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EMBO Mol Med. 2018 Oct 30. pii: e9172. doi: 10.15252/emmm.201809172. [Epub ahead of print]

A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation.

Author information

1
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
2
High Risk and Familial Cancer Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
3
Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
4
Oncogenetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
5
Genome Stability Laboratory, CHU de Québec Research Center, Québec City, QC, Canada.
6
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, QC, Canada.
7
CHU de Quebec - Université Laval Research Center, Genomics Center CHUL, Québec City, QC, Canada.
8
Department of Medical Oncology, University Hospital of Parma, Parma, Italy.
9
Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
10
Oncology Data Science (OdysSey Group), Vall d'Hebron Institute of Oncology, Barcelona, Spain.
11
Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
12
Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
13
CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
14
Department of Radiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
15
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
16
Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
17
Breast Surgical Unit, Breast Cancer Center, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
18
AstraZeneca, Waltham, MA, USA.
19
Breast Cancer Programme, Cancer Research UK (CRUK) Cambridge Cancer Centre, Cambridge, UK.
20
Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, USA.
21
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
22
Department of Oncology, Ramón y Cajal University Hospital, Madrid, Spain.
23
Vall d'Hebron Institute of Oncology, Barcelona, Spain.
24
XenTech, Evry, France.
25
Division of Molecular Pathology and Cancer Genomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
26
Oncology Innovative Medicines and Early Clinical Development Biotech Unit, AstraZeneca, Cambridge, UK.
27
Clinical and Molecular Genetics Area, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
28
High Risk and Familial Cancer Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain jbalmana@vhio.net vserra@vhio.net.
29
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain jbalmana@vhio.net vserra@vhio.net.

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:

BRCA1 ; PALB2 ; PARP inhibitors; RAD51; homologous recombination

PMID:
30377213
DOI:
10.15252/emmm.201809172
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