A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation Journal Article
| Authors: | Castroviejo-Bermejo, M.; Cruz, C.; Llop-Guevara, A.; Gutiérrez-Enríquez, S.; Ducy, M.; Ibrahim, Y. H.; Gris-Oliver, A.; Pellegrino, B.; Bruna, A.; Guzmán, M.; Rodríguez, O.; Grueso, J.; Bonache, S.; Moles-Fernández, A.; Villacampa, G.; Viaplana, C.; Gómez, P.; Vidal, M.; Peg, V.; Serres-Créixams, X.; Dellaire, G.; Simard, J.; Nuciforo, P.; Rubio, I. T.; Dientsmann, R.; Barrett, J. C.; Caldas, C.; Baselga, J.; Saura, C.; Cortés, J.; Déas, O.; Jonkers, J.; Masson, J. Y.; Cairo, S.; Judde, J. G.; O'Connor, M. J.; Díez, O.; Balmaña, J.; Serra, V. |
| Article Title: | A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation |
| 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. © 2018 The Authors. Published under the terms of the CC BY 4.0 license |
| Keywords: | adult; clinical article; controlled study; promoter region; frameshift mutation; nonhuman; prospective study; mouse; homologous recombination; gene expression; tumor volume; animal experiment; animal model; gene locus; genetic variability; gene frequency; in vivo study; antineoplastic activity; dna methylation; tumor suppressor gene; feasibility study; messenger rna; epigenetics; brca1; rad51 protein; olaparib; palb2; veliparib; rad51; hereditary breast and ovarian cancer syndrome; niraparib; recombination repair; human; priority journal; article; parp inhibitors; whole exome sequencing; homologous recombination deficiency score |
| Journal Title: | EMBO Molecular Medicine |
| Volume: | 10 |
| Issue: | 12 |
| ISSN: | 1757-4676 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2018-12-01 |
| Start Page: | e9172 |
| Language: | English |
| DOI: | 10.15252/emmm.201809172 |
| PROVIDER: | scopus |
| PMCID: | PMC6284440 |
| PUBMED: | 30377213 |
| DOI/URL: | |
| Notes: | EMBO Mol. Med. -- Cited By :1 -- Export Date: 2 January 2019 -- Article -- Source: Scopus C7 - e9172 C2 - 30377213 |
