EMBO Molecular Medicine (Oct 2018)
A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation
- Marta Castroviejo‐Bermejo,
- Cristina Cruz,
- Alba Llop‐Guevara,
- Sara Gutiérrez‐Enríquez,
- Mandy Ducy,
- Yasir Hussein Ibrahim,
- Albert Gris‐Oliver,
- Benedetta Pellegrino,
- Alejandra Bruna,
- Marta Guzmán,
- Olga Rodríguez,
- Judit Grueso,
- Sandra Bonache,
- Alejandro Moles‐Fernández,
- Guillermo Villacampa,
- Cristina Viaplana,
- Patricia Gómez,
- Maria Vidal,
- Vicente Peg,
- Xavier Serres‐Créixams,
- Graham Dellaire,
- Jacques Simard,
- Paolo Nuciforo,
- Isabel T Rubio,
- Rodrigo Dienstmann,
- J Carl Barrett,
- Carlos Caldas,
- José Baselga,
- Cristina Saura,
- Javier Cortés,
- Olivier Déas,
- Jos Jonkers,
- Jean‐Yves Masson,
- Stefano Cairo,
- Jean‐Gabriel Judde,
- Mark J O'Connor,
- Orland Díez,
- Judith Balmaña,
- Violeta Serra
Affiliations
- Marta Castroviejo‐Bermejo
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Cristina Cruz
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Alba Llop‐Guevara
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Sara Gutiérrez‐Enríquez
- Oncogenetics Group, Vall d'Hebron Institute of Oncology
- Mandy Ducy
- Genome Stability Laboratory, CHU de Québec Research Center
- Yasir Hussein Ibrahim
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Albert Gris‐Oliver
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Benedetta Pellegrino
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Alejandra Bruna
- Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge
- Marta Guzmán
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Olga Rodríguez
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Judit Grueso
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- Sandra Bonache
- Oncogenetics Group, Vall d'Hebron Institute of Oncology
- Alejandro Moles‐Fernández
- Oncogenetics Group, Vall d'Hebron Institute of Oncology
- Guillermo Villacampa
- Oncology Data Science (OdysSey Group), Vall d'Hebron Institute of Oncology
- Cristina Viaplana
- Oncology Data Science (OdysSey Group), Vall d'Hebron Institute of Oncology
- Patricia Gómez
- Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona
- Maria Vidal
- Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona
- Vicente Peg
- Pathology Department, Vall d'Hebron University Hospital
- Xavier Serres‐Créixams
- Department of Radiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona
- Graham Dellaire
- Department of Pathology, Dalhousie University
- Jacques Simard
- CHU de Quebec ‐ Université Laval Research Center, Genomics Center, CHUL
- Paolo Nuciforo
- CIBERONC, Instituto de Salud Carlos III
- Isabel T Rubio
- CIBERONC, Instituto de Salud Carlos III
- Rodrigo Dienstmann
- Oncology Data Science (OdysSey Group), Vall d'Hebron Institute of Oncology
- J Carl Barrett
- AstraZeneca
- Carlos Caldas
- Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge
- José Baselga
- Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center
- Cristina Saura
- Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona
- Javier Cortés
- CIBERONC, Instituto de Salud Carlos III
- Olivier Déas
- XenTech
- Jos Jonkers
- Division of Molecular Pathology and Cancer Genomics, The Netherlands Cancer Institute
- Jean‐Yves Masson
- Genome Stability Laboratory, CHU de Québec Research Center
- Stefano Cairo
- XenTech
- Jean‐Gabriel Judde
- XenTech
- Mark J O'Connor
- Oncology Innovative Medicines and Early Clinical Development Biotech Unit, AstraZeneca
- Orland Díez
- Oncogenetics Group, Vall d'Hebron Institute of Oncology
- Judith Balmaña
- High Risk and Familial Cancer Group, Vall d'Hebron Institute of Oncology
- Violeta Serra
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology
- DOI
- https://doi.org/10.15252/emmm.201809172
- Journal volume & issue
-
Vol. 10,
no. 12
pp. 1 – 16
Abstract
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