, medac, Genomic Health. N. Maass: No conflicts of interest. C. Mundhenke: Not specified. U. Nitz: Not specified. T.-W. Park-Simon: Advisory role or expert testimony and lecture honoraria: Roche, AstraZeneca, Tesaro, Pfizer, Daiichi Sankyo, Lilly, MSD. Participation in clinical trials: Roche, AstraZeneca, Tesaro, Pfizer, Daiichi Sankyo, Lilly, MSD, Novartis, Seattle Genetics. Other financial relationships such as travel: Roche, AstraZeneca, Tesaro, Pfizer, Lilly, MSD, Novartis. T. Reimer: Grants: German Cancer Aid, Else Kröner-Fresenius-Stiftung. Personal fees. Pfizer, Roche, Novartis, AstraZeneca outside the submitted work. K. Rhiem: AstraZeneca, Tesaro, Pfizer, Roche. A. Rody: Roche, Pfizer, Novartis, Celgene, Novartis, Genomic Health/Exact Sciences, AstraZeneca, Eisai, MSD, Hexal, Amgen. M. Schmidt: Personal fees: AstraZeneca, Roche, Lilly, SeaGen, MSD, Eisai. Grants: Pierre Fabre, Pantarhei Bioscience, BioNTech, Genentech outside the submitted work. Patent issued for EP 2390370 B1 and EP 2951317 B1. A. Schneeweiss: Grants: Celgene, Roche, Abbvie, Molecular Partner. Personal fees: Roche, AstraZe­neca, Celgene, Pfizer, Novartis, MSD, Tesaro, Lilly. F. Schütz: Amgen, AstraZeneca, Lilly, Hexal, MSD, Novartis, Pfizer, Roche, Onkozert, Eickeler Kongressorganisation. H.-P. Sinn: No conflicts of interest related to the submitted manuscript. C. Solbach: Travel, accommodations: Roche, Novartis, AstraZeneca, Amgen, Celgene, Hexal, Daiichi Sankyo, Dialog Service GmbH, Lilly, Pfizer, MSD Oncology, ESAI, Gedon Richter, Mylan, Tesaro. E.-F. Solomayer: Roche, AstraZeneca, Pfizer, Amgen, Celgene, Tesaro, AstraZeneca, Storz, Erbe, Gedeon Richter, Eisai, Medac, MSD, Vifor, Teva, Ethikon. E. Stickeler: Counseling: Novartis, Pfizer, AstraZeneca, Roche, Tesoro. Fees: Novartis, Pfizer, AstraZeneca, Roche. C. Thomssen: Advisory boards and lectures: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, MSD, Mylan, Nanostring, Novartis, Pfizer, Pierre Fabre, Puma, Roche, Vifor. Research support (by discount prizes): American Diagnostica, Affymetrix, Nanostring. I. Witzel: Not specified. A. Wöckel: Amgen, AstraZeneca, Aurikamed, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Genomic Health, Pierre Fabre, Clovis. M. Thill: Advisory boards: Amgen, AstraZeneca, Celgene, ClearCut, Clovis, Daiichi Sankyo, Exact Sciences, Lilly, MSD, Neodynamics, Novartis, Pfizer, pfm medical, Pierre Fabre, Roche, Tesaro. Manuscript support: Amgen, Celgene, Roche. Travel expenses: Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Daiichi Sankyo, Exact Sciences, Hexal, I-Med Institute, Lilly, MCI, MSD, Novartis, Pfizer, pfm medical, Roche, Tesaro. Congress fees: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Hexal, Novartis, Pfizer, Roche. Lectures: Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Exact Sciences, Hexal, I-Med Institute, Lilly, MCI, MSD, Novartis, OnkoLive, Pfizer, pfm medical, Roche. Trial funding: Exact Sciences.

Competing Interests: M. Thill: Advisory boards: Amgen, AstraZeneca, Celgene, ClearCut, Clovis, Daiichi Sankyo, Exact Sciences, GSK, Lilly, MSD, Neodynamics, Novartis, Pfizer, pfm medical, Pierre Fabre, Roche, Sysmex, Tesaro. Manuscript support: Amgen, Celgene, Clearcut, Roche. Travel reimbursement: Amgen, art tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med Institute, Lilly, MCI, Medtronic, MSD, Novartis, Pfizer, pfm medical, Roche, Sysmex, Tesaro. Congress support: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Hexal, Novartis, Pfizer, Roche. Lectures: Amgen, art tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Daiichi Sankyo, Exact Sciences, Hexal, I-Med Institute, Lilly, MCI, Medtronic, MSD, Novartis, Pfizer, pfm medical, Roche, Seagen, Sysmex, Tesaro, Vifor. Trial funding: Endomagnetics, Exact Sciences. M. Friedrich: Roche, Pfizer, AstraZeneca, Novartis. C. Kolberg-Liedtke: Advisory boards: Phaon Scientific, Novartis, Pfizer, SurgVision, Carl Zeiss Meditec, Amgen, Onkowissen. Lectures: Roche, Novartis, Pfizer, Lilly, Genomic Health, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, TEVA, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Theramex. Travel grants: Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo. U.-S. Albert: Lectures and/or consulting: Medexo GmbH, Institut für Versicherungsmedizin, Pfizer. M. Banys-Paluchowski: Pfizer, Roche, Novartis, Eli Lilly. I. Bauerfeind: Aurikamed, J. Eickeler. J.-U. Blohmer: Honoraria: Amgen, AstraZeneca, Genomic Health Recipient, MSD Oncology, Myriad Genetics, Novartis, Pfizer, Roche, Sonoscape. Travel, accommodations, expenses: Pfizer, Roche. W. Budach: No conflicts of interest. P. Dall: Advisory boards: Olympus, Roche, Novartis, Tesaro. Congress support: Roche. Lectures: Amgen, Roche. E.M. Fallenberg: GE Healthcare, Siemens, ECR, EUSOBI, ESOR, KCR, Esor, DFG. P.A. Fasching: Grants: Novartis, BioNTech, Cepheid. Personal fees: Novartis, Roche, Pfizer, Celgene, Daiichi Sankyo, AstraZeneca, MSD, Myelo Therapeutics, Macrogenics, Eisai, Puma, Lilly. T. Fehm: AstraZeneca, Celgene, Pfizer, Novartis, Roche, Teva, Daiichi Sankyo. B. Gerber: No conflicts of interest. O. Gluz: Advisory boards/lectures: Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, MSD Travel. Grants: Celgene, Roche, Daiichi Sankyo. N. Harbeck: Honoraria for lectures and/or consulting: Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. Minority share holder: Westdeutsche Studiengruppe. J. Heil: No conflicts of interest. J. Huober: Trial funding: Celgene, Novartis, Hexal. Lectures: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie. Advisory boards: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie. Travel expenses: Roche, Pfizer, Novartis, Celgene, Daiichi Sankyo. C. Jackisch: Roche, AstraZeneca, Novartis. H.-H. Kreipe: Reimbursement for attending symposia: Ventana. Other expenses (advisory boards, lectures): Amgen, AstraZeneca, Genomic Health, Lilly, Roche. D. Krug: MSD. T. Kühn: Celgene, Roche, Pfizer. S. Kümmel: Roche, Genentech, Novartis, AstraZeneca, Amgen, Celgene, SOMATEX, Daiichi Sankyo, Puma Biotechnology, pfm medical, Pfizer, MSD Oncology. S. Loibl: Abbvie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Seattle Genetics, PriME/Medscape, Chugai, Teva, Vifor, Daiichi Sankyo, Lilly, Samsung, Eirgenix, BMS, Puma, MSD, Immunomedics. D. Lüftner: Advisory boards/lectures: Amgen, AstraZeneca, Celgene, GSK, Lilly, L'Oréal, MSD, Mundi­pharma, Mylan, Novartis, Pfizer, Roche, Teva, Tesaro. M.P. Lux: Advisory boards, lectures, travel support: Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, medac, Genomic Health. N. Maass: No conflicts of interest. C. Mundhenke: Not specified. U. Nitz: Not specified. T.-W. Park-Simon: Advisory role or expert testimony and lecture honoraria: Roche, AstraZeneca, Tesaro, Pfizer, Daiichi Sankyo, Lilly, MSD. Participation in clinical trials: Roche, AstraZeneca, Tesaro, Pfizer, Daiichi Sankyo, Lilly, MSD, Novartis, Seattle Genetics. Other financial relationships such as travel: Roche, AstraZeneca, Tesaro, Pfizer, Lilly, MSD, Novartis. T. Reimer: Grants: German Cancer Aid, Else Kröner-Fresenius-Stiftung. Personal fees: Pfizer, Roche, Novartis, AstraZeneca, outside the submitted work. K. Rhiem: AstraZeneca, Tesaro, Pfizer, Roche. A. Rody: Roche, Pfizer, Novartis, Celgen, Genomic Health/Exact Sciences, AstraZeneca, Eisai, MSD, Hexal, Amgen. M. Schmidt: Personal fees: AstraZeneca, Roche, Lilly, SeaGen, MSD, Eisai. Grants: Pierre Fabre, Pantarhei Bioscience, BioNTech, Genentech outside the submitted work. Patent issued for EP 2390370 B1 and EP 2951317 B1. A. Schneeweiss: Grants: Celgene, Roche, Abbvie, Molecular Partner. Personal fees: Roche, AstraZeneca, Celgene, Pfizer, Novartis, MSD, Tesaro, Lilly. F. Schütz: Amgen, AstraZeneca, Lilly, Hexal, MSD, Novartis, Pfizer, Roche, Onkozert, Eickeler Kongressorganisation. H.-P. Sinn: No conflicts of interest related to the submitted manuscript. C. Solbach: Travel, accommodation: Roche, Novartis, AstraZeneca, Amgen, Celgene, Hexal, Daiichi Sankyo, Dialog Service GmbH, Lilly, Pfizer, MSD Oncology, ESAI, Gedon Richter, Mylan, Tesaro. E.-F. Solomayer: Roche, AstraZeneca, Pfizer, Amgen, Celgen, Tesaro, Storz, Erbe, Gedeon Richter, Eisai, Medac, MSD, Vifor, Teva, Ethikon. E. Stickeler: Advisory boards: Novartis, Pfizer, AstraZeneca, Roche, Tesoro. Fees: Novartis, Pfizer, AstraZeneca, Roche. C. Thomssen: Advisory boards, lectures: Amgen, AstraZeneca, Celgen, Daiichi Sankyo, Eisai, Lilly, MSD, Mundipharma, Medapharm, Novartis, Pfizer, Pierre Fabre, Roche, Tesaro, Vifor. M. Untch: presentations, travel grants, all paid to his institution by Abbvie, Amgen, AstraZe­neca, BMS, Celgene, Daiichi Sankyo, Eisai, Janssen Cilag, Johnson & Johnson, Lilly Deutschland, Lilly Int., MSD, Mundipharma, Myriad Genetics GmbH Zürich, Odonate, Pfizer GmbH Berlin, Puma Biotechnology, Riemser, Roche, Sanofi Aventis Deutschland GmbH, Sividon Diagnostics Köln, TEVA Pharmaceuticals Ind. Ltd. Berlin. I. Witzel: Not specified. A. Wöckel: Amgen, AstraZeneca, Aurikamed, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro. V. Müller: Speaker honoraria: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics Consultancy honoraria: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Nektar. Institutional research support: Novartis, Roche, Seattle Genetics, Genentech. W. Janni: Research grants and/or honoraria: Sanofi-Aventis, Novartis, Roche, Pfizer, AstraZeneca, Chugai, GSK, Eisai, Celgene, Lilly, Janssen, Menarini. N. Ditsch: MSD, Novartis, Pfizer, Roche, AstraZeneca, TEVA, Mentor, MCI Healthcare.

We evaluated the role of early response after 3 weeks of neoadjuvant treatment (NAT) assessed by ultrasound (US), magnetic resonance imaging (MRI) and Ki-67 dynamics for prediction of pathologic complete response (pCR) in different early breast cancer subtypes. Patients with HR+/HER2+, HR-/HER2- and HR-/HER2+ tumors enrolled into three neoadjuvant WSG ADAPT subtrials underwent US, MRI and Ki-67 assessment at diagnosis and after 3 weeks of NAT. Early response was defined as complete or partial response (US, MRI) and ≥30% proliferation decrease or <500 invasive tumor cells (Ki-67). Predictive values and area under the receiver operating characteristic (AUC) curves for prediction of pCR (ypT0/is ypN0) after 12-week NAT were calculated. Two hundred twenty-six had MRI and 401 US; 107 underwent both MRI and US. All three methods yielded a similar AUC in HR+/HER2+ (0.66-0.67) and HR-/HER2- tumors (0.53-0.63), while MRI and Ki-67 performed better than US in HR-/HER2+ tumors (0.83 and 0.79 vs 0.56). Adding MRI+/-Ki-67 increased AUC of US in HR-/HER2+ tumors to 0.64 to 0.75. MRI and Ki-67 demonstrated highest sensitivity in HR-/HER2- (0.8-1) and HR-/HER2+ tumors (1, both). Negative predictive value was similar for all methods in HR+/HER2+ (0.71-0.74) and HR-/HER2- tumors (0.85-1), while it was higher for MRI and Ki-67 compared to US in HR-/HER2+ subtype (1 vs 0.5). Early response assessed by US, MRI and Ki-67 is a strong predictor for pCR after 12-week NAT. Strength of pCR prediction varies according to tumor subtype. Adding MRI+/-Ki-67 to US did not improve pCR prediction in majority of our patients., (© 2021 Westdeutsche Studiengruppe GmbH. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Background: The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored., Methods: Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression., Results: Compared with no change in immune cell composition and functional markers, transition from 'cold' to 'hot' (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after 'hot-to-cold' transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with 'altered' distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14)., Conclusion: Our exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with triple-negative primary breast cancer (TNBC) who have residual invasive carcinoma after neoadjuvant chemotherapy have poor prognosis. Proven adjuvant approaches to reduce the risk of recurrence and improve outcome in patients with non-pathological complete response (non-pCR) are limited., Methods: From our institutional registry, a consecutive case series of patients with operable, unilateral, primary invasive noninflammatory early TNBC of stage I-IIIB and pathologically verified residual cancer cells (no pathological complete response) after neoadjuvant chemotherapy underwent adjuvant treatment with gemcitabine plus cisplatin combined with regional hyperthermia. For quality assurance, we analyzed feasibility, efficacy, and toxicity of all treated patients. Outcome was evaluated for the entire group of patients as well as for the subgroups of patients with or without lymph node involvement at baseline (cN0/ cN+)., Results: From August 2012 to January 2019, we offered this treatment to 53 patients at our center as part of routine care. The median follow-up was 38 months. The majority of patients (64.2%) had cT2 tumors at baseline. Twenty-four patients (45%) were clinically node positive as evaluated by sonography. Thirty-nine patients (74%) had grade 3, and 14 patients (26%) had grade 2 tumors. Forty-one patients (76%) showed a regression grade 1 according to Sinn. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1-6) combined with 12 applications of regional hyperthermia (median 12, range 2-12). Disease-free survival (DFS) at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS at 3 years was significantly higher than in initially node-positive (cN+) patients (80 vs. 31%; p = 0.001). Overall survival (OS) at 3 years was 81.6%. In patients with no lymph node involvement at baseline (cN0), OS at 3 years was significantly higher than in node-positive (cN+) patients (93 vs. 70.4%; p = 0.02). Overall, grade 3/4 toxicities were leukopenia (38%), thrombocytopenia (4%), and anemia (4%)., Conclusion: After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of adjuvant gemcitabine plus cisplatin in combination with regional hyperthermia was safe and effective in TNBC patients with non-pCR., Competing Interests: O. Stoetzer and C. Salat received honoraria from MedTherm. D. Di Gioia received travel support from PharmaMar, Novartis, Merck, and Lilly. R. Issels received honoraria for invited lectures and reimbursement of travel expenses from PharmaMar, Bayer, Pyrexar, and MedTherm. S. Abdel-Rahman received travel support and honoraria from Dr. Sennewald Medizintechnik and MedTherm. L. Lindner received research and travel support from Dr. Sennewald Medizintechnik; travel support and honoraria from PharmaMar, Novartis, Lilly, Eisai, Bayer, Roche, and EL Medconsult. O. Gluz received advisory board and travel support from Celgene, Amgen, and Roche and honoraria from Genomic Health, Nanostring, Pfizer, Lilly, Novartis, Daiichi and Eisai. R. Würstlein received travel support, honoraria and consultancy from Celgene, Roche, MSD, Eisai, Pfizer, Astra Zeneca, Novartis, and Lilly. M. Braun received advisory board, honoraria and travel expenses from AstraZeneca, Celgene, Genomic Health, Medac, MSD, Novartis, Pfizer, Roche and Teva. All other authors declare no conflicts of interest., (Copyright © 2021 by S. Karger GmbH, Freiburg.)

Background: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes., Methods: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values., Results: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors., Conclusions: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT., Trial Registration: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).

Background: Protroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT)., Patients and Methods: Of the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed., Results: Nine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis ( n = 222) had febrile neutropenia of grade 3-4 (5 patients) or infection of grade 3-4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim., Conclusions: Application of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer., Competing Interests: Rachel Wuerstlein received personal fees/travel support from Agendia, Amgen, Astra Zeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Esai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, MSD, Mundipharma, NanoString Technologies, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, and Teva. Nadia Harbeck received personal fees (lectures and/or consulting) and research funding from Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis, Pfizer, Roche, AstraZeneca, Hexal, Roche/Genentech, Sandoz, and Boehringer Ingelheim (Inst). Ulrike Nitz received personal fees from Genomic Health and Roche. Oleg Gluz received personal fees/travel support from Genomic Health, NanoString Technologies, Roche, Celgene, and Teva. Eva-Maria Grischke received personal fees from Roche. Dirk Forstmeyer received personal fees (speaker's bureau and consulting) from Pfizer, Novartis, Roche, and MSD., (Copyright © 2020 by S. Karger AG, Basel.)

Background: Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC)., Methods: The prospective WSG-ADAPT HR+/HER2- trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical-pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0-11 or RS 12-25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy., Results: The ADAPT HR+/HER2- trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0-11, 58.3% RS 12-25, and 18.7% RS 26-100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26-100 versus others, RS 0-11 versus others) were significant (both p  < 0.001); Ki-67 quotients were higher for RS 26-100 ( p  = 0.02, Mann-Whitney). In premenopausal women ( n  = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women ( n  = 222, mostly aromatase-inhibitor treated; 0.67 versus 0.25, p  < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry ( p  = 0.002) or real-time polymerase chain reaction ( p  < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (R S  = 0.7, n  = 181)., Conclusions: This phase of the WSG-ADAPT HR+/HER2- trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%., Clinicaltrialsgov Identifier: NCT01779206., Competing Interests: Conflict of interest statement: U Nitz has minority non-profit ownership at WSG Study Group; received honoraria from Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Zodiac Pharma; has a consulting/advisory board role at Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, Seattle Genetics, received research funding from Lilly (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), Pfizer (Inst), Roche/Genentech (Inst), provided expert testimony for Genomic Health; and received travel accommodations/expenses from Roche, Genomic Health, Pfizer, Celgene. O Gluz has minority non-profit ownership at WSG Study Group; received honoraria from Genomic Health, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, AstraZeneca; has a consulting/advisory board role at Amgen, Roche, Daiichi Sankyo, Genomic Health, Merck Sharp & Dohme; and received travel accommodations/expenses from Roche, Celgene, Daiichi Sankyo. HH Kreipe received honoraria from Roche, Novartis, AstraZeneca, Genomic Health; has a consulting/advisory board role at Roche, Novartis, AstraZeneca, Genomic Health; and received travel accommodations/expenses from Genomic Health, Roche Pharma, Novartis, AstraZeneca. S Kuemmel has minority non-profit ownership at WSG Study Group; has a consulting/advisory board role at Roche, Genomic Health, Novartis, AstraZeneca, Amgen, Celgene, SOMATEX Medical Technologies, Daiichi Sankyo, pfm medical, Pfizer, MSD, Lilly, Sonoscape; and received travel accommodations/expenses from Roche, Daiichi Sankyo, Sonoscope. FL Baehner was an employee at Genomic Health. S Shak was an employee, had a leadership role, had stock, and PI related to Genomic Health. M Christgen, H Forstbauer, E Grischke, M Darsow, M Warm, and RE Kates declare no conflict of interest. B Aktas received honoraria from Pfizer, Roche Pharma, Novartis Pharma, AstraZeneca, Amgen, Tesaro Bio Germany, PharmaMar, Eisai; has a consulting/advisory board role at Novartis Pharma, Roche Pharma, Pfizer, Tesaro Bio; and received travel accommodations/expenses from AstraZeneca, Amgen, Roche Pharma, Pfizer, Novartis Pharma, Tesaro Bio Germany, PharmaMar, Eisai. M Braun received honoraria from AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Medac, Novatis, Pfizer, Roche, RTI Surgical, Teva; has a consulting/advisory board role at AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Medac, Novatis, Pfizer, Roche, RTI Surgical, Teva; and received travel accommodations/expenses from AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Medac, Novatis, Pfizer, Roche, RTI Surgical, Teva. K Lüdtke-Heckenkamp has a consulting/advisory board role at Roche, Lilly, Novartis, Celgene; received research funding from Roche (Inst), Lilly (Inst), Novartis (Inst), Pfizer (Inst); and received travel accommodations/expenses from Roche, Celgene, Pfizer, Novartis. B Nuding has a consulting/advisory board role at Roche, Novartis, Pfizer; and received travel accommodations/expenses from Novartis. C Schumacher received research funding from Roche (Inst), Novartis (Inst), Boehringer (Inst); and serves on the Speaker’s bureau of Roche. K Krauss has stock/interest at Fresenius (Fam); received honoraria from Roche, Celgene; received research funding from Novartis, Pfizer; and received travel accommodations/expenses from Medtronic. W Malter received honoraria from Nanostring, Celgene, Roche; and has a consulting/advisory board role at Genomic Health, Pfizer, Novartis, Hologic. M Thill received honoraria from Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Eisai, Exact Sciences, Daiichi Sanyko, Gedeon Richter, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Novartis, onkowissen.de, Omniamed, Pfizer, pfm Medical, Roche, RTI Surgical; has a consulting/advisory board role at Amgen, AstraZeneca, Biom‘Up, Celgene, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Lilly, MSD, Norgine, Neodynamics, Novartis, onkowissen.de, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Sysmex, Tesaro; received research funding from Exact Sciences; received travel accommodation/expenses from Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Norgine, Novartis, Omniamed, Pfizer, pfm Medical, Roche, RTI Surgical, Tesaro. R Wuerstlein has a consulting/advisory board role at Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva; received travel accommodation/expenses from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva; and is on the Speaker’s bureau of Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. N Harbeck has minority non-profit ownership at WSG Study Group; received honoraria for consulting and/or lectures from Agendia, Amgen, AstraZeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Samsung, Sandoz/Hexal, Seattle Genetics., (© The Author(s), 2020.)

Background: Invasive lobular breast cancer (BC) is the second most common BC subtype. Prognostic parameters (tumor classification, lymph node status, histologic grade, Oncotype DX recurrence score [RS], progesterone receptor status, and Ki67 index) were retrospectively studied in a large, prospective clinical trial encompassing 2585 patients who had hormone receptor-positive early BC (the West German Study Group PlanB trial)., Methods: BCs were centrally reviewed and classified as lobular (n = 353; 14%) or nonlobular (n = 2232; 86%). The median follow-up was 60 months. Five-year disease-free survival (DFS) estimates were obtained using the Kaplan-Meier method. Prognostic parameters were evaluated using Cox proportional hazard models., Results: Lobular BC was associated with higher tumor classification, higher lymph node status, lower histologic grade, lower Ki67 index, and low or intermediate RS. The prevalence of high RS (RS range, 26-100) was 3-fold lower in patients who had lobular BC compared with those who had nonlobular BC (8% vs 24%; P < .001). However, 5-year DFS estimates for lobular and nonlobular BC were similar (92.1% and 92.3%, respectively; P = .673). In multivariate analyses, prognostic parameters for DFS in lobular BC included grade 3 (hazard ratio, 5.06; 95% CI, 1.91-13.39) and a pathologic lymph node status (pN) of pN3 (hazard ratio, 12.16; 95% CI, 3.87-38.24), but not RS. By contrast, prognostic parameters in nonlobular BC included grade 3 (hazard ratio, 1.65; 95% CI, 1.11-2.44), pN3 (hazard ratio, 3.68; 95% CI, 1.60-8.46), and high RS (hazard ratio, 2.49; 95% CI, 1.69-3.68)., Conclusions: Lobular BC is associated with low and intermediate RS, although 5-year DFS is similar to that of nonlobular BC. The effect of the RS in lobular BC appears to be distinct from that in nonlobular BC. For risk assessment, the RS needs to be complemented by clinicopathologic parameters for therapy decision making., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20-8.41% of tumors across 15 cancer types as ERBB2 -high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2-4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis., Competing Interests: Competing interestsM.D. is on advisory board in Lilly, H3Biomedicine, AbbVie, Orion and consultancy: Radius; Honoraria for lectures: Nanostring, Myriad. M.J.E. reports ownership and income from Veracyte/Nanostring for Royalties for Prosigna and ad hoc consulting fees from Novartis, Pfizer, AstraZenica, GI therapeutics, Foundation Medicine, Sermonix, Abbvie. O.G. has Lecture/consultancy fees from Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, MSD; assistance with travel costs: Celgene, Roche, Daiichi Sankyo; S.K. reports personal fees from Roche/Genentech, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, MSD, Pfizer, Puma Biotechnology, PFM Medical, Lilly, Sonoscape. C.X.M. reports research funding from Pfizer, consulting fees from AstraZeneca, Novartis, Eli Lilly, Seattle Genetics, and Athenex Oncology. N.H. reports personal fees (lectures / consulting) from Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. The remaining authors declare no conflict of interests., (© The Author(s) 2020.)

Competing Interests: Prof. Dr. med. Nina Ditsch: MSD, Roche, AstraZeneca, TEVA, Mentor, and MCI Healthcare. Prof. Dr. med. Michael Untch: Presentations, travel grants, all paid to his institution from: Abbvie, Amgen GmbH München, AstraZeneca, BMS, Celgene GmbH München, Daiji Sankyo, Eisai GmbH München, Janssen Cilag, Johnsen & Johnsen, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics GmbH Zürich, Odonate, Pfizer GmbH Berlin, PUMA Biotechnology, Riemser, Roche Pharma AG, Grenzach Wyhlen, Sanofi Aventis Deutschland GmbH, Sividon Diagnostics Köln, TEVA Pharmaceuticals Ind. Ltd., and Berlin Pharmaceutical Industry. Prof. Dr. med. Cornelia Kolberg-Liedtke: Consulting: Phaon Scientific, Novartis, Pfizer, Pfizer, Novartis, SurgVision, Carl Zeiss Meditec, Amgen, and Onkowissen; presentations: Roche, Novartis, Pfizer, Lilly, Pfizer, Novartis, Roche, Genomic Health, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, TEVA, Theraclion Janssen-Cilag, GSK, LIV Pharma, and Theramex; travel grants: Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, and Daiichi Sankyo. Prof. Dr. med. Christian Jackisch: Roche, AstraZeneca, and Novartis. Dr. David Krug: Merck Sharp & Dome. Prof. Dr. med. Michael Friedrich: Roche, Pfizer, AstraZeneca, and Novartis. Prof. Dr.med. Wolfgang Janni: Research grants and/or honoraria from: Sanofi-Aventis, Novartis, Roche, Pfizer, AstraZeneca, Chugai, GSK, Eisai, Cellgene, Lilly, Janssen, and Menarini. Prof. Dr. med. Volkmar Müller: Speaker honoraria from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, and Seattle Genetics; consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, and Nektar; institutional research support from Novartis, Roche, Seattle Genetics, and Genentech. Prof. Dr. med. Ute-Susann Albert: Lectures and/or consulting: Medexo GmbH, Institut für Versicherungsmedizin (IMV), and Pfizer. PD Dr. Malgorzata Banys-Paluchowski: Pfizer, Roche, Novartis, and Eli Lilly. Dr. med. Ingo Bauerfeind: Aurikamed and J. Eickeler. Prof. Dr. med. Jens-Uwe Blohmer: Honoraria: Amgen, AstraZeneca, Genomic Health Recipient, MSD Oncology, Myriad Genetics, Novartis, Pfizer, Roche, and Sonoscape; travel, accommodations, expenses: Pfizer and Roche. Prof. Dr. med. Wilfried Budach: No conflicts of interest. Prof. Dr. med. Peter Dall: Advisory boards: Olympus, Roche, Novartis, and Tesaro; congress support: Roche; lecture fees: Amgen and Roche. Prof. Dr. med. Ingo Diel: No conflicts of interest regarding this manuscript. PD Dr. med. Eva Maria Fallenberg: GE-Healthcare, Siemens, ECR, EUSOBI, ESOR, KCR, and DFG. Prof. Dr. med. Peter A. Fasching: Grants from Novartis, Biontech, and Cepheid; personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi-Sankyo, AstraZeneca, Merck Sharp & Dohme, Myelo Therapeutics, Macrogenics, Eisai, Puma, and Lilly. Prof. Dr. med. Tanja Fehm: AstraZeneca, Celegene, Pfizer, Novartis, Roche, Teva, and Daichii Sankyo. Prof. Dr. med. Bernd Gerber: No conflicts of interest. PD Dr. med. Oleg Gluz: Honoraria for lectures and/or consulting: Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, and MSD; travel grants: Celgene, Roche, and Daiichi Sankyo. Prof. Dr. Volker Hanf: No conflicts of interest regarding this manuscript. Prof. Dr. med. Nadia Harbeck: Honoraria for lectures and/or consulting: Agendia, Amgen, AstraZeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics; Minority shareholder: Westdeutsche Studiengruppe (WSG). Prof. Dr. med. Jörg Heil: No conflicts of interest. Prof. Dr. med. Jens Huober: Research grants: Celgene, Novartis, and Hexal; lecture honoraria: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, and Abbvie; consulting: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, and Abbvie; travel expenses: Roche, Pfizer, Novartis, Celgene, and Daiichi. Herr Prof. Dr. med. habil. Hans H. Kreipe: Reimbursement for attending symposia: Ventana; other expenses (advisory boards, lectures): AMGEN, AstraZeneca, Genomic Health, Lilly, and Roche Pharma. Prof. Dr.med. Thorsten Kühn: Celgene, Roche, and Pfizer. Prof. Dr. med. Sherko Kümmel: Roche, Genentech, Novartis, AstraZeneca, Amgen, Celegene, SOMATEX, Daiichi Sankyo, Puma Biotechnologx, pfm medical, Pfizer, and MSD Oncology. Prof. Dr. med. Sibylle Loibl: Abbvie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Seattle Genetics, PriME/Medscape, Chugai, Teva, Vifor, Daiichi-Sankyo, Lilly, Samsung, Eirgenix, BMS, Puma, MSD, and Immunomedics. Prof. Dr. med. Diana Lüftner: Advisory boards/oral presentations: Amgen, AstraZeneca, Celegene, Lilly, Loreal, MSD, Mundipharma, Mylan, Novartis, Pfizer, Roche, Teva, and Tesaro. Prof. Dr. med. Michael Lux: Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, Medac, and Genomic Health for advisory boards, lectures, and travel support. Prof. Dr. med. Nicolai Maass: No conflicts of interest. Prof. Dr. med. Volker Moebus: Amgen, Celegene, Roche, Myelotherapeutics, Roche, and Amgen. Prof. Dr. med. Christoph Mundhenke: Not specified. Prof. Dr. Tjoung-Won Park-Simon: Advisory role or expert testimony and lecture honoraria: Roche, AstraZeneca, Tesaro, Pfizer, Daichii, Lilly, and MSD; participation in clinical trials: Roche, AstraZeneca, Tesaro, Pfizer Daichii, Lilly, MSD, Novartis, and Seattle Genetics; other financial relationships, e.g., travel: Roche, AstraZeneca, Tesaro, Pfizer, Lilly, MSD, and Novartis. Prof. Dr. med. Toralf Reimer: grants from German Cancer Aid and Else Kroener-Fresenius-Stiftung; personal fees from Pfizer, Roche, Novartis, and AstraZeneca, outside the submitted work. PD. Dr. med. Kerstin Rhiem: AstraZeneca, Tesaro, Pfizer, and Roche. Prof. Dr. med. Achim Rody: Roche, Pfizer, Novartis, Celgen, Novartis, Genomic Health/Exact Sciences, AstraZeneca, Eisai, MSD, Hexal, and Amgen. Prof. Dr. med. Markus Schmidt: Honoraria: AstraZeneca, Novartis, Pfizer, and Roche; consulting or advisory role: AMGEN, AstraZeneca, BioNTech, Eisai, Lilly, Myelo Therapeutics, Novartis, Pantarhei Bioscience, Pfizer, and Roche; travel, accommodations, expenses: BioNTech, Pantarhei Bioscience, Pfizer, and Roche; patents, royalties, other intellectual property: Patent issued EP2951317. Prof. Dr. med. Andreas Schneeweiss: Grants: Celgene, Roche, Abbvie, and Molecular Partner; personal fees: Roche, AstraZeneca, Celgene, Pfizer, Novartis, MSD, Tesaro, and Lilly. Prof. Dr. med. Christine Solbach: Travel, accommodations: Roche, Novartis, AstraZeneca, Amgen, Celgene, Hexal, Daiichi Sankyo, Dialog Service GmbH, Lilly, Pfizer, MSD Oncology, ESAI, Gedon Richter, Mylan, and Tesaro. Prof. Dr. med. Erich-Franz Solomayer: Roche, AstraZeneca, Pfizer Roche, Amgen, Celgen, Tesaro, AstraZeneca, Pfizer, Storz, Erbe, Gedeon Richter, Eisai, Medac, MSD, Vifor, Teva, and Ethikon. Prof. Dr. med. Elmar Stickeler: Consulting: Novartis, Pfizer, AstraZeneca, Roche, and Tesoro; honoraria: Novartis, Pfizer, AstraZeneca, and Roche. Prof. Dr. med. Christoph Thomssen: Advisory boards, lectures: Amgen, AstraZeneca, Celgen, Daiichi-Sankyo, Eisai, Lilly, MSD, Mundipharma, Medapharm, Novartis, Pfizer, Pierre-Fabre, Roche, Tesaro, and Vifor. PD Dr. Isabell Witzel: Not specified. Prof. Dr. med. Achim Wöckel: Amgen, AstraZeneca, Aurikamed, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, and Tesaro. PD. Dr. med. Marc Thill: Advisory board: Amgen, AstraZeneca, Celgene, ClearCut, Clovis, Daiichi Sankyo, Exact Sciences, Lilly, MSD, Neodynamics, Novartis, Pfizer, pfm Medical, Pierre-Fabre, Roche, and Tesaro; manuscript support: Amgen, Celgene, and Roche; travel expenses: Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Daiichi Sankyo, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, MSD, Novartis, Pfizer, pfm Medical, Roche, and Tesaro; congress costs: Amgen, AstraZeneca, Celgene, Daiichi Sanyko, Hexal, Novartis, Pfizer, and Roche; lectures: Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, MSD, Novartis, OnkoLive, Pfizer, pfm Medical, and Roche; trial funding: Exact Sciences.

Background: The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies., Methods: The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm., Results: Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories., Conclusion: Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.

The most important goal of treatment of patients with metastatic breast cancer is maintenance or even improvement of quality of life. In this setting, chemotherapy should be used with as much restraint as possible. If palliative chemotherapy is indicated, the taxane drug class is an established treatment option. The updated guidelines of the Gynaecological Oncology Working Group (AGO), Breast Committee, of the German Society for Gynaecology and Obstetrics (DGGG) and the German Cancer Society e. V. (DKG) provide recommendations with the greatest possible evidence on which of the licensed taxanes can be used in which treatment situation in the metastatic setting., Competing Interests: Conflict of Interest/Interessenkonflikt Oleg Gluz: lecture/consultancy fees: Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, MSD; assistance with travel costs: Celgene, Roche, Daiichi Sankyo. Cornelia Liedtke: lecture/consultancy fees: Phaon Scientific, Novartis, Pfizer, Celgene, Roche, AstraZeneca, Lilly, Hexal, Amgen, Eisai, SonoScape; research sponsorship: Roche, Novartis, Pfizer; travel costs: Roche, Novartis. Marc Thil: lecture/consultancy fees: Amgen, AstraZeneca, Aurikamed, BiomʼUp, Celgene, Daiichi Sankyo, Eisai, Genomic Health, Hexal, Lilly, MCI, Medtronic, MSD, Myriad, Neodynamics, Norgine, Novartis, OnkoLive, OmniaMed, pfmMedical, Pfizer, Roche, Tesaro, Teva, RTI Surgical and research support by Genomic Health. Frederik Marme: lecture/consultancy fees: AstraZeneca, Tesaro, Roche, Novartis, Pfizer, PharmaMar, GenomicHealth, CureVac, Amgen, Eisai, MSD, Celgene, Clovis, Vaccibody, Immunomedics, Janssen-Cilag./ Oleg Gluz: Vortrags/Beratungshonorare: Celgene, Roche, Genomic Health, Amgen, Pfizer, Novartis, Lilly, Nanostring, Eisai, MSD; Reisekostenunterstützung Celgene, Roche, Daiichi Sankyo. Cornelia Liedtke: Vortrags/Beratungshonorare: Phaon Scientific, Novartis, Pfizer, Celgene, Roche, AstraZeneca, Lilly, Hexal, Amgen, Eisai, SonoScape; Forschungsförderung: Roche, Novartis, Pfizer; Reisekosten: Roche, Novartis. Marc Thil: Vortrags/Beratungshonorare: Amgen, AstraZeneca, Aurikamed, BiomʼUp, Celgene, Daiichi Sankyo, Eisai, Genomic Health, Hexal, Lilly, MCI, Medtronic, MSD, Myriad, Neodynamics, Norgine, Novartis, OnkoLive, OmniaMed, pfmMedical, Pfizer, Roche, Tesaro, Teva, RTI Surgical und Forschungsunterstützung von Genomic Health. Frederik Marme: Vortrags/Beratungshonorare: AstraZeneca, Tesaro, Roche, Novartis, Pfizer, PharmaMar, GenomicHealth, CureVac, Amgen, Eisai, MSD, Celgene, Clovis, Vaccibody, Immunomedics, Janssen-Cilag.

The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. We find that hypoxia fosters relative resistance to T-DM1 in HER2 + cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking. IMPLICATIONS: Together, our data for the first time identify hypoxic regulation of caveolin-1 as a resistance mechanism to T-DM1 with potential implications for individualized treatment of breast cancer., (©2020 American Association for Cancer Research.)

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

In the neoadjuvant WSG-ADAPT-TN trial, 12-week nab-paclitaxel + carboplatin (nab-pac/carbo) was highly effective and superior to nab-paclitaxel + gemcitabine (nab-pac/gem) in triple-negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab-pac 125 mg/m 2 (plus carbo AUC2 or gem 1,000 mg/m 2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow-up. Basal-like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki-67 (IHC; p < 0.001). For nab-pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab-pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event-free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal-like subtype, higher Ki-67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches., (© 2019 UICC.)

Purpose: Although dose-dense (dd) chemotherapy plays a fundamental role in the treatment of breast cancer (BC), a variety of trials have presented divergent survival results. Here, we present data of patients with more than 3 positive axillary lymph nodes (+aLN) receiving dd chemotherapy after a median follow-up period of 12.3 years., Methods: In the years 1996-2000, 231 patients with invasive BC, ≥pN2a and no evidence of distant metastases were recruited to receive treatment A, i.e. dd 3 × epirubicin (E, 90 mg/m 2 ) + paclitaxel (P, 175 mg/m 2 ) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m 2 , q2w), or treatment B, i.e. 4 × E + C (C, 600 mg/m 2 ) q3w followed by 3 × CMF q3w., Results: 113 patients in arm A and 113 patients in arm B were analysed after an updated median follow-up of 12.3 years. The median age was 55 years, with a median number of 6 +aLN, 50.4% had a T2 and 79.2% hormone receptor-positive BC. The disease-free survival (DFS) rate was 53.1% in arm A and 42.5% in arm B (adjusted p = 0.027). The overall survival (OS) rate was 54.9% in arm A and 48.7% in arm B (adjusted p = 0.058). In the multivariable analysis, the tumour burden was a significant predictor for DFS and OS., Conclusion: The adjuvant use of dd chemotherapy led to a statistically significant improvement of DFS after a follow-up of 12.3 years.

Purpose: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer., Methods: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires., Results: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in "discordant" groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients' State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients., Conclusions: MammaPrint and BluePrint test results strongly impacted physicians' therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

The rapid increase in knowledge in tumour biology and tumour pathogenesis of triple-negative breast cancer (TNBC) has resulted in new therapeutic approaches and new therapeutic concepts for treatment. For years, TNBC has been considered to be a difficult-to-treat tumour due to its generally aggressive tumour biology and in view of limited therapeutic options. The risk of recurrence and metastasis is higher than in the case of other breast cancer subtypes of the same stage. In addition to surgery and radiation in the curative situation, systemic chemotherapy with anthracyclines and/or taxanes is still the therapy of choice. New therapeutic approaches are based on the knowledge that TNBC is a molecularly very heterogeneous disease. Research groups are working to classify TNBC better and better on a molecular level and use this molecular subtyping as the basis for new therapeutic strategies. The most promising new approaches and considerations regarding the therapy of TNBCs are shown below. In addition, the current therapeutic strategies are discussed using a fictitious case history, taking the current data and the resultant therapeutic consequence into account.

The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial, written by Ulrike Nitz, Oleg Gluz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Wolfram Malter, Benno Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Andrea Stefek, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne Just, Doris Augustin, Cornelia Liedtke, Calvin Chao, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe, Nadia Harbeck, was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 29, 2017 without open access.With the author(s)' decision to opt for Open Choice the copyright of the article changed on January 6, 2019 to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated. The original article has been corrected.

Purpose: The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC)., Patients and Methods: Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E) 90 /cyclophoshamide (C) 600 followed by four cycles of docetaxel (T) 100 or six cycles of T 75 C 600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined., Results: Of the 3,198 registered patients, 348 (RS ≤ 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v 60.8%; pN0, 58.2% v 59.5%; pT1, 57.6% v 52.3%; HR positive, 81.4% v 82.2%; RS greater than 25 [in HR-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v 89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v 94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status., Conclusion: In the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease.