Search

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20–50%), and specific locus.Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers.In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well.Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options.Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options.

Background: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer., Methods: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival., Results: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index., Conclusions: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

BRCA1 and BRCA2 are tumor suppressor genes that have been linked to inherited susceptibility of breast cancer. Germline BRCA1/2 pathogenic or likely pathogenic variants (gBRCAm) are clinically relevant for treatment selection in breast cancer because they confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. BRCA1/2 mutation status may also impact decisions on other systemic therapies, risk-reducing measures, and choice of surgery. Consequently, demand for gBRCAm testing has increased. Several barriers to genetic testing exist, including limited access to testing facilities, trained counselors, and psychosocial support, as well as the financial burden of testing. Here, we describe current implications of gBRCAm testing for patients with breast cancer, summarize current approaches to gBRCAm testing, provide potential solutions to support wider adoption of mainstreaming testing practices, and consider future directions of testing., (© 2024. The Author(s).)

Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes., Patients and Methods: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]., Results: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype)., Conclusions: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset., Methods: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05., Results: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS., Conclusions: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in 2021, virtual, and ABC 7 in 2023, in Lisbon, Portugal), organized by the ABC Global Alliance. It provides the main recommendations on how to best manage patients with advanced breast cancer (inoperable locally advanced or metastatic), of all breast cancer subtypes, as well as palliative and supportive care. These guidelines are based on available evidence or on expert opinion when a higher level of evidence is lacking. Each guideline is accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage of consensus reached at the consensus conferences. Updated diagnostic and treatment algorithms are also provided. The guidelines represent the best management options for patients living with ABC globally, assuming accessibility to all available therapies. Their adaptation (i.e. resource-stratified guidelines) is often needed in settings where access to care is limited., Competing Interests: Declaration of competing interest Matti S. Aapro: Consultant for Accord Pharmaceuticals, Amgen, BMS, Celgene, Clinigen Group, Daiichi Sankyo, Eisai Co.Ltd, Eli Lilly, Genomic Health (Exact Sciences), G1 Therapeutics, Inc., GlaxoSmithKline (GSK), Helsinn Healthcare SA, Hospira (Pfizer), Johnson & Johnson, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro (GSK), Teva Pharmaceuticals Industries Ltd., Vifor Pharma. Received honoraria for lectures at symposia of Accord Pharmaceuticals, Amgen, Astellas, Bayer HealthCare Pharmaceuticals (Schering), Biocon, Boeringer Ingelheim, Cephalon, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Dr Reddy's Laboratories, Genomic Health (Exact Sciences), Glenmark Pharmaceuticals Limited, GSK, Helsinn Healthcare SA, Hospira (Pfizer), Ipsen, Janssen Biotech, Kyowa Kirin Group, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro (GSK), Taiho Pharmaceutical, Teva Pharmaceutical Industries Ltd., Vifor Pharma. Grant/Research supports: Amgen, Eisai, Genomic Health (Exact Sciences), Helsinn, Hospira, Novartis, Merck, Mundipharma, Pfizer, Roche, Sandoz, Tesaro, Teva, Vifor. Jyoti Bajpai: Institutional financial interests for conducting research: Eli Lilly, MSD, Novartis, Roche, Paxman Coolers Ltd, Samsung Bioepis co. Ltd, Sun Pharma. Carlos H. Barrios: Receipt of grants/research supports: (to the institution) Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Lilly, Seagen, Roche, BMS, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, Servier. Receipt of honoraria or consultation fees: Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Lilly, Sanofi, Daiichi. Stock shareholder: Ownership or stocks: Tummi, MEDSir. Jonas Bergh: Receipt of grants/research supports: Research grants from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche & Sanofi-Aventis to Karolinska Institutet and/or University Hospital. No personal payments. Other support: Payment for a chapter in UpToDate on breast cancer prediction to Asklepios Medicin HB. Laura Biganzoli: Personal financial interests (Honoraria, consultancy or advisory role): Amgen, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Menarini, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, SeaGen. Institutional financial interests: Celgene, Genomic Health, Novartis. Travel grants: AstraZeneca, Daiichi-Sankyo. Fatima Cardoso: Receipt of honoraria or consultation fees: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, Touchime. Maria-Joao Cardoso: Receipt of honoraria or consultation fees: AstraZeneca, Merck-Sharp, Novartis and Roche. Lisa A. Carey: Other support: Research funding (institution): NanoString Technologies, Seagen, Veracyte, AstraZeneca. Uncompensated relationships: Lilly, Seagen, Novartis, Genentech/Roche, GlaxoSmithKline. Mariana Chavez-MacGregor: Receipt of grants/research supports: BCRF, Susan G Komen. Receipt of honoraria or consultation fees: Astra Zeneca, Pfizer, Lilly, Roche, Merck. Javier Cortés: Receipt of grants/research supports: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies. Receipt of honoraria or consultation fees: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca. Stock shareholder: MedSIR, Nektar Pharmaceuticals, Leuko (relative). Other support: Research funding to the Institution: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London. Travel, accommodation, expenses: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca, Gilead. Patents: Pharmaceutical Combinations of a Pi3k Inhibitor and A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED. Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED. Giuseppe Curigliano: Receipt of grants/research supports: Merck. Receipt of honoraria or consultation fees: Merck, Lilly, Pfizer, Daichi Sankyo, Seagen, Novartis, Roche, Astra Zeneca, Ellipsis. Participation in a sponsored speakers' bureau: Seagen, Novartis, Lilly, Pfizer, Daichii Sankyo. Rebecca A. Dent: Receipt of grants/research supports: AstraZeneca, Roche. Receipt of honoraria or consultation fees: AstraZeneca, DKSH, Eisai, Merck, Novartis, Pfizer, Roche. Nagi S. El Saghir: Receipt of honoraria or consultation fees: Roche, Novartis, Lilly. Alexandru Eniu: Receipt of honoraria or consultation fees: Astra Zeneca, Daiichi Sankyo, Gilead, Janssen, MSD, Novartis, SeaGen. Receipt of grants/research supports: AstraZeneca. Full or part-time employment: European School of Oncology (ESO). Lesley Fallowfield: Receipt of grants/research supports: Novartis, Bristol-Myers Squibb, Lilly. Receipt of honoraria or consultation fees: Voluntis, Genomic Health, NanoString Technologies, Novartis, Pfizer, MSD, Novartis, Abbvie, Clovis Oncology, Puma Biotechnology, AstraZeneca, Takeda, Genomic Health/Exact Sciences, Lilly, Seagen, Roche. Sandra X. Franco Millan: Receipt of honoraria or consultation fees: Novartis, Pfizer, Eli Lilly. Participation in a sponsored speakers' bureau: Novartis, Pfizer, Eli Lilly. Karen Gelmon: Receipt of grants/research supports: Pfizer, AstraZeneca. Receipt of honoraria or consultation fees: Pfizer, Lilly, Novartis, AstraZeneca, Merck, Gilead, Seagen. Jenny Gilchrist: Receipt of honoraria or consultation fees: Eli-Lilly, AstraZeneca, Novartis, Pfizer, MSD, Gilead, Juniper Biologics. Joseph Gligorov: Receipt of grants/research supports: Eisai, Exact Science, Guardant, Roche Genentech. Receipt of honoraria or consultation fees: Astra Zeneca, Daiichi, Eisai, Evapharma, Exact Science, Gilead, Guardant Lilly, Merck, Novartis, Onxeo, Pfizer, Roche Genentech, Seattle Genetics. Participation in a sponsored speakers' bureau: Eisai, Eva Pharm, Novartis, Roche Genentech, Seattle Genetics. Other support (please specify): Institutional: Institut Universitaire de Cancérologie AP-HP Sorbonne Université; French breast cancer guidelines St Paul. Nadia Harbeck: Receipt of grants/research supports: all to institution. Receipt of honoraria or consultation fees: AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, PierreFabre, Pfizer, Roche, Sandoz, Seagen, Viatris, Zuelligpharma. Participation on a sponsored speakers' bureau: EPG Communication, MEDSCAPE, Springer. Stock shareholder: WSG minority ownership. Spouse/Partner: Consulting for WSG. Ranjit Kaur: Receipt of grants/research supports: Novartis, Roche, Pfizer, Astrazeneca. Receipt of honoraria or consultation fees: Novartis, Roche, Pfizer, Astrazeneca. Participation in a sponsored speakers' bureau: Novartis, Roche, Pfizer, Astrazeneca. Belinda Kiely: Receipt of honoraria or consultation fees: Speakers fees: Novartis, Eisai. Advisory boards: Roche, Gilead, Novartis. Other support (please specify): meeting registrations fees: Novartis, Pfizer, MSD. Sung-Bae Kim: Receipt of grants/research supports: Novartis, Sanofi-Aventis, and DongKook Pharm Co. Receipt of honoraria or consultation fees: Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, OBI pharma, Beigene and Daiichi-Sankyo. Stock shareholder: Genopeaks. Smruti Koppikar: Receipt of honoraria or consultation fees: Eli Lilly, Novartis, Cipla, Roche. Participation in a sponsored speakers' bureau: Eli Lilly, Novartis, Cipla, Roche. Marion Kuper-Hommel: Receipt of honoraria or consulting fees: Astra Zeneca. Ginny Mason: Participation in a sponsored speakers' bureau: Novartis. Volkmar Mueller: Receipt of grants/research supports: Institutional research support from Novartis, Roche, Seagen, Genentech, Astra Zeneca. Receipt of honoraria or consultation fees: Speaker honoraria: Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre. Consultancy honoraria from Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, DaiichiSankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, Stemline, ClinSol. Other support (please specify): Travel grants: Roche, Pfizer, Daiichi Sankyo, Gilead. Claire Myerson: Receipt of honoraria or consultation fees: Novartis Pharma. Silvia Neciosup: Receipt of grants/research supports: Roche, Pfizer. Participation in a sponsored speakers' bureau: Tecnofarma, AZ, Roche, Pfizer. Larry Norton: Receipt of honoraria or consultation fees: Blackrock QLS Advisors, Cold Spring Harbor Laboratory, UNC Breast Spore EAB Meeting, Codagenix Scientific Advisory Board Meeting, Martell Diagnostic Laboratories, Inc., Celgene, Agenus, Immix Biopharma, Inc. Shinji Ohno: Participation in a sponsored speakers' bureau: Chugai, Lilly, MSD, Nippon Kayaku. Shani Paluch-Shimon: Receipt of grants/research supports: Pfizer. Receipt of honoraria or consultation fees: Pfizer, Lily, Novartis, Astra Zeneca, Roche, MSD, Gilead, Rhenium/Exact Sciences, Stemline, Daichi Sankyo. Participation in a sponsored speakers' bureau: Pfizer, Lily, Novartis, Astra Zeneca, Roche, MSD, Gilead. Ann H. Partridge: Uptodate Royalties. Aleix Prat: Receipt of grants/research supports: Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia inno. Research, SL, Celgene, Astellas and Pzifer. Receipt of honoraria or consultation fees: Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardan Health, Peptomyc and Lilly, Nanostring Technologies and Daiichi Sankyo. Other support: Clinical trials: Boehringer, Lilly, Roche, Novartis, Amgen and Daiichi Sankyo. Hope S. Rugo: Receipt of grants/research supports: Astellas Pharma Inc.; AstraZeneca; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Gilead Sciences, Inc.; GlaxoSmithKline; Lilly; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer; Pionyr Immunotherapeutics; Sermonix Pharmaceuticals Inc.; Taiho Oncology, Inc. and Veru Inc. Receipt of honoraria or consultation fees: Puma, NAPO, Blueprint, and Scorpion Therapeutics Daichi Sankyo. Elzbieta Senkus: Receipt of honoraria or consultation fees: AstraZeneca, Curio Science, Egis, Eli Lilly, Gilead, high5md, MSD, Novartis, Pfizer, Roche, Swixx. Other support: travel support: AstraZeneca, Egis, Gilead, Novartis, Roche. Contracted research: Amgen, AstraZeneca, Eli Lilly, Gilead, Novartis, OBI Pharma, Roche, Samsung, Seagen. Medical writing: AstraZeneca, Eli Lilly. Royalties: Springer. Sandra M. Swain: Receipt of grants/research supports: Kailos Genetics, Genentech/Roche. Receipt of honoraria or consultation fees: Athenex, AstraZeneca, Biotheranostics, Natera, Exact Sciences, Lilly, Merck, Genentech/Roche, Sanofi, Daiichi Sankyo, Molecular Templates, Napo Pharmaceuticals. Stock shareholder: SEAGEN. Other support: CO- PI of INAVO 122 Genentech/Roche with in-kind travel to investigator meetings, Travel related expenses in kind Sanofi and Daiichi Sankyo. Peter Vuylsteke: Receipt of grants/research supports: UICC grant. Receipt of honoraria or consultation fees: Roche, Novartis and MSD. Theresa Wiseman: Receipt of grants/research supports: Receiver of SPCC Pfizer grant. Binghe Xu: Receipt of grants/research supports: sponsored research to my institution from Roche, AstraZeneca and Pfizer. Receipt of honoraria or consultation fees: advisory or consultancy fees from Novartis and Roche. Participation in a sponsored speakers' bureau: speakers’ bureau fees from AstraZeneca, Pfizer, Roche, Eisai. Elizabeth Bergsten-Nordström, Alberto Costa, Runcie C. W. Chidebe, Prudence A. Francis, Xichun Hu, Renate Haidinger, Leonor Matos, Shirley A. Mertz, Birgitte V. Offersen, Olivia Pagani, Eva Schumacher-Wulf, Daniel A. Vorobiof, Frédéric E. Lecouvet, and Eric P. Winer reported no significant relationships. William J. Gradishar, George W. Sledge and Christoph Thomssen have not submitted a disclosure of interests’ form., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3., Patients and Methods: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint., Results: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed., Conclusions: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We compared 21-gene recurrence score (RS) distribution and expression of the single-gene/gene groups within this assay between BC patients with pathogenic variants (PV) in BRCA1/2 vs the general 21-gene-tested BC population., Methods: This retrospective study included consecutive 21-gene-tested female ER + HER2-negative BC patients with germline PVs in BRCA1/2. RS/gene expression data were compared to a previously described commercial use database (CDB, N = 799,986). Chi-square and 1-sample t test were used to compare RS distribution and single-gene/gene group scores between the study group and the CDB., Results: Study group patients (N = 81) were younger and their RS results were higher compared to the CDB (age: median [IQR], 56 [47-61.5] vs 60 [51-67] years; p < 0.001; proportion of patients with RS ≥ 26: 49.4% vs 16.4%, p < 0.001). Expression of 12/16 cancer genes in the assay and the ER, proliferation, and invasion gene group scores differed significantly between the study group and the CDB, all in a direction contributing to higher RS. The differences between the study group and the CDB were mostly retained, upon stratifying the patients by menopausal status., Conclusion: BC patients with PVs in BRCA1/2 have higher RS results that stem from distinct gene expression profiles in the majority of genes in the 21-gene assay., (© 2024. The Author(s).)

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers., Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers., Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023., Exposure: Pregnancy after breast cancer., Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes., Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival., Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival., Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Data on using the 21-gene Recurrence Score (RS) testing on second breast cancer (BC; second primary or local recurrence) are lacking. This cohort study examined patients with first and second BC, who underwent 21-gene testing both times. It included a 'study-cohort' (60 N0/N1mi/N1 ER + HER2‒ BC patients with ≥2 RS results >1 year apart) and a 'general 21-gene-tested BC-cohort' (2044 previously described N0/N1mi/N1 patients). The median time between the first and second BC was 5.2 (IQR, 3.1-7.1) years; the second BC was ipsilateral in 68%. Patient/tumor characteristics of the first- and second-BC in the 'study-cohort' were similar, except for the RS which was higher in the second BC (median [IQR]: 23 [17-30] vs 17 [14-22], p < 0.001). Overall, 56 patients had follow-up data, of whom 5 experienced distant recurrence (2 RS 11-25 patients and 3 RS 26-100 patients). Studies exploring the prognostic utility of the RS in this setting are warranted., (© 2023. The Author(s).)

Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan-Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4-99.2%) vs 97.9% (94.6-99.2%); DRFS, 91.5% (86.6-94.7%) vs 91.2% (86.0-94.6%); BCSM, 0.5% (0.1-3.7%) vs 1.6% (0.5-4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2-8.6%] vs 6.2% [2.0-17.7%] for CT-treated and untreated patients, respectively, p = 0.024)., (© 2023. The Author(s).)

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Eva Blondeaux reports research grant (to the Institution) from Gilead to pursue research effort in the field of TP53 pathogenic variants. Kevin Punie reports honoraria for consultancy/advisory roles from Astra Zeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead Sciences, MSD, Novartis, Pfizer, Roche, Seagen; honoraria for consultancy/advisory roles paid to my institution from Astra Zeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, Seagen. Research funding paid to my institution from Sanofi and MSD. Stock options: Need Inc. Travel support: Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche. Carmine De Angelis reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, and GSK, Travel Grants from Gilead and research support (to the Institution) from Novartis outside the submitted work. Sabine C. Linn reports an advisory role for AstraZeneca and Daiichi Sankyo Europe GmbH (paid to the institution), travel and accommodation expenses from Daiichi Sankyo Europe GmbH, and research support (to the institution) from Genentech/Roche, AstraZeneca, Bristol Myers Squibb, Tesaro (now GSK), Merck, Immunomedics (now Gilead), Eurocept Pharmaceuticals, Agendia, and Novartis. Mara Cruellas reports speaker honoraria from Roche and Astrazeneca. Shani Paluch-Shimon reports - advisory Board consultancy, speaker’s bureau: AstraZeneca, Pfizer, Novartis, Lilly, Roche, MSD, Exact Sciences. Gilead. Travel: Roche. Research Funding: Pfizer. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda, Travel Grants from Gilead and research support (to the Institution) from Gilead outside the submitted work. All the other authors declare no conflict of interest.’, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients., Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE., Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated., Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months)., Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population., Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib., Competing Interests: SPS reports fees for from Pfizer for corporate-sponsored research; fees for speaker’s bureau, honoraria, consultancy from Roche, Novartis, Pfizer, and AstraZeneca; fees for consultancy from Eli Lilly and Company and Gilead; and fees for speaker’s bureau and consultancy from MSD, outside the submitted work. PN reports institutional fees for consultancy from Pfizer, Novartis, Eli Lilly and Company, Roche, and Astrazeneca; institutional fees for advisory board participation from Pfizer, Novartis, Eli Lilly and Company, Roche, and Sanofi; institutional fees for lecturing and attendance at scientific exchange meetings, and research funding from Kom op Tegan Kanker, outside the submitted work. JH receives fees for advisory board participation from Eli Lilly and Company, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, and Abbvie; fees for corporate-sponsored research from Celgene, Novartis, Hexal, and Eli Lilly and Company; and fees for travel expenses from Roche, Pfizer, Novartis, Celgene, and Daiichi Sankyo, outside the submitted work; IC has nothing to disclose, outside the submitted work; MPG reports institutional fees for consultancy from Eli Lilly and Company, Biovica, Novartis, Sermonix, Context Pharm, Pfizer, AstraZeneca, Eagle Pharmaceuticals; personal fees from Genomic Health; institutional grant from Pfizer, Eli Lilly and Company, Sermonix; institutional honoraria for advisory board participation from ARC Therapeutics, Blueprint Medicines, Sanofi Genzyme, Biotheranostics; personal fees for CME presentation from Research to Practice, Clinical Education Alliance, Medscape; personal fees for session moderating from Curio Science; personal fees for serving as a panelist from Total Health Conferencing, outside the submitted work; CS reports grants for corporate-sponsored research from Eli Lilly and Company, outside the submitted work. CSH reports personal fees and grants for advisory board participation and speaker’s bureau from Eli Lilly and Company, Novartis, and Daiichi Sankyo; grants, personal fees, and non-financial support for advisory board participation, and speaker’s bureau from Pfizer, Roche and AstraZeneca; grants from EirGenix and OBI Pharma, grants and personal fees for speaker’s bureaus from MSD; outside the submitted work. HJL reports fees for corporate-sponsored research and travel support from Eli Lilly and Company, outside the submitted work. JB reports institution fees for advisory board participation from Eli Lilly and Company, Roche, and Pfizer, outside the submitted work. ET reports personal fees for lectures from Eli Lilly and Company, AstraZeneca and Daiichi Sankyo, outside the submitted work. JRC reports corporate-sponsored research fees from Eli Lilly and Company. ROS reports corporate-sponsored research fees from Eli Lilly and Company. RW, AS, SCN, TF are employees and stock shareholders of Eli Lilly and Company. SRDJ reports personal fees for consulting, advisory role, speaker’s bureau, and research funding from AstraZeneca, Novartis, Pfizer; personal fees for consulting, advisory role, research funding from Eli Lilly and Company, Puma Biotechnology; personal fees for speaker’s bureau from Eisai; and personal fees for speaker’s bureau, research funding from Roche/Genentech, outside the submitted work. NH reports personal fees for lectures and consulting from AstraZeneca, Eli Lilly and Company, Novartis, and Pfizer, outside the submitted work., (© The Author(s), 2023.)

Competing Interests: Disclosure CS has reported non-remunerated activities as Coordinator Gynecological Programme for the European School of Oncology. JB has reported fees for advisory board membership for AstraZeneca and Pfizer; fees paid to her institute for roles as local principal investigator for AstraZeneca, MedSire and Pfizer. SLB has reported fees as an author for UpToDate. She has also reported non-remunerated activities as the chair of the Scientific Network on Female Sexual Health and Cancer (academic organisation). MJC has reported fees as an invited speaker for Roche (industry-sponsored symposium in National Conference). She has also reported non-remunerated activities as a member of the Board of Directors of EUSOMA, faculty member of ESO, project lead/lead investigator for the Breast Research Group of INESC TEC and President of MAMA Help (non-profit association for breast cancer patients in Portugal). She serves as a Specialty Editor for The Breast. NC has reported fees for advisory board membership for AstraZeneca, BIOCAD, Clovis Oncology, Eisai, GlaxoSmithKline (GSK), ImmunoGen, Mersana, Merck Sharp & Dohme (MSD)/Merck, Nuvation Bio, OncXerna, Pfizer, PharmaMar, Pieris and Roche; fees as an invited speaker for AstraZeneca, Clovis Oncology, GSK and MSD/Merck; institutional research grants from AstraZeneca, PharmaMar and Roche. She has also reported non-remunerated activities as member of the ESMO Guidelines Steering Committee and chair of the Scientific Committee of Alleanza contro il Tumore Ovarico (ACTO). GC has reported fees for advisory board membership for AstraZeneca, Bristol Myers Squibb (BMS), Celcuity, Daiichi Sankyo, Ellipsis, Exact Sciences, Lilly, Merck, Pfizer, Roche and Veracyte; fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Novartis, Pfizer and Roche; fees for a writing engagement from Pfizer; institutional research grant from Merck for an investigator-initiated trial; institutional funding for phase I studies from Astellas, AstraZeneca, Blueprint Medicine, BMS, Daiichi Sankyo, Kymab, Novartis, Philogen, Relay Therapeutics, (coordinating principal investigator), Roche and Sanofi. He has also reported non-remunerated activities as an Italian National Health Council as Advisor for Ministry of Health (Consiglio Superiore di Sanità), member of the Scientific Council for the patient advocacy association Europa Donna, advisory role at the Fondazione Beretta cancer research foundation, member of the Board of Directors for Lega Italian Lotta ai Tumori (public national company for cancer prevention) and member of the Advisory Council of EUSOMA. SMD has reported personal honoraria from AstraZeneca, BMS and Clovis; fees paid to her institute as coordinating principal investigator for AstraZeneca. DGE has reported fees for advisory board membership for Recursion, SpringWorks and Syantra; consultancy fees for a writing engagement for AstraZeneca. DF has declared no conflicts of interest. NH has reported fees for advisory board membership for Aptitude Health, AstraZeneca, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Sandoz-Hexal, Sanofi and SeaGen; fees as an invited speaker for Art Tempi, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, Medscape, MSD, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi and SeaGen; institutional funding from AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Palleos, Pierre Fabre, Roche, SeaGen, TRIO and WSG; ownership interest in the West German Study Group. She has also reported non-remunerated activities as a member of the AGO Breast Guideline Committee and member of the ESO/ESCO Breast Cancer Educational Programs. She is the Founding Editor of the Breast Care journal. CK has reported fees for advisory board membership for Guerbet; fees as an invited speaker for Bayer and Bracco. BL has reported fees received from the Rising Tide Foundation as a patient reviewer. She has also reported non-remunerated activities as a member of the European Society of Gynaecological Oncology (ESGO) ENGAGe (Past Executive Board Member) and chair of KIU—Danish Patient Organisation for Women with Gynaecological Cancer. ELL has reported employment as the Director of the Medical Genetics Institute of the Shaare Zedek Medical Center. She has also reported non-remunerated activity as the vice president of the Israel National Academy of Science in Medicine (non-profit). ML has reported fees for advisory board membership and speaker fees for AstraZeneca, Exact Sciences, Gilead, Lilly, MSD, Novartis, Roche and SeaGen; fees as an invited speaker for Ipsen, Knight, Libbs, Pfizer, Sandoz, SeaGen and Takeda. JAL has reported fees for advisory board membership for Artios Pharma, AstraZeneca, BMS, Clovis Oncology, Eisai, Ellipses, GSK, ImmunoGen, Merck/MSD, Nuvation, Pfizer and VBL Therapeutics; speaker fees from AstraZeneca, Clovis Oncology, GSK and Neopharm; fees related to an independent data monitoring committee for Regeneron; institutional research grants from AstraZeneca, Clovis Oncology, Eisai, GSK, MSD/Merck and Pfizer. He has also reported non-remunerated activities as vice president of the European Society of Gynaecological Oncology (2019-2021). He serves as an associate editor of Therapeutic Advances in Medical Oncology (Sage Publishing). SL has reported fees paid to her institute for advisory board membership for AbbVie, Amgen, AstraZeneca, BMS, Celgene, DSI, EirGenix, Gilead, GSK, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi and SeaGen; fees paid to her institute as an invited speaker for AstraZeneca, DSI, Gilead, Novartis, Pfizer and Roche; employment as the Chief Executive officer (CEO) of GBG Forschungs GmbH; licensing fees paid to her institute by VM Scope GmbH; research grants to her institute from AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics/Gilead, Novartis, Pfizer and Roche; institutional funding from AbbVie and Molecular Health; fees paid to her institute as principal investigator (Penelope/Padma) from Pfizer; fees paid to her institute from AstraZeneca (SC Capitello), Daiichi Sankyo (SC Destiny B05), Immunomedics/Gilead (SC ASCENT), Novartis (SC SOLAR1), Pfizer (SC PALOMA3), Roche (SC Inavo and SC Katherine), SeaGen (SC HERCLIMB). She has also reported non-remunerated activities as principal investigator for Aphinity, advisory role to Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Kommission Mamma (group in Germany responsible for breast cancer guidelines), membership of AGO, Deutsche Krebsgesellschaft (DKG), American Society of Clinical Oncology (ASCO) and ESMO including membership of the ESMO Guidelines Committee and past chair of the ESMO Breast Congress. She has reported institutional patents for which she has no financial interests: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8. K-AP has reported non-remunerated activities as advisory board member for AstraZeneca, Scientific Advisory Committee member for Breast Cancer Trials, project lead in Australia for the DECRESENDO and OlympiA studies, member of the Expert Advisory Group on Cancer Clusters for the Victorian Department of Health and Human Services, Strategic Advisory Committee member for Breast Cancer Network Australia, Cancer Genetics Reference Committee Member for New South Wales Cancer Institute; advisory role on the register of experts for breast and hereditary cancer for the Medical Oncology Group of Australia and breast cancer optimal care pathway committee member for Cancer Council Victoria. She is also a leadership fellow of the National Health and Medical Research Council (Australia) and a practitioner fellow of the National Breast Cancer Foundation (Australia). SP-S has reported fees paid to her institute for advisory board membership for AstraZeneca, Eli Lilly, Exact Sciences, Medison, Pfizer and Roche; fees paid to her institute as an invited speaker for AstraZeneca, Eli Lilly, Exact Sciences, Medison, Novartis, Pfizer and Roche; fees paid to her institute for consultancy for Medison; personal and institutional research grant for an request for proposal for independent research put out by Shared Progress in Cancer Care and Pfizer.

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed., Competing Interests: Declaration of interest statements Matti Aapro: Advisor for Eisai, Helsinn, Merck, Mundipharma, Roche, and Tesaro; honoraria from Eisai, Helsinn, Merck, Mundipharma, Roche, and Tesaro; grants from Helsinn, Merck, Roche, and Tesaro. Fatima Cardoso: Consultancy fees for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, IQVIA, MacroGenics, Medscape, Merck Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, touchIME. Giuseppe Curigliano: Personal fees from Roche, Pfizer, Novartis, Lilly, Foundation Medicine, Samsung, AstraZeneca, Daichii Sankyo, GSK, Seagen; non-financial support from Roche, Pfizer; grants from Merck; other from Ellipses, outside the submitted work. Alexandru Eniu: Grants/Research support from AstraZeneca, Roche Celltrion, Pfizer, and Novartis; honoraria or consultation fees from Merck Sharp & Dohme, Gilead, Seagen, Novartis, and Janssen. Joseph Gligorov: Grants, personal fees and non-financial support for clinical trials, travel support, advisory boards, and speakers' bureaus from Roche-Genentech, Eisai, Exact Sciences, and Pfizer; personal fees and nonfinancial support for clinical trials, travel support, advisory boards, and speakers' bureaus from Novartis and Lilly; personal fees and nonfinancial support for clinical trials and advisory boards from Daiichi Sankyo and MSD; grants and personal fees for travel support, advisory boards, and speakers' bureaus from Mylan; personal fees and nonfinancial support for travel support, advisory boards, and speakers' bureaus from Pierre Fabre; and personal fees for advisory boards and speakers’ bureaus from AstraZeneca, outside the submitted work. Nadia Harbeck: Honoraria for lectures and/or consulting: Amgen, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, and Seagen. Andreas Mueller: Stock and other ownership interests from Vifor Pharma; honoraria from Eli Lilly and Novartis; consulting or advisory role for Novartis, Eli Lilly, Pfizer, Genomic Health, AstraZeneca, Roche, Daiichi Sankyo, Merck Sharp & DohmeMerck Sharp & Dohme, Pierre Fabre, Exact Sciences, Myriad Genetics, Gilead Sciences, GlaxoSmithKline; research funding from Eisai; travel, accommodations, expenses from Roche. Olivia Pagani: Participation in advisory boards for Roche, Eli Lilly, Novartis, Takeda, Pfizer, Debiopharm, Ipsen. Educational activity for Takeda, Pfizer, and Ipsen. Shani Paluch-Shimon: Speaker's bureau, honoraria, advisory board and consultancy for Roche, Pfizer, AstraZeneca, Novartis, Medison, Lilly. Elzbieta Senkus: Honoraria from Amgen, AstraZeneca, Cancérodigest, Clinigen, Curio Science, Egis, Eli Lilly, Genomic Health, Gilead, high5md, Novartis, Oncompass Medicine, Pfizer, Pierre Fabre, Roche, Sandoz, TLC Biopharmaceuticals; fees for travel support from Amgen, AstraZeneca, Egis, Novartis, Pfizer, and Roche; grants from Amgen, AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche, and Samsung; stock from AstraZeneca, Eli Lilly, and Pfizer. Beat Thürlimann: Holds stock of Roche, Merck, and Novartis; advisory board member for Pierre Fabre, Pfizer, Roche, AstraZeneca, Eli Lilly; honoraria Oncogenomics, Daiichi Sankyo, Merck Sharp & Dohme, and InnoMedica. Khalil Zaman: Participation in advisory board or talk: AstraZeneca, Daiichi, Exact Sciences, Eli Lilly, Pierre Fabre, Gilead, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seagen, and Viatris/Mylan., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We dedicate this manuscript in memory of a dear friend and colleague Bella Kaufman. The fifth International Consensus Symposium for Breast Cancer in Young Women (BCY5) took place virtually in October 2020, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY4 with incorporation of new evidence to inform the guidelines. Areas of research priorities as well as specificities in different geographic and minority populations were identified. This manuscript summarizes the ESO-ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA)., Competing Interests: Disclosure SPS: Advisory Board consultancy, speaker's bureau: AstraZeneca, Pfizer, Novartis, Lilly, Roche, MSD, Exact Sciences. Research Funding: Pfizer. HAA: Recipient of grants/research supports: Amgen. Recipient of honoraria or consultation fees: Novartis, Roche. Employment: Pierre Fabre. FC: Recipient of honoraria or consultation fees: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Samsung Bioepis. GC: Recipient of grants/research supports: Merck, Astra Zeneca. Recipient of honoraria or consultation fees: Daichii Sankyo. Participation in a sponsored speakers’ bureau: Novartis, Pfizer, Lilly. KAG: Recipient of grants/research supports: Pfizer, Astra Zeneca. Recipient of honoraria or consultation fees: Pfizer, Lilly, Astrazeneca, Novartis, Mylan, Benentech, Merck, Roche, Nanostring. NH: Honoraria for lectures and/or consulting from Amgen, Astra Zeneca, Daiichi-Sankyo, Exact Sciences, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Seagen (all outside the submitted work). SBK: Research funding from Novartis, Sanofi-Aventis and DongKook Pharm Co; consultant in advisory boards—Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, Daiichi-Sankyo and Beigene; and stocks—Genopeaks, NeogeneTC (all outside the submitted work). FP: Recipient of honoraria or consultation fees: Roche Diagnostics, Ipsen, Merck (all outside the submitted work). ES: Recipient of grants/research supports: Amgen, AstraZeneca, Boehringer, Eli Lilly, Merck, Novartis, Pfizer, Roche, Samsung. Recipient of honoraria or consultation fees: Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, TLC Biopharmaceuticals. Travel support: Amgen, AstraZeneca, Egis, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Abnormal molecular processes occurring throughout the genome leave distinct somatic mutational patterns termed mutational signatures. Exploring the associations between mutational signatures and clinicopathological features can unravel potential mechanisms driving tumorigenic processes. We analyzed whole genome sequencing (WGS) data of tumor and peripheral blood samples from 37 primary breast cancer (BC) patients receiving neoadjuvant chemotherapy. Comprehensive clinico-pathologic features were correlated with genomic profiles and mutational signatures. Somatic mutational landscapes were highly concordant with known BC data sets. Remarkably, we observed a divergence of dominant mutational signatures in association with BC subtype. Signature 5 was overrepresented in hormone receptor positive (HR+) patients, whereas triple-negative tumors mostly lacked Signature 5, but expectedly overrepresented Signature 3. We validated these findings in a large WGS data set of BC, demonstrating dominance of Signature 5 in HR+ patients, mostly in luminal A subtype. We further investigated the association between Signature 5 and gene expression signatures, and identified potential networks, likely related to estrogen regulation. Our results suggest that the yet elusive Signature 5 represents an alternative mechanism for mutation accumulation in HR+ BC, independent of the homologous recombination repair machinery related to Signature 3. This study provides theoretical basis for further elucidating the processes promoting hormonal breast carcinogenesis., (© 2022 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20-50%), and specific locus. Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers. In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well. Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options. Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients., Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor., Results: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations., Conclusions: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally., Patients and Methods: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site., Results: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific., Conclusions: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area., Competing Interests: Disclosure ER reports consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, and Pfizer; research funding from Novartis, Demo Pharmaceutical, Celldex, Radius Health, Tesaro, Parexel, and AnaBIOsis Pharmaceuticals; travel funding from Sanofi, Ipsen, Genesis Pharmaceuticals, LEO Pharma, Merck, Roche, and GENEKOR. CP reports grant funding from Pfizer and Daiichi Sankyo; honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, Seagen, and Eli Lilly. VM reports honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Seagen, Novartis, Roche, Teva, Janssen-Cilag, and Gilead; playing an advisory role for Hexal, Roche, Pfizer, Amgen, Daiichi-Sankyo, Nektar, Seagen, Gilead, and Eisai; research funding from Roche, Novartis, Seagen, Pfizer, and Genentech. RB reports advisory role for Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, and Seagen; lecture honoraria from Astra-Zeneca, Daiichi, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, and Seagen; research support from Daiichi, MSD, Novartis, and Roche. GR reports research funding (institution) from AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, Servier, Biovica, GlaxoSmithKline, and Sanofi/Aventis; and patents, royalties, other intellectual property from Agendia for MammaPrint due to the collaboration on the conduct of the MINDACT trial (Institution). SPG reports honoraria from Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; advisory/consultancy roles with Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; research grant from Roche; travel/accommodation/expenses from Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, and Daiichi Sankyo. HCK reports honoraria and travel support from AstraZeneca, Pfizer, Roche, Daiichi Sankyo, Tesaro, MSD, Onkowissen, Eli Lilly, SurgVision, Exact Sciences, and Genomic Health; and Stock ownership from Theraclion and Phaon scientific. NZ is on the advisory board for Lilly, Eisai, and AstraZeneca; reports receiving honorarium from Roche, Pfizer, Eisai, and Amgen; research funding (institutional) from Pfizer, Roche, and GSK; education funding from Roche, Novartis, and Amgen (none considered relevant to the current work). MP is on the advisory boards, and has participated in educational programs and conferences for Pfizer, BMS, Novartis, Astellas, Janssen, MD Serono, Merck, Amgen, and Sanofi; reports research funding (institutional) from Astellas, Novartis, Roche, Merck, BMS, Sanofi, and AstraZeneca. RMC has received (to institution) an unrestricted educational grant from Pfizer; and research funds from MSD Ireland and Pfizer. HT reports employment or management position with Partner and Medical Director Oncology Practice at Bethanien Hospital, Frankfurt; honoraria from Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science; consulting activities for Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science. AM reports advisory/consultant role, honoraria, and research grant from Lilly and Roche; advisory/consultant role for Novartis, Merck, Seagen, and Daiichi-Sankyo. LDM reports grants from Eli Lilly during the conduct of the study; personal fees from Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Seagen, Ipsen, and Gilead; personal fees and nonfinancial support from Roche, Pfizer, and Eisai, outside the submitted work. CC reports honoraria from Amgen, AstraZeneca, BMS, Genesis, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche. SO reports lecture fees, honoraria, or other fees paid by a single company or for-profit organization for the time or labor of a researcher engaged for conference attendance from Chugai, Lilly, AstraZeneca, and Pfizer. IM reports performing consultancy roles for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer, and Roche; travel/conference registration activities for Eli Lilly, Daiichi Sankyo, Gilead, and Novartis. ME serves on the advisory boards of Pfizer and Novartis; lecturing for Astra Zeneca (institution), but has no conflicts of interest related to this publication. KZ serves on the advisory board or performs talk for AstraZeneca, Daiichi, Exact Sciences, Lilly, Pierre Fabre, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Viatris/Mylan; unrestricted funding for organization of academic symposium from Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead, Novartis, Pfizer, Roche, Seagen, Viatris/Mylan, and Vifor; support for participation in international congress from AstraZeneca, Daiichi, Pierre Fabre, and Roche; is a member of steering committee of Eleanor study (Pierre Fabre); and research funding from Roche. MV reports honoraria from Roche, Novartis, Pfizer, and Daiichi; consulting or advisory role for Novartis and Roche; travel funds from Roche and Pfizer. DF’s institution receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi, and Pfizer for the conduct of clinical trials outside the submitted work. MG-G reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, and Pierre Fabre; travel/attending meetings for Pfizer, Roche, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo and AstraZeneca. BL reports consulting or advisory role for AstraZeneca, Pfizer, Merck, Eli Lilly, Pierre Fabre, and Daiichi Sankyo. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Young breast cancer survivors often go through a rapid change in menopause status due to cancer treatment and suffer from abrupt symptoms. This transition compels them to deal with unique medical and psychological side effects on their quality of life. One of the most affected quality of life domains is sexual functioning. This study explored the differences in frequency of sexual activity between young breast cancer survivors and young healthy women. It also examined whether this difference in sexual activity frequency was mediated by discomfort and/or pleasure during intercourse, both of which are affected by symptoms of premature menopause., Methods: A total of 97 young breast cancer survivors and 75 young healthy women completed a sociodemographic questionnaire: the Fallowfield's Sexual Activity Questionnaire (FSAQ) and the Menopausal Rating Scale (MRS). Additionally, the breast cancer participants completed a medical data questionnaire., Results: Findings revealed a significant direct effect between group and menopausal symptoms, menopausal symptoms and pleasure, and pleasure and frequency of sexual activity. Structural equation modeling explained the differences between the groups in frequency of sexual activity as mediated by menopausal symptoms and both pleasure and discomfort., Conclusions and Implications: These results highlight the impact of pleasure on the frequency of young breast cancer survivors' sexual activity, and its relation to menopausal symptoms. These young women should be provided with appropriate information and interventions that will help them experience increased pleasure during sexual activity despite their early and induced menopausal symptoms., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Our aim was to determine whether breast cancer survivors are at increased risk of obstetric and maternal complications at time of delivery., Methods: The USA 'National Inpatient Sample' database was queried for hospitalizations associated with deliveries, between 2015 and 2018. The incidence of maternal and fetal complications was compared between women with, and without, a personal history of breast cancer., Results: Of the 2,103,216 birth related admissions, 617 (0.03%) of the women were breast cancer survivors, with the proportion increasing over time (from 0.02% in 2015 to 0.04% in 2018). Breast cancer survivors had a higher socioeconomic status (p < 0.001) and were significantly older compared to other mothers (34 vs. 28 years, p < 0.001). Additionally, they were more likely to suffer from preexisting chronic diseases including cardiopulmonary disease and diabetes mellitus, and had a higher incidence of multiple gestation (4.4% vs. 1.6%) [OR 2.7, 95% CI 1.9-4.0, p < 0.001]. The incidence of acute adverse events at time of delivery including fetal distress, preterm labor, cesarean section and maternal infection was higher amongst the breast cancer survivors. On multivariate analysis age, ethnic group, comorbidities, multiple gestations, and a previous breast cancer diagnosis, but not cancer treatment, were associated with an increased risk of an obstetric adverse event., Conclusion: Breast cancer survivors have more comorbidities and are at increased risk of acute obstetrical complications at time of delivery. Further studies are required to validate these findings, and evaluate the ability of interventions to improve obstetrical outcomes amongst breast cancer survivors., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure FA reports receipt of research funding and has served as speaker/advisor (compensated to the hospital) for Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Eli Lilly. CHB reports grants/research support (to the institution) from Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline (GSK), Roche/Genentech, Eli Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, BioMarin, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Abraxis Biosciences, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Merck KGaA, Shanghai Henlius Biotech, Polyphor and PharmaMar; ownership or stocks in Biomarker, Tummi and MEDSir; and advisory boards and consulting for Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, Merck Sharp & Dohme (MSD), AstraZeneca, Zodiac, Eli Lilly and Sanofi. JC has served as a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab and Gilead; received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, MSD and Daiichi Sankyo; received research funding to the institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GmbH/Servier Affaires, Bayer Healthcare, Eisai, Roche, Guardanth Health, MSD, Pfizer, Piqur Therapeutics, Puma C and Queen Mary University of London; owns stock, patents and intellectual property for MedSIR; and received travel, accommodation and expenses from Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. GC has served as consultant or advisor for Roche, Eli Lilly and BMS; served on a speaker’s bureau for Roche, Pfizer and Eli Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca and SeaGen, all outside the submitted work. EdA reports honoraria and/or advisory boards for Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs and Pierre Fabre and Eli Lilly; travel grants from Roche/Genentech and GSK/Novartis; and research grants for his institute from Roche/Genentech, AstraZeneca, Novartis and Servier. AD reports research funding to institute from Genentech, Novartis, Pfizer and Calithera. RD reports research funding from AstraZeneca; and honoraria for consultancy/advisory board participation from AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer and Roche. DF reports honoraria for participation in symposia from Roche. AG reports honoraria for advisory boards from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Pfizer and Roche; honoraria for lectures from Eisai and Eli Lilly; and honoraria for expert testimony from Gentili. JG has served as a consultant/advisor for AstraZeneca, Daiichi Sankyo, Eisai, Exact Science, Eli Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Seattle Genetics; received honoraria from AGM communication, Amgen, AstraZeneca, Daiichi Sankyo, Decision Santé, Edimark, Eisai, Exact Science, Kephren, Eli Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Seattle Genetics; received research funding to the institution from Eisai, Exact Science and Roche/Genentech; is an ABC Global Alliance member; has a leadership role in AROMe and Nice St Paul de Vence Cours; and is involved in educational programmes for ESO. NH reports honoraria for lectures, advisory boards and/or personal fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and SeaGen; and minority ownership interest in the West German Study Group. SAH reports contracted research paid to institution from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Cytomx, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA Biotechnologies, Radius, Sanofi, Seattle Genetics/SeaGen, Zymeworks, Phoenix Molecular Designs, Ltd. and Samumed; unpaid steering committee member for Novartis, Eli Lilly, Daiichi Sankyo/AstraZeneca, Genentech/Roche and Sanofi; travel expenses from Eli Lilly (2019); and uncompensated consulting/advisory boards for 4DPharma, Ambrx, Amgen, Artios, Arvinas, Daiichi Sankyo, Dantari, Genentech/Roche, Immunomedics, Macrogenics, Eli Eli Lilly, Novartis, NK Max, Pieris, Pyxis, SeaGen, Biotheranostics and Loxo. SAI reports advisory board participation (uncompensated) for Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GSK, Hanmi, Eli Lilly, MSD, Novartis, Pfizer and Roche; and receipt of research funding/clinical trial budget from AstraZeneca, Dae Woong, Daiichi Sankyo, Eisai, Hanmi, Pfizer and Roche. DK reports honoraria from the European School of Oncology and MSD; non-renumerated membership of American Society for Clinical Oncology, American Society for Radiation Oncology, Arbeitsgemeinschaft Gynäkologische Onkologie, Arbeitsgemeinschaft Radiologische Onkologie, Deutsche Gesellschaft für Radioonkologie, Deutsche Gesellschaft für Senologie, European Society for Radiotherapy and Oncology and The Radiosurgery Society. WGK reports institutional research funding by the German Research Foundation and the medical faculty of LMU Munich; and serves as a non-compensated committee member of the European Organisation for Research and Treatment of Cancer and the European Society of Oncologic Imaging. SLoi reports research funding to her institution from Novartis, BMS, Merck, PUMA Biotechnologies, Eli Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics; consultancy (not compensated) to Seattle Genetics, Novartis, BMS, Merck, AstraZeneca and Roche/Genentech; consultancy (paid to institution) to Aduro Biotech, Novartis, GSK, Roche/Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics and BMS; and Scientific Advisory Board Member of Akamara Therapeutics. SLoibl reports honoraria for advisory boards (to institute) from Bayer, BMS, Eirgenix, GSK, Eli Lilly and Merck; honoraria for lecture (to institute) from Samsung; honoraria for advisory boards and lectures (to institute) from Pierre Fabre and Prime/Medscape; grants and honoraria for advisory boards (to institute) from AbbVie and Celgene; grants and honoraria for advisory boards and lectures (to institute) from AstraZeneca; grants, non-financial support and honoraria for advisory boards, lectures and medical writing (to institute) from Daiichi Sankyo, Novartis, Pfizer and Roche; grants, non-financial support and honoraria for advisory boards and medical writing (to institute) from Immunomedics/Gilead, non-financial support and honoraria for advisory boards and medical writing (to institute) from PUMA Biotechnologies and SeaGen; and non-financial support and honoraria for advisory boards (to institute) from Amgen, all outside the submitted work. In addition, SLoibl has patents EP14153692.0, EP21152186.9, EP19808852.8 and Digital Ki67 Evaluator pending and patent EP15702464.7 issued, with royalties paid. SP-S reports honoraria and/or advisory board and/or speaker’s bureau and/or travel funding from Roche, Pfizer, Eli Eli Lilly, Novartis, AstraZeneca, MSD, Exact Sciences and Nanostring. Institutional research funding from Sharing Progress in Cancer Care and Pfizer. FP-L has received honoraria and/or advisory board and/or speaker’s bureau and/or travel funding from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca, MSD, SeaGen, Illumina, Exact Sciences, Myriad and Nanostring; and institutional research funding from AstraZeneca, Roche, MSD and Illumina. JR reports honoraria or research grants (to the institution) from Terumo, Sirtex Medical, Boston Scientific, Roche and AstraZeneca. MR reports honoraria from Research to Practice, Intellisphere and Physicians’ Education Resource; consultant or advisor for Artios Pharma (uncompensated), AstraZeneca (uncompensated), Change Healthcare, Daiichi Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated) and Zenith Pharmaceuticals (uncompensated); research funding to institute from AstraZeneca, Merck and Pfizer; and editorial services for AstraZeneca and Pfizer. HSR reports research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Eli Lilly, Roche, Daiichi Sankyo, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala and Gilead; and honoraria from PUMA Biotechnologies (grant reviews for the US National Comprehensive Cancer Network 2021, steering committee 2020), Mylan (educational talk 2019), Samsung (educational talk and consultant 2019) and Napo Pharmaceuticals, Inc (consultant). CFS reports institutional research funding from Amgen, AstraZeneca, Daiichi Sanyko and the US Department of Defence; and travel funding and speaker honoraria from Novartis, AstraZeneca, Roche and Amgen. PS reports honoraria for participation in advisory boards and satellite symposia from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, PUMA Biotechnologies, Roche, Eisai and Celgene; research funding to institute from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche and Medivation. CS has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, Roche, MediTech, MSD, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, PUMA Biotechnologies, Sanofi-Aventis, SeaGen and Zymeworks. TS reports receipt of honoraria for advisory board participation for Roche and Pfizer. SMT reports receipt of institutional research funding from AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Odonate and Seattle Genetics; and has served as an advisor/consultant (compensated) for AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, BMS, Eisai, Nanostring, PUMA Biotechnologies, Sanofi, Silverback Therapeutics, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi Sankyo, Ellipsis, Infinity, 4D Pharma, Samsung Bioepsis Inc., Chugai Pharmaceuticals, BeyondSpring Pharmaceuticals, OncXerna, OncoSec Medical Incorporated, Certara, Mersana Therapeutics, CytomX and Seattle Genetics. NCT reports receipt of advisory board honoraria from AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, GSK, Zentalis Pharmaceuticals, Repare Therapeutics and Arvinas; and research funding from AstraZeneca, BioRad, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis and Natera.

Background: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants., Patients and Methods: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy., Results: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group., Conclusion: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing., Competing Interests: Disclosure EdA has acted as a scientific advisory board member and has received honoraria from Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; has received travel grants from Roche/GNE and GlaxoSmithKline (GSK)/Novartis; and has received research grants through his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier, outside the submitted work. FAP has acted as consultant for Ipsen, Roche Diagnostic, and Merck outside the submitted work. CRJ has acted as a scientific advisory board member and her institution has received honoraria from Bristol Myers Squibb (BMS), Theramex, and Roche; and her institution has received speaker's fees from Theramex and BMS, outside the submitted work. AS has acted as a consultant for Eli Lilly, Pfizer, Novartis, and Roche; has received speaker's fees from Teva, Roche, Pfizer, and Novartis; has received travel grants from Neopharm, Celgene, and Medison; and has received grant support from Novartis and Roche, outside the submitted work. CVG has acted as a consultant, as a scientific advisory board member, and has received speaker's fees from Roche, Novartis, Pfizer, Lilly, and Merck Sharp & Dohme (MSD); and has received research funding from AstraZeneca, Roche, and Pfizer, outside the submitted work. OCC has acted as a scientific advisory board member for Ascires Sistemas Genómicos; and has received grant support from Roche Diagnostics, Neomedic, and Takeda, outside the submitted work. KP has acted as a scientific advisory board member for AstraZeneca, Eli Lilly, Gilead Sciences, MSD, Novartis, Pierre Fabre, Roche, Teva, and Vifor Pharma; has acted as a consultant for AstraZeneca, Novartis, Pfizer, and Roche; has received speaker's fees from Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer, and Roche; has received travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche, outside the submitted work. FP has acted as a scientific advisory board member and has received speaker's fees from Amgen, AstraZeneca, Daichi-Sankyo, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, and Takeda; has received travel grants from Celgene, GlaxoSmithKline, and Roche; and has received research funding from AstraZeneca, Eisai, and Roche, outside the submitted work. ARF has received honoraria from Bayer, Daiichi Sankyo, Novartis, and Roche; and has received travel grants from Roche, outside the submitted work. JB has acted as consultant for AstraZeneca and Pfizer outside the submitted work. ID has acted as a scientific advisory board member and received grant from Roche; has received speaker's fees from Novartis; and has received travel grants from Theramex and Ferring, outside the submitted work. ML has acted as a consultant for Roche, Lilly, AstraZeneca, Exact Sciences, and Novartis; and has received honoraria from Sandoz, Roche, Lilly, Pfizer, Novartis, Ipsen, and Takeda, outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The increased susceptibility of cancer patients to coronavirus disease-2019 (COVID-19) infections and complications calls for special precautions while treating cancer patients during COVID-19 pandemics. Thus, oncology departments have had to implement a wide array of prevention measures., Objectives: To address issues associated with cancer care during the COVID-19 pandemic and to assess the implementation of measures aimed at containment of COVID-19 diffusion while allowing continuation of quality cancer care., Methods: A national survey among oncology departments in Israel was conducted between 12 April 2020 and 14 April 2020. Eighteen heads of hospital-based oncology departments completed a self-report questionnaire regarding their institute's preparedness for treatment of cancer patients during the COVID-19 pandemic., Results: In this national survey, prevention measures against COVID-19 spread were taken prior to patients' arrival and at arrival or while staying in the departments. Most participants (78-89%) reported using a quick triage of patients and caregivers prior to their entrance to the oncology units, limiting the entrance of caregivers, and reducing unnecessary visits to the clinic. Switching to oral therapies rather than intravenous ones when possible was considered by 82% and shortage in personal protective equipment was reported by five (28%) heads of oncology departments. Some differences between large and small/medium sized medical centers were observed regarding issues related to COVID-19 containment measures and changes in treatment., Conclusions: Oncology departments in Israel were able to prepare and adapt their services to guidelines and requirements related to the COVID-19 pandemic with little harm to their treatment capacity.

Purpose of Review: In recent years there has been a dramatic evolution in the clinical utility of genetic testing with expanding therapeutic implications for individuals with breast cancer who harbor a germline mutation in BRCA1/2. As these therapeutic opportunities expand and evolve, this requires the clinical and research community to rethink the approach to genetic testing for individuals with breast cancer., Recent Findings: Genetic testing is evolving from traditional testing models based on pretest counseling with the aim of identifying hereditary and individual risk for purposes of screening and risk reduction to contemporary models that utilize technology to improve accessibility and oncology led mainstreaming of testing where the oncologist refers for genetic testing, discloses the results and formal counseling occurs later in the process than in traditional models. The cost and accessibility to multigene panel testing have resulted in broad uptake despite the fact that clinical utility and appropriate interpretation of results are not yet well established. Furthermore, somatic testing for genomic alterations may also yield results beyond the disease with detection of germline mutations impacting the individual and their family more broadly than anticipated., Summary: With the establishment of poly (adenosine diphosphate-ribose) polymerase inhibitors as part of the treatment armamentarium for early and advanced breast cancer, paradigms, algorithms, and resources for genetic testing need to rapidly change in order to adapt to the evolution of germline mutations from hereditary and individual risk predictors to predictive therapeutic biomarkers., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting., Patients and Methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors., Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months)., Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design., Competing Interests: Disclosure DM has received honoraria for advisory boards from Roche/Genentech, Genomic Health and Eisai, and has been an invited speaker for Roche/Genentech and Genomic Health. EC has received consultancy fees from Roche, Lilly, Novartis and Pfizer, and has received honoraria for speaker engagements from Celgene, Roche, Novartis and Pfizer. AS has received honoraria for scientific talks from Roche, Celgene, AstraZeneca, Pfizer and Novartis, and travel support from Roche and Celgene. FP reports consultant/advisory roles for Amgen, AstraZeneca, Daichii-Sankyo, Eli Lilly, Ipsen, MSD, Novartis, Pierre Fabre, Pfizer and Roche, and research funding from AstraZeneca, Eisai and Roche. TP-Y has received honoraria for advisory boards and lectures from F. Hoffmann-La Roche, Pfizer, Neopharm, MSD, AstraZeneca, Janssen, Teva, Screen Cell, Medison, AbbVie and Takeda, and has received travel support from F. Hoffmann-La Roche, Bristol-Myers Squibb, AstraZeneca and Janssen. MC reports participation in advisory boards for AstraZeneca, Novartis, AbbVie, Sanofi, Pfizer, Sandoz, ACCORD and Lilly GT1 group, consultancy roles for Pierre Fabre Oncology, Sanofi, Novartis, Servier and Sanofi, speaker bureau/expert testimony for Novartis and travel/accommodation/expenses from Pfizer, Novartis, Roche and AstraZeneca. IB and his institution have received an investigator fee from Roche for the PERUSE study. ZN has received travel/accommodation/expenses from Roche. HE reports advisory/consultancy roles for Roche, MSD, Pfizer, Astellas and Merck and speaker bureau/expert testimony for Novartis and Amgen. SP-S has received honoraria for consultancy and speaker engagements from Roche, Novartis, Pfizer, AstraZeneca, Nanostring and Teva. AW reports personal fees from Roche, NAPP, Amgen, MSD, Novartis, Pfizer, AstraZeneca, Pierre Fabre, ACCORD, Athenex, Gerson Lehmann Group, Coleman Expert Network Group and Guidepoint global; he also reports personal fees and other from Lilly and Daichii-Sankyo (all outside the submitted work) and employment with AstraZeneca after completion of this work. J-LM is employed by IQVIA, a clinical research organisation contracted by F. Hoffmann-La Roche. PT is an employee of Genentech and holds shares in F. Hoffmann-La Roche Ltd. YdT, CP-M, VR and DK are employees and shareholders of F. Hoffmann-La Roche Ltd. TB has received research funding from AstraZeneca, Novartis and Pfizer, and has acted as a consultant for and received travel grants from AstraZeneca, Roche, Novartis and Pfizer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Shani Paluch-Shimon: advisory boards, consultancy, speaker's bureau of Pfizer, Novartis, Astra Zeneca, Lilly, Exact Sciences, Nanostring, Roche. Karen A. Gelmon: advisory boards of Pfizer, Novartis, Astra Zeneca, Lilly, Merck, Nanostring, Genomic Health, BMS, Roche, Mylan, Ayala; research funding from BMS, Pfizer, Novartis, Roche, AstraZeneca; expert testimony for Genentech. Alexandru Eniu: received research support from AstraZeneca, Roche, Pfizer, Celltrion, Novartis; none in relation to this presentation. Joseph Gligorov: Astra Zeneca, Daiichi, Esai, Exact Science, Lilly, Merck, Novartis, Pfizer, Roche, Seattle Genetics.

Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV identified through high-risk clinics in Israel, and Manchester England from 1998-2018 were eligible. Data were retrieved from patients records and confirmed (in Israel) by cross referencing with the Israeli National Cancer Registry. Overall, 2503 female carriers were included: 1715 (71.4%) Ashkenazi Jews (AJ), 201 (8.3%) Iraqi Jews and 383 (15.9%) of mixed ethnicity. In 102 (4.2%) cases ethnicity could not be ascertained. Of Israeli AJ carriers 649 (37.8%), 256 (14.9%) and 62 (3.6%) were diagnosed with BC, OvC or both cancers, respectively. For the Iraqi Jews these frequencies were 76 (37.8%), 43 (21.4%), and 8 (3.98%), respectively. Age at diagnosis of BC in AJ and Iraqi Jews was 46.7 ± 12.3 years and 52.8 ± 12.2 years, respectively (p = 0.001). For OvC age at diagnosis for AJ was 53.5 ± 10.7 years and for Iraqi Jews 50.1 ± 8.8 years (p = 0.0027). No differences in these parameters were noted between English Jews (n = 110) and non-Jews (n = 32). Age at diagnosis of BC and OvC differs between AJ and Iraqi Jews who carry an identical BRCA1 PSV. This finding supports the existence of modifier factors that may be ethnic specific.

Introduction: BRCA1/BRCA2 mutation carriers often undergo risk-reducing salpingo-oophorectomy (RRSO) before natural menopause, raising the issue of hormonal replacement treatment (HRT) use. There is conflicting evidence on the effect of HRT on breast cancer (BC) risk, and there are limited data on risk based on age at exposure. In the general population, HRT users have an increased BC risk (hazard ratio = 1.34). We assessed the impact of short-term HRT use on BC risk among healthy BRCA1/2 mutation carriers, with emphasis on age at exposure to HRT., Methods: A retrospective cohort of 306 consecutive healthy BRCA1/2 mutation carriers who had undergone RRSO was followed up for a mean of 7.26 years. We compared BC incidence over time in carriers who received HRT with that in those who did not receive., Results: Thirty-six of the carriers were diagnosed with BC, 20 of 148 patients (13.5%) in the HRT group compared with 16 of 155 (10.3%) in the non-HRT group (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 0.7-2.7). In women who were aged 45 years or younger at RRSO, HRT did not affect BC rates. However, in those older than 45 years at RRSO, BC rates were significantly higher in HRT users than in non-users (OR = 3.43, p < 0.05, 95% CI = 1.2-9.8)., Conclusions: In BRCA1/BRCA2 carriers in this study, short-term post-RRSO HRT use was associated with a threefold risk of BC in carriers older than 45 years. These results suggest that risk may be related to time of exposure to HRT around the natural age of menopause, even among BRCA1/2 carriers. Further studies are needed for validation and to guide future recommendations., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.