A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation.
Date
2018-12-01ICR Author
Author
Castroviejo-Bermejo, M
Cruz, C
Llop-Guevara, A
Gutiérrez-Enríquez, S
Ducy, M
Ibrahim, YH
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, IT
Dienstmann, R
Barrett, JC
Caldas, C
Baselga, J
Saura, C
Cortés, J
Déas, O
Jonkers, J
Masson, J-Y
Cairo, S
Judde, J-G
O'Connor, MJ
Díez, O
Balmaña, J
Serra, V
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
BRCA1
PALB2
PARP inhibitors
RAD51
homologous recombination
Animals
Antineoplastic Agents
Biomarkers, Tumor
Breast Neoplasms
Drug Resistance, Neoplasm
Female
Heterografts
Homologous Recombination
Humans
Mice
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Rad51 Recombinase
Research team
Preclin Paed Cancer Evo
Language
eng
Date accepted
2018-12-01
License start date
2018-12-01
Citation
EMBO Molecular Medicine, 2018, 10 (12), pp. e9172 -
Publisher
WILEY