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Clin Cancer Res. 2018 Dec 15;24(24):6277-6287. doi: 10.1158/1078-0432.CCR-18-0063. Epub 2018 Aug 23.

Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects.

Author information

1
Department of Molecular Genetics and Oncode Institute, Erasmus MC University Medical Center Rotterdam, the Netherlands.
2
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC University Medical Center Rotterdam, the Netherlands.
3
Erasmus MC University Medical Center Rotterdam, Cancer Computational Biology Center, Rotterdam, the Netherlands.
4
Department of Urology, Erasmus MC University Medical Center Rotterdam, the Netherlands.
5
Department of Pathology, Erasmus MC University Medical Center Rotterdam, the Netherlands.
6
Maasstad ziekenhuis, Rotterdam, the Netherlands.
7
Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
8
Department of Molecular Genetics and Oncode Institute, Erasmus MC University Medical Center Rotterdam, the Netherlands. d.vangent@erasmusmc.nl.

Abstract

PURPOSE:

Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test.

EXPERIMENTAL DESIGN:

Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI).

RESULTS:

RECAP was completed successfully in 148 of 170 samples (87%). Twenty-four tumors showed HRD (16%), whereas six tumors were HR intermediate (HRi; 4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts (P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017).

CONCLUSIONS:

RECAP is a robust functional HR assay detecting both BRCA1/2-deficient and BRCA1/2-proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.

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