Abstract 163P
Background
Breast cancer (BC) in women aged≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated to aggressive features. 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’s 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 (OS). Statistical significance was considered for p≤0.05.
Results
Of 3,547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive (HR+) and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p<0.001), HR+ (p<0.001), and node-positive (p=0.003). BRCA2 PVs were more associated to HER2-low than BRCA1 (p<0.001). HER2-low vs. 0 showed better DFS (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.76–0.97) in the overall population and more favorable DFS (HR: 0.78, 95%CI: 0.64-0.95) and OS (HR: 0.65, 95%CI: 0.46–0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p=0.014), and TN and Luminal A-like in HER2-0 (p=0.019) showed the worst DFS.
Conclusions
In young HER2-negative BC patients with germline BRCA1/2 PVs, HER2-low disease was less frequent than expected, more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated to modestly improved prognosis. Nevertheless, women with Luminal A-like tumors had worse prognosis regardless of HER2 status, highlighting the need for a better understanding of the biology underlying this tumor subgroup in young patients with germline BRCA1/2 PVs.
Legal entity responsible for the study
The authors.
Funding
Italian Association for Cancer Research (Associazione Italiana per la Ricerca sul Cancro, AIRC).
Disclosure
F. Schettini: Financial Interests, Personal, Other, honoraria and travel expenses: Novartis, Gilead and Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Pfizer. E. Blondeaux: Financial Interests, Institutional, Funding: Gilead. C. Molinelli: Financial Interests, Personal, Invited Speaker: Novartis and Lilly; Financial Interests, Other, travel grant: Gilead. A. Di Meglio: Financial Interests, Personal, Expert Testimony: Kephren, Medycis, Techspert. S. Linn: Other, Personal, Other, Patent (WO 2023/031121A1): Patent; Financial Interests, Personal, Research Grant: AstraZeneca, Eurocept Plaza, Roche, Genentech, Immunomedics (now Gilead Sciences), Tesaro (now GSK), Novartis, and Agendia; Financial Interests, Institutional, Other, Consulting fees: AstraZeneca; Financial Interests, Institutional, Other, payment or honoraria: Daiichi Sankyo; Financial Interests, Personal, Other, financial support for attending meetings: Daiichi Sankyo; Financial Interests, Institutional, Funding: Genentech (drug), Roche (drug), Gilead Sciences (drug), Novartis (drug), Tesaro (drug), Agendia (gene expression tests), and AstraZeneca (drug). K. Pogoda: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Gilead, Novartis, Eli Lilly, Pfizer; Financial Interests, Personal, Advisory Board: Sandoz, AstraZeneca; Financial Interests, Personal, Full or part-time Employment, Assistant Professor: Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Financial Interests, Personal and Institutional, Other, SI: Novartis, Roche, Eli Lilly, AstraZeneca; Non-Financial Interests, Other, Breast Cancer Group - Steering Committee Member, Quality of Life Group: EORTC; Non-Financial Interests, Member: Polish Society of Clinical Oncology, Polish Society of Oncology. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Invited Speaker: Sanofi, AstraZeneca, Exact Sciences, Focus Patient, Pfizer, Gilead Sciences; Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca, Pfizer; Financial Interests, Personal, Ownership Interest: Need Inc.; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Leadership Role, Vice President: Belgian Society of Medical Oncology BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Leadership Role: EORTC Breast Cancer Task Force Steering Committee Member; Non-Financial Interests, Institutional, Product Samples, Drug provision for academic research: Gilead Sciences; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. E. Agostinetto: Financial Interests, Personal, Other, consultancy fee or honoraria: Eli Lilly, Sandoz, AstraZeneca; Financial Interests, Institutional, Research Grant: Gilead; Financial Interests, Personal, Other, meeting/travel grants: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, AstraZeneca . K. Phillips: Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Funding: AstraZeneca. A. Toss: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Pfizer, Gilead; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Pfizer, Eli Lilly, Seagen; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo, Gilead; Financial Interests, Personal, Expert Testimony: Novartis; Non-Financial Interests, Member: AIOM. C. Rousset-Jablonski: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Theramex, Roche; Financial Interests, Institutional, Invited Speaker: Novartis, Theramex, Organon; Financial Interests, Institutional, Funding: Bayer Healthcare. M. Acheritogaray: Financial Interests, Personal, Invited Speaker: MSD. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO; Non-Financial Interests, Member of Board of Directors, Chair of Clinical Practice Guidelines Committee: ESMO. A. Prat: Financial Interests, Personal, Invited Speaker: Roche, 1TRIALSP, S.L.; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Invited Speaker, 2-year research grant paid to my Institution: Gilead. All other authors have declared no conflicts of interest.