Genomic instability and amplification as emerging biomarkers for stratifying high-grade serous ovarian cancer.

Introduction: Ovarian cancer (OC) is one of the leading causes of cancer-related death in women worldwide. Treatment with PARP-inhibitors has significantly improved survival in patients with high-grade serous cancer (HGSC) bearing mutations (~22% of the cases), and/or homologous recombination deficiency (HRD, ~50%). Unfortunately, limited therapeutic alternatives are available for wild type/HR proficient HGSC patients, who usually exhibit resistance to standard treatments and poor prognosis.

Methods: Herein, we present the results of a comprehensive genomic profiling (CGP) analysis using the Oncomine Comprehensive Assay® (OCA) Plus in a consecutive retrospective cohort of 102 HGSC patients characterized in our institution.

Results: Genomic instability, measured by Genomic Instability Metric (GIM) >16, was found in 40% of the cases and was significantly associated with mutations (p=0.009), with a better prognosis in terms of recurrence-free survival (p=0.01). amplification was observed in 29% of cases and was negatively correlated with BRCA1/2 mutations (p=0.001), without any association with GIM, supporting as a strong and independent driver of tumorigenesis. Additionally, amplification was validated with fluorescent in situ hybridization (FISH), supporting the analytical robustness of NGS data (rho=0.93), and investigated by immunohistochemistry (IHC), revealing that protein overexpression was observed in the absence of gene amplification in 45% of cases.

Discussion: Our real-world study supports the clinical utility of the GIM metric and the analytical validity of amplification, a new promising biomarker for personalizing treatment in HR proficient HGSC patients. The discordance between amplification and protein expression raises intriguing questions about the mechanisms of -driven tumorigenesis and warrants further investigation.