Abstract
Simple SummaryRapid and reliable identification of patients with homologous recombination deficient (HRD) tumors is important for treatment choice as these tumors tend to respond well to platinum-based chemotherapy and PARP inhibitors (PARPi). In this study, a RAD51-based functional HRD test that can be performed on routine diagnostic formalin-fixed paraffin-embedded (FFPE) tissues (RAD51-FFPE test), was further improved and optimal test parameters were determined. The RAD51-FFPE test was able to determine tumor HR status with high sensitivity and specificity, making it an attractive test to be applied as routine diagnostic tool in the near future.PARP inhibitor (PARPi) sensitivity is related to tumor-specific defects in homologous recombination (HR). Therefore, there is great clinical interest in tests that can rapidly and reliably identify HR deficiency (HRD). Functional HRD tests determine the actual HR status by using the (dis)ability to accumulate RAD51 protein at sites of DNA damage as read-out. In this study, we further improved and calibrated a previously described RAD51-based functional HRD test on 74 diagnostic formalin-fixed paraffin-embedded (FFPE) specimens (RAD51-FFPE test) from endometrial cancer (EC n = 25) and epithelial ovarian cancer (OC n = 49) patients. We established optimal parameters with regard to RAD51 foci cut-off (≥2) and HRD threshold (15%) using matched endometrial and ovarian carcinoma specimens for which HR status had been established using a RAD51-based test that required ex vivo irradiation of fresh tissue (RECAP test). The RAD51-FFPE test detected BRCA deficient tumors with 90% sensitivity and RECAP-HRD tumors with 87% sensitivity, indicating that it is an attractive alternative to DNA-based tests with the potential to be applied in routine diagnostic pathology.
Highlights
In 2020, the European Society for Medical Oncology (ESMO) published their recommendations regarding applications of predictive biomarkers for homologous recombination deficiency (HRD) detection and subsequent predictive capacity for PARP inhibitors (PARPi) benefit in epithelial ovarian cancer [1]
With respect to the first approach, i.e., detection of pathogenic genetic alterations/gene silencing by promotor hypermethylation in HR-related genes, Konstantinopolous et al reported that an HRD phenotype in terms ofgenetic alterations in BRCA1, BRCA2, PALB2 and additional HR-related genes was observed in approximately 50% of high grade serous epithelial ovarian cancers (HGSOC) [16]
Both tests are able to detect HRD beyond BRCA1/2 pathogenic variants; the predictive capacity of genomic scar-based HRD tests for therapy response after treatment with PARPi is suboptimal, since the greatest benefit is observed among BRCA deficient HRD cases
Summary
In 2020, the European Society for Medical Oncology (ESMO) published their recommendations regarding applications of predictive biomarkers for homologous recombination deficiency (HRD) detection and subsequent predictive capacity for PARP inhibitors (PARPi) benefit in epithelial ovarian cancer [1]. PARPi sensitivity could be observed among HR-Proficient (HRP) patients [6,23,24] This apparent discrepancy may at least partially result from the fact that genome-based approaches capture the genomic history of the tumor instead of the actual HR status of tumors. The latter is especially important in the context of reversion mutations, as has been described for BRCA1/2 or loss of function variants of the 53BP1 gene that may subsequently lead to restoration of HR function [25,26,27,28,29,30,31]
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