Homologous recombination deficiency and tumor suppressor heterozygosity mediate resistance to front-line therapy in breast cancer

Germline and somatic variants that drive breast tumorigenesis and therapeutic sensitivity are widely prevalent. The clinical and biologic significance of co-occurring disease-defining germline and somatic events have yet to be defined and exploited. Using multiple, independent clinical cohorts comprising over 4500 patients, we identify that pathogenic RB1 variants are enriched in gBRCA2-associated cancers, and manifest poor outcomes on standard-of-care frontline CDK4/6i plus antiestrogen combinations. We demonstrate gBRCA2-associated cancers commonly give rise to allelic configurations manifesting RB1 heterozygosity and readily lose the second copy through gBRCA2 loss-mediated homologous recombination deficiency (HRD)under the therapeutic pressure of CDK4/6i. The findings unveil a novel therapeutic strategy of targeting the underlying HRD through PARPi prior to CDK4/6i to intercept the deleterious RB1-loss trajectory. The work reveals how germline-somatic driven genomic configurations can shape treatment responses and be exploited in biomarker-directed clinical strategies. ### Competing Interest Statement S.C. has received research support and clinical trial support (funding to institution) from Daiichi-Sankyo, Novartis, Sanofi, AstraZeneca, Ambrx, Paige.ai, and Lilly, has received consulting honoraria from Novartis, Paige.ai, AstraZeneca, Boxer Capital, and Lilly, is co-founder and board member of Odyssey Biosciences and has shares in Totus Medicines. P.R. received institutional grant/funding from Grail, Illumina, Novartis, AstraZeneca, Epic Sciences, Invitae/ArcherDx, Tempus, Inivata, Guardant and consultation/Ad board/honoraria from Novartis, Foundation Medicine, AstraZeneca, Pfizer, Epic Sciences, Inivata, Natera, Tempus, Biovica, Saga and is co-founder and board member at Odyssey Biosciences. J.S.R.-F., M.S., E.N., N.L., and E.S. are employed at AstraZeneca. Y.L. and X.H. are employed at Pfizer. N.C.T. has acted as an adviser to Astra Zeneca, Exact Sciences, Gilead, GlaxoSmithKline, Guardant, Inivata, Lilly, Novartis, Pfizer, Relay therapeutics, Repare therapeutics, Roche/Genentech and Zentalis, and has received research funding from Astra Zeneca, Guardant Health, Inivata, Invitae, Merck Sharpe and Dohme, Natera, Personalis, Pfizer and Roche/Genentech. D.B.S. has consulted with and received honoraria from Pfizer, Loxo/Lilly Oncology, Illumina, Vividion Therapeutics, Scorpion Therapeutics, Fore Biotherapeutics and BioBridge Pharma. M.F.B. reports receiving research funding from Illumina and Grail and advisory board activities for Roche. M.E.R. reports honoraria from Research to Practice, Intellisphere and Physicians Education Resource; consulting and advisory activities for AstraZeneca, Daiichi-Sankyo, Epic Science, Merck and Pfizer (all uncompensated), and Change Healthcare; institutional research funding from AbbVie, AstraZeneca, Merck and Pfizer; and editorial services for AstraZeneca and Pfizer. S.M.D. has received honoraria from AstraZeneca. The remaining authors declare no competing interests.