A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation.
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Authors
Castroviejo-Bermejo, Marta
Cruz, Cristina
Ducy, Mandy
Ibrahim, Yasir Hussein
Guzmán, Marta
Rodríguez, Olga
Grueso, Judit
Bonache, Sandra
Moles-Fernández, Alejandro
Villacampa, Guillermo
Viaplana, Cristina
Gómez, Patricia
Vidal, Maria
Simard, Jacques
Nuciforo, Paolo
Rubio, Isabel T
Dienstmann, Rodrigo
Barrett, J Carl
Baselga, José
Cortés, Javier
Déas, Olivier
Masson, Jean-Yves
Cairo, Stefano
Judde, Jean-Gabriel
O'Connor, Mark J
Díez, Orland
Publication Date
2018-12Journal Title
EMBO molecular medicine
ISSN
1757-4676
Volume
10
Issue
12
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Castroviejo-Bermejo, M., Cruz, C., Llop-Guevara, A., Gutiérrez-Enríquez, S., Ducy, M., Ibrahim, Y. H., Gris-Oliver, A., et al. (2018). A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation.. EMBO molecular medicine, 10 (12)https://doi.org/10.15252/emmm.201809172
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. A test to identify additional HRR-deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2-related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi-sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2-related cancers.
Keywords
Animals, Humans, Mice, Breast Neoplasms, Piperazines, Phthalazines, Antineoplastic Agents, Drug Resistance, Neoplasm, Female, Rad51 Recombinase, Homologous Recombination, Heterografts, Biomarkers, Tumor, Poly(ADP-ribose) Polymerase Inhibitors
Sponsorship
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (A3086)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
Cancer Research UK (20544)
European Commission Horizon 2020 (H2020) Research Infrastructures (RI) (731105)
Identifiers
External DOI: https://doi.org/10.15252/emmm.201809172
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292100