Abstract
Simple SummaryThe sensitivity to PARP inhibitors (PARPi) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2-related deficiencies. A robust method to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we evaluated the use of a functional test (the RECAP test) for the identification of HRD ovarian carcinomas. Forty-nine epithelial ovarian carcinomas (EOC) were analyzed by the RECAP test. Thirty-nine of these tumors were of the high-grade serous (HGSOC) histologic subtype. Ten out of these 39 HGSOC specimens showed HRD (26%), whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Eight out of 9 sequenced HRD tumors showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation. This study shows that the RECAP test is a reliable and rapid test to identify functional deficiencies in HR and a good alternative to DNA-based HRD tests.Recent studies have shown that the efficacy of PARP inhibitors in epithelial ovarian carcinoma (EOC) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2 deficient EOC. A robust method with which to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we investigated the proficiency of a functional HR assay based on the detection of RAD51 foci, the REcombination CAPacity (RECAP) test, in identifying HRD tumors in a cohort of prospectively collected epithelial ovarian carcinomas (EOCs). Of the 39 high-grade serous ovarian carcinomas (HGSOC), the RECAP test detected 26% (10/39) to be HRD, whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Of the HRD tumors that could be sequenced, 8/9 showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation, indicating that the RECAP test reliably identifies HRD, including but not limited to tumors related to BRCA1/2 deficiency. Furthermore, we found a trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is clearly warranted.
Highlights
Surgical cytoreduction combined with platinum-based chemotherapy has traditionally been the standard of care in the treatment of epithelial ovarian carcinoma (EOC) patients [1,2]
8.0 and Adobe Creative Suite CS6 (Adobe, San Jose, CA, USA). In this manuscript we describe the use of the REcombination CAPacity (RECAP) test to identify
We found that all HR Deficiency (HRD) ovarian carcinomas in our cohort were of the high-grade serous (HGSOC) histologic subtype
Summary
Surgical cytoreduction combined with platinum-based chemotherapy has traditionally been the standard of care in the treatment of epithelial ovarian carcinoma (EOC) patients [1,2]. A series of recent clinical trials showed that Poly (ADP-Ribose) Polymerase inhibitor (PARPi) as maintenance treatment of EOC patients with platinum-sensitive cancers results in significant improvement of both progression-free survival (PFS) and overall survival (OS) in newly diagnosed and recurrent. EOC [3,4,5,6,7,8,9,10,11] This led to FDA and EMA approval of various PARPi as maintenance therapy in patients with platinum-sensitive EOC, both in the primary and recurrent setting. Using gene-specific analyses, the percentage of HRD high-grade serous ovarian carcinomas (HGSOC) is estimated to be as high as
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