Homologous recombination deficiency and hemizygosity drive resistance in breast cancer
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.
Authors
- Fresia Pareja (ORCID: https://orcid.org/0000-0003-3748-8049)
- Violeta Serra
- Anna D. Staniszewska (ORCID: https://orcid.org/0000-0003-1328-1959)
- L. Boscolo Bielo
- Colombe Chappey (ORCID: https://orcid.org/0009-0003-3623-3383)
- Marc Ladanyi
- Natalia Lukashchuk (ORCID: https://orcid.org/0009-0006-6678-0072)
- Pedram Razavi (ORCID: https://orcid.org/0000-0003-4236-0576)
- Anton Safonov (ORCID: https://orcid.org/0000-0002-4100-8071)
- Miika M. Mehine (ORCID: https://orcid.org/0000-0003-0443-0625)
- Enrico Moiso (ORCID: https://orcid.org/0000-0002-4405-8357)
- Emanuela Ferraro (ORCID: https://orcid.org/0000-0001-5863-2391)
- Elisabetta Marangoni (ORCID: https://orcid.org/0000-0002-3337-6448)
- Daniel M. Muldoon (ORCID: https://orcid.org/0000-0001-7936-4365)
- Eleni Sofianopoulou (ORCID: https://orcid.org/0000-0002-6067-5486)
- Marie Will (ORCID: https://orcid.org/0000-0002-8819-537X)
- Emily Nizialek (ORCID: https://orcid.org/0000-0001-5447-7371)
- Julia An (ORCID: https://orcid.org/0000-0003-2029-0335)
- Mark R. Albertella (ORCID: https://orcid.org/0000-0003-4406-6135)
- Chaitanya Bandlamudi (ORCID: https://orcid.org/0000-0003-1108-4919)
- Laura Courtois
- Bièche Ivan
- Mehnaj Ahmed
- Kara N. Maxwell
- Britta Weigelt
- Ben O’Leary
- Maurizio Scaltriti
- Rania El Botty
- Mark T. A. Donoghue
- David B Solit
- Sohrab Shah
- Minna Lee
- Allen Zhu
- Diana Mandelker
- Yuan Liu
- Kenneth Offit
- Susan M. Domchek
- Larry Norton
- Hong Shao
- David N. Brown
- Nicholas C. Turner
- Jorge S. Reis-Filho
- Mark E. Robson
- Michael F. Berger
- Nikolaus Schultz
- Bradley Wubbenhorst
- Bob T. Li
- Antonio Marra (ORCID: https://orcid.org/0000-0002-7310-7824)
- Susana Ros
- Pier Selenica
- Xin Huang
- Fergus Couch
- Sarat Chandarlapaty
- Katherine L. Nathanson
- Laia Vicente
Institutions
- AstraZeneca (United Kingdom) (GB)
- Mayo Clinic (US)
- Memorial Sloan Kettering Cancer Center (US)
- Institute of Cancer Research (GB)
- Pfizer (United States) (US)
- Cornell University (US)
- WinnMed (US)
- Royal Marsden Hospital (GB)
- Molecular Oncology (United States) (US)
- AstraZeneca (United States) (US)
- Vall d'Hebron Institute of Oncology (ES)
- European Institute of Oncology (IT)
- University of Pennsylvania (US)
- Institut Curie (FR)
Publication Details
- Journal
- Nature
- Published
- 2026-03-04
- DOI
- https://doi.org/10.1038/s41586-026-10197-0
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00