Open AccessA RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation
Author(s) -
CastroviejoBermejo Marta,
Cruz Cristina,
LlopGuevara Alba,
GutiérrezEnríquez Sara,
Ducy Mandy,
Ibrahim Yasir Hussein,
GrisOliver Albert,
Pellegrino Benedetta,
Bruna Alejandra,
Guzmán Marta,
Rodríguez Olga,
Grueso Judit,
Bonache Sandra,
MolesFernández Alejandro,
Villacampa Guillermo,
Viaplana Cristina,
Gómez Patricia,
Vidal Maria,
Peg Vicente,
SerresCréixams Xavier,
Dellaire Graham,
Simard Jacques,
Nuciforo Paolo,
Rubio Isabel T,
Dienstmann Rodrigo,
Barrett J Carl,
Caldas Carlos,
Baselga José,
Saura Cristina,
Cortés Javier,
Déas Olivier,
Jonkers Jos,
Masson JeanYves,
Cairo Stefano,
Judde JeanGabriel,
O'Connor Mark J,
Díez Orland,
Balmaña Judith,
Serra Violeta
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809172
Subject(s) - rad51 , medicine , library science , oncology , humanities , biology , art , homologous recombination , genetics , gene , computer science
Poly( ADP ‐ribose) polymerase ( PARP ) inhibitors ( PARP i) are effective in cancers with defective homologous recombination DNA repair ( HRR ), including BRCA 1/2‐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 PARP i olaparib in patient‐derived tumor xenografts ( PDX s) from breast cancer ( BC ) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA 1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD 51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD 51 score and the homologous recombination deficiency ( HRD ) score were compared. To examine the clinical feasibility of the RAD 51 assay, we scored archival breast tumor samples, including PALB 2‐related hereditary cancers. The RAD 51 score was highly discriminative of PARP i sensitivity versus PARPi resistance in BC PDX s and outperformed the genomic test. In clinical samples, all PALB 2‐related tumors were classified as HRR ‐deficient by the RAD 51 score. The functional biomarker RAD 51 enables the identification of PARP i‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA 1/2‐related cancers.