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

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 BRCA1 (11.7%) and BRCA2 (6.5%) variants, CGP revealed further potentially actionable alterations (amplifications and/or mutations) in CCNE1 (16%), FGFR1/2/3/4 (6.5%), PIK3CA (3.9%), TP53^Y220C (3.7%), ERBB2 (3.5%), CDK12 (2.3%), ARID1A (2.2%), KRAS (2.1%), and BRAF (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 BRCA mutations, at similar frequency in the three groups, in 54/439 patients (12.3%). Patients with pathogenic BRCA mutations had better event-free survival (EFS) compared with those with BRCA^wt. 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 v PARPi 1.77 [95% CI, 1.21 to 2.58]). Interestingly, in 206 BRCA^wt 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.