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