Abstract
Our hypothesis was that the predictive accuracy of pathogenic variants in genes participating in the homologous recombination repair (HRR) system in patients with epithelial ovarian cancer (EOC) could be improved by considering additional next-generation sequencing (NGS) metrics. NGS genotyping was performed in tumor tissue, retrospectively and prospectively collected from patients with EOC, diagnosed from 8/1998 to 10/2016. Variants were considered clonal when variant allele frequencies corresponded to >25%. The primary endpoint was overall survival (OS). This study included 501 patients with EOC, predominantly with high-grade serous (75.2%) and advanced stage tumors (81.7%); median age was 58 years (22-84). Pathogenic and clonal pathogenic variants in HRR and/or TP53 genes were identified in 72.8% and 66.5% tumors, respectively. With a median follow-up of 123.9 months, the presence of either pathogenic or clonal pathogenic HRR-only variants was associated with longer OS compared to HRR/TP53 co-mutation (HR=0.54; 95% CI, 0.34-0.87, Wald’s p=0.012 and HR=0.45; 95% CI, 0.27-0.78, Wald’s p=0.004, respectively). However, only the presence of clonal HRR-only variants was independently associated with improved OS (HR=0.55; 95% CI, 0.32-0.94, p=0.030). Variant clonality and co-occuring TP53 variants affect the predictive value of HRR pathogenic variants for platinum agents in patients with EOC.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT04716374].
Highlights
Precision oncology uses tumor histopathology, genomic/ molecular alterations and immune profile, in combination with patient’s clinical characteristics and comorbidities to select the optimal treatment [1]
The American Society of Clinical Oncology [5], the National Cancer Comprehensive Network [6], the Society of Gynecologic Oncology [7] and the European Society of Medical Oncology [8] recommend the implementation of tumor molecular profiling at the time of diagnosis of epithelial ovarian cancer (EOC). These recommendations focus on the identification of pathogenic tumor and/or germline variants in BRCA1/2 and other genes participating in the homologous recombination repair (HRR) of double-strand DNA breaks
The clinical phenotype, i.e., platinum sensitivity, appears to be a surrogate for response to poly ADP-ribose polymerase (PARP) inhibitors in EOC, in the absence of reliable homologous recombination repair deficiency (HRD) testing [19,20,21]. As these drugs are being used as front-line treatment [21], and since more than 70% of patients does not respond to therapy or progresses soon after standard platinumbased chemotherapy or during maintenance therapy with PARP inhibitors [20], it is critical to improve currently used markers predictive of platinum sensitivity
Summary
Precision oncology uses tumor histopathology, genomic/ molecular alterations and immune profile, in combination with patient’s clinical characteristics and comorbidities to select the optimal treatment [1]. Tumor and germline testing provide clinically relevant information for the use of innovative treatments, including poly ADP-ribose polymerase (PARP) inhibitors and immunotherapy [1,2,3,4] On this basis, the American Society of Clinical Oncology [5], the National Cancer Comprehensive Network [6], the Society of Gynecologic Oncology [7] and the European Society of Medical Oncology [8] recommend the implementation of tumor molecular profiling at the time of diagnosis of epithelial ovarian cancer (EOC). As these drugs are being used as front-line treatment [21], and since more than 70% of patients does not respond to therapy or progresses soon after standard platinumbased chemotherapy or during maintenance therapy with PARP inhibitors [20], it is critical to improve currently used markers predictive of platinum sensitivity
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