Tumor Genotyping and Homologous Recombination Repair Gene Variants in Patients With Epithelial Ovarian Cancer: Is Pathogenic Enough?

Elena Fountzilas, Vassiliki Kotoula, Georgia-Angeliki Koliou, Michalis Liontos, Kyriaki Papadopoulou, Eleni Giannoulatou, Alexios Papanikolaou, Ioannis Tikas, Sofia Chrisafi, Davide Mauri, Kyriakos Chatzopoulos, Florentia Fostira, Dimitrios Pectasides, Georgios Oikonomopoulos, Dimitra Aivazi, Angeliki Andrikopoulou, Anastasios Visvikis, Gerasimos Aravantinos, Flora Zagouri, George Fountzilas, Elena Fountzilas, Vassiliki Kotoula, Georgia-Angeliki Koliou, Michalis Liontos, Kyriaki Papadopoulou, Eleni Giannoulatou, Alexios Papanikolaou, Ioannis Tikas, Sofia Chrisafi, Davide Mauri, Kyriakos Chatzopoulos, Florentia Fostira, Dimitrios Pectasides, Georgios Oikonomopoulos, Dimitra Aivazi, Angeliki Andrikopoulou, Anastasios Visvikis, Gerasimos Aravantinos, Flora Zagouri, George Fountzilas

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].

Keywords: BRCA; biomarker; co-mutation; homologous recombination repair; predictive; prognostic.

Conflict of interest statement

EF: Advisory Role: LEO Pharma. Speaker fees: Roche, Pfizer, AstraZeneca. Stock ownership: GENPREX INC, Deciphera Pharmaceuticals, Inc. Travel grant: Merck, Pfizer, and K.A.M Oncology/Hematology and DEMO. DP: Advisory Role: Roche, MSD, Astellas. Honoraria: Roche, MSD, Astellas. GA: Advisory Boards: Novartis, BMS, Roche Hellas, Astra Zeneca, Sanofi, Amgen, Genesis Pharma, Merck, Pfizer. GF: Advisory Board: Pfizer, Novartis and Roche. Honoraria: Astra Zeneca. Stock ownership: ARIAD, GENPREX, Daiichi Sankyo, RFL Holdings, FORMYCON. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Fountzilas, Kotoula, Koliou, Liontos, Papadopoulou, Giannoulatou, Papanikolaou, Tikas, Chrisafi, Mauri, Chatzopoulos, Fostira, Pectasides, Oikonomopoulos, Aivazi, Andrikopoulou, Visvikis, Aravantinos, Zagouri and Fountzilas.

Figures

Figure 1
Figure 1
Description and distribution of alterations in HRR and TP53 genes. (A) Incidence of alterations for each studied gene and for grouped HRR genes. Variants were classified as pathogenic, by simple presence, and as clonal or position-LOH, based on mutation and tumor DNA load in the examined sample. X-axis: number of affected tumors. Percentages are shown for rates >5% among all tumors with pathogenic variants (n=406). (B) Distribution of TP53/HRR gene co-mutations in the same tumor, among tumors bearing the same class of alteration in any of these genes. (C) Distribution of multiple HRR gene pathogenic variants in the same tumor, among tumors bearing the same class of alteration in these genes. (D) Map showing profiled HRR and TP53 gene mutations among tumors bearing any class of alterations in these genes, in comparison to germline mutation status and standard clinicopathological parameters. Up or down showing arrows: non-BRCA1 alterations. Tumors with only TP53 mutations and non-mutated tumors were not included in this chart.
Figure 2
Figure 2
(A) Overall survival based on the presence of HRR and/or TP53 pathogenic variants (excluding mucinous tumors). (B) Overall survival based on the presence of HRR and/or TP53 clonal pathogenic variants (excluding mucinous tumors). (C) Forest plot of hazards ratios showing the risk of death for patients with HRR and/or TP53 clonal pathogenic variants upon adjustment for clinicopathological parameters (excluding mucinous tumors). *Statistically significant parameters.
Figure 3
Figure 3
Analysis was performed in patients with high-grade serous ovarian cancer. (A) Progression-free survival (PFS) and (B) Overall survival (OS) based on the presence of pathogenic variants in HRR and/or TP53 genes. (C) PFS and (D) OS based on the presence of clonal pathogenic variants in HRR and/or TP53 genes. (E) Forest plot of hazard ratios showing the risk of death for patients with HRR and/or TP53 clonal pathogenic variants upon adjustment for clinicopathological parameters. *Statistically significant parameters.

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