Germline mutations in advanced high-grade serous ovarian cancer: are they predictive of long-term survival?

Abstract

Background: High-grade serous ovarian cancers (HGSOC) are heterogeneous and aggressive malignancies, often diagnosed in advanced stages (FIGO III-IV) and associated with poor survival (OS, 39% at five years). Limited information exists regarding genetic prognostic factors for long-term survivors (≥ 5 years) of advanced HGSOC. Objective: This study aims to describe the differences in genetic characteristics of advanced HGSOC long-survivors in contrast with short-survivors (≤ 2 years) to improve outcomes for the latter group. Methods: A retrospective descriptive analysis of patients diagnosed with advanced HGSOC at Hospital Universitari Doctor Josep Trueta between 2009 and 2019 was conducted. Genetic studies were performed to detect germline mutations, focusing on BRCA1/2 and other relevant hereditary cancer-associated genes: BRIP1, MLH1, MSH2, MSH6, RAD51C and RAD51D. Results: The study analysed 126 patients with advanced HGSOC, split into 63 long-term (≥ 5 years) and 63 short-term (≤ 2 years) survivors. Genetic testing was available for 83 patients. Germline mutations were significantly more common in long-term survivors (32.73%) than in short-term survivors (7.14%). BRCA1 and BRCA2 mutations, found exclusively in long-term survivors, accounted for 30.91% of this group. Non-BRCA mutations, such as PALB2 and BRIP1, were identified in short-term survivors, though at lower frequencies. Variants of Uncertain Significance (VUS) were also identified in the short-term survival group, particularly in MMR-related genes (MSH6, MSH2) and HRR genes (CHEK2, ATM), suggesting potential but unconfirmed genetic contributions to prognosis. Conclusion: Long-term survivors have distinct genetic profiles compared to short-term survivors, including a higher prevalence of BRCA1/2 mutations. These findings highlight the potential of germline mutations as biomarkers for prognosis and treatment decisions in advanced HGSOC patients

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