Homologous recombination deficiency and hemizygosity drive resistance in breast cancer.
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Safonov Anton, Lee Minna, Brown David N, Boscolo Bielo Luca, Mehine Miika, Bandlamudi Chaitanya, O'Leary Ben, Shao Hong, Vicente Laia, Muldoon Daniel, Zhu Allen, Ros Susana, Marra Antonio, Selenica Pier, Bieche Ivan, Wubbenhorst Bradley, Ferraro Emanuela, Courtois Laura, El Botty Rania, Ahmed Mehnaj, Moiso Enrico, An Julia Ah-Reum, Donoghue Mark T A, Will Marie, Pareja Fresia, Nizialek Emily, Lukashchuk Natalia, Sofianopoulou Eleni, Liu Yuan, Huang Xin, Chappey Colombe, Staniszewska Anna D, Ross Dara, Mandelker Diana, Ladanyi Marc, Schultz Nikolaus, Berger Michael F, Scaltriti Maurizio, Reis-Filho Jorge S, Li Bob T, Offit Kenneth, Norton Larry, Shen Ronglai, Maxwell Kara N, Couch Fergus, Domchek Susan M, Marangoni Elisabetta, Shah Sohrab, Albertella Mark R, Serra Violeta, Weigelt Britta, Solit David B, Nathanson Katherine L, Robson Mark E, Turner Nicholas C, Chandarlapaty Sarat, Razavi Pedram
Аннотация
The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, yet their combined influence on tumour evolution and therapy resistance remains poorly defined. Through an integrated clinicogenomic analysis of more than 5,800 patients, we show that germline (g) pathogenic variants dictate the evolutionary trajectory of acquired resistance. We specifically find that gBRCA2-associated tumours are uniquely predisposed to develop acquired RB1 loss-of-function alterations, resulting in poor outcomes on standard-of-care frontline CDK4/6 inhibitor (CDK4/6i) combinations. This vulnerability is driven by a dual mechanism: baseline RB1 hemizygosity (heterozygous loss resulting in a single functional RB1 allele), which lowers the evolutionary barrier to biallelic inactivation, and ongoing homologous recombination deficiency, which promotes acquisition of RB1 loss-of-function alterations under the selective pressure of CDK4/6i. Preclinical models from gBRCA2 carriers showed near-uniform resistance to CDK4/6i, with consistent post-treatment Rb loss. Across multiple independent models and in our clinical data, PARP inhibition consistently outperformed CDK4/6i. Our findings suggest that prioritizing PARP inhibition in gBRCA2 carriers may intercept RB1-loss trajectories and delay resistance. More broadly, we establish a predictive framework for forecasting drug-resistant trajectories based on pre-treatment allelic configuration and mutational signatures.