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

Petra Brugge, Sarah C. Moser, Ivan Bièche, Petra Kristel, Sabrina Ibadioune, Alexandre Eeckhoutte, Roebi Bruijn, Eline Burg, Catrin Lutz, Stefano Annunziato, Julian Ruiter, Julien Masliah Planchon, Sophie Vacher, Laura Courtois, Rania El-Botty, Ahmed Dahmani, Elodie Montaudon, Ludivine Morisset, Laura Sourd, Léa Huguet, Heloise Derrien, Fariba Nemati, Sophie Chateau-Joubert, Thibaut Larcher, Anne Salomon, Didier Decaudin, Fabien Reyal, Florence Coussy, Tatiana Popova, Jelle Wesseling, Marc-Henri Stern, Jos Jonkers () and Elisabetta Marangoni ()
Additional contact information
Petra Brugge: The Netherlands Cancer Institute
Sarah C. Moser: The Netherlands Cancer Institute
Ivan Bièche: PSL University
Petra Kristel: The Netherlands Cancer Institute
Sabrina Ibadioune: PSL University
Alexandre Eeckhoutte: PSL University
Roebi Bruijn: The Netherlands Cancer Institute
Eline Burg: The Netherlands Cancer Institute
Catrin Lutz: The Netherlands Cancer Institute
Stefano Annunziato: The Netherlands Cancer Institute
Julian Ruiter: The Netherlands Cancer Institute
Julien Masliah Planchon: PSL University
Sophie Vacher: PSL University
Laura Courtois: PSL University
Rania El-Botty: PSL University
Ahmed Dahmani: PSL University
Elodie Montaudon: PSL University
Ludivine Morisset: PSL University
Laura Sourd: PSL University
Léa Huguet: PSL University
Heloise Derrien: PSL University
Fariba Nemati: PSL University
Sophie Chateau-Joubert: BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort
Thibaut Larcher: INRA, APEX-PAnTher, Oniris
Anne Salomon: PSL University
Didier Decaudin: PSL University
Fabien Reyal: PSL University
Florence Coussy: PSL University
Tatiana Popova: PSL University
Jelle Wesseling: The Netherlands Cancer Institute
Marc-Henri Stern: PSL University
Jos Jonkers: The Netherlands Cancer Institute
Elisabetta Marangoni: PSL University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37537-2

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