TY - JOUR
T1 - A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation
AU - Castroviejo-Bermejo, Marta
AU - Cruz, Cristina
AU - Llop-Guevara, Alba
AU - Gutiérrez-Enríquez, Sara
AU - Ducy, Mandy
AU - Ibrahim, Yasir Hussein
AU - Gris-Oliver, Albert
AU - Pellegrino, Benedetta
AU - Bruna, Alejandra
AU - Guzmán, Marta
AU - Rodríguez, Olga
AU - Grueso, Judit
AU - Bonache, Sandra
AU - Moles-Fernández, Alejandro
AU - Villacampa, Guillermo
AU - Viaplana, Cristina
AU - Gómez, Patricia
AU - Vidal, Marc
AU - Peg, Vicente
AU - Serres-Créixams, Xavier
AU - Dellaire, Graham
AU - Simard, Jacques
AU - Nuciforo, Paolo
AU - Rubio, Isabel T.
AU - Dientsmann, Rodrigo
AU - Barrett, J. Carl
AU - Caldas, Carlos
AU - Baselga, José
AU - Saura, Cristina
AU - Cortés, Javier
AU - Déas, Olivier
AU - Jonkers, Jos
AU - Masson, Jean Yves
AU - Cairo, Stefano
AU - Judde, Jean Gabriel
AU - O'Connor, Mark J.
AU - Díez, Orland
AU - Balmaña, Judith
AU - Serra, Violeta
PY - 2018/12/1
Y1 - 2018/12/1
N2 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.
AB - © 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.
KW - BRCA1
KW - homologous recombination
KW - PALB2
KW - PARP inhibitors
KW - RAD51
U2 - 10.15252/emmm.201809172
DO - 10.15252/emmm.201809172
M3 - Article
C2 - 30377213
VL - 10
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
M1 - e9172
ER -
