Leveraging Real-World Data From a Clinicogenomic Database Addresses the Treatment Gap in Patients With High-Grade Serous Ovarian Cancer.

Abstract

This study used a deidentified nationwide (US-based) high-grade serous ovarian cancer (HGSOC) clinicogenomic database (CGDB) to enrich our understanding of HGSOC's genomic heterogeneity and assess the utility of comprehensive genomic profiling (CGP) in clinical settings. We conducted a retrospective observational analysis on 856 patients with HGSOC profiled with CGP genomic tests, retrieved from CGDB from January 2011 to September 2023. In addition to <i>BRCA1</i> (11.7%) and <i>BRCA2</i> (6.5%) variants, CGP revealed further potentially actionable alterations (amplifications and/or mutations) in <i>CCNE1</i> (16%), <i>FGFR1/2/3/4</i> (6.5%), <i>PIK3CA</i> (3.9%), <i>TP53</i>^<i>Y220C</i> (3.7%), <i>ERBB2</i> (3.5%), <i>CDK12</i> (2.3%), <i>ARID1A</i> (2.2%), <i>KRAS</i> (2.1%), and <i>BRAF</i> (1%) genes. Then, 439 patients were selected, presenting both CGP test performed on specimen collected at the time of surgery and initiation of first-line therapy within ±8 months from surgery, and categorized into no (NS, n = 74), interval (IS, n = 157), and upfront surgery (n = 208) groups, each comparable by clinical features. The CGP revealed <i>BRCA</i> mutations, at similar frequency in the three groups, in 54/439 patients (12.3%). Patients with pathogenic <i>BRCA</i> mutations had better event-free survival (EFS) compared with those with <i>BRCA</i>^<i>wt</i>. Loss-of-heterozygosity (LOH) ≥16 (LOH-positive patients) was found in 142/433 (32.8%) patients, with different prevalence across treatment groups (12.8% NS; 9% IS; 8.8% upfront surgery). Patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) had improved EFS (hazard ratio for other drugs <i>v</i> PARPi 1.77 [95% CI, 1.21 to 2.58]). Interestingly, in 206 <i>BRCA</i>^<i>wt</i> and LOH-negative patients, not eligible for PARPi, CGP detected potentially targetable alterations in 99 of them (48%). Overall, our study provides evidence that CGP significantly improves the identification of molecular targets in HGSOC, supporting its importance in the clinical practice to provide patients with more therapeutic options.