Functional ex vivo assay reveals homologous recombination deficiency in breast cancer beyond BRCA gene defects
Clinical Cancer Research , Volume 24 - Issue 24 p. 6277- 6287
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 ¼ 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 ¼ 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.
|Clinical Cancer Research|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Meijer, T.G, Verkaik, N.S, Sieuwerts, A.M, van Riet, J, Naipal, K.A.T, van Deurzen, C.H.M, … van Gent, D.C. (2018). Functional ex vivo assay reveals homologous recombination deficiency in breast cancer beyond BRCA gene defects. Clinical Cancer Research, 24(24), 6277–6287. doi:10.1158/1078-0432.CCR-18-0063