Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

• Published in: Nature communications Vol. 14; no. 1; pp. 1958 - 15
• Main Authors: ter Brugge, Petra, Moser, Sarah C., Bièche, Ivan, Kristel, Petra, Ibadioune, Sabrina, Eeckhoutte, Alexandre, de Bruijn, Roebi, van der Burg, Eline, Lutz, Catrin, Annunziato, Stefano, de Ruiter, Julian, Masliah Planchon, Julien, Vacher, Sophie, Courtois, Laura, El-Botty, Rania, Dahmani, Ahmed, Montaudon, Elodie, Morisset, Ludivine, Sourd, Laura, Huguet, Léa, Derrien, Heloise, Nemati, Fariba, Chateau-Joubert, Sophie, Larcher, Thibaut, Salomon, Anne, Decaudin, Didier, Reyal, Fabien, Coussy, Florence, Popova, Tatiana, Wesseling, Jelle, Stern, Marc-Henri, Jonkers, Jos, Marangoni, Elisabetta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38/77; 45; 45/23; 64/60; 692/4028/67/1347; Biomarkers; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Breast cancer; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; DNA methylation; Gene expression; Gene sequencing; Genes; Genomes; Homologous Recombination; Homology; Humanities and Social Sciences; Humans; Identification methods; In vivo methods and tests; Life Sciences; Methylation; multidisciplinary; Mutation; Platinum; Platinum - therapeutic use; Science; Science (multidisciplinary); Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors; Whole Genome Sequencing; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37537-2

The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response. Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy.