Beyond HRD Status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Advanced epithelial ovarian cancer (AOC) management benefits from molecular diagnostics predicting response to Poly (ADP-ribose) polymerase inhibitors (PARPi).
• Homologous recombination deficiency (HRD) status is a key biomarker, but its predictive power for PARPi sensitivity is inconsistent.
• Understanding resistance mechanisms beyond HRD is crucial for optimizing treatment strategies.

Purpose of the Study:

• To investigate molecular factors influencing PARPi sensitivity and resistance in AOC, beyond established HRD status.
• To identify novel genetic variants associated with treatment response and progression-free survival (PFS).
• To explore the role of specific BRCA1 variants in predicting response to combination therapy.

Main Methods:

• Post hoc translational analysis of tumor samples from the ENGOT-ov24/NSGO-AVANOVA trial.
• DNA sequencing using the TruSight Oncology 500 HT gene panel on formalin-fixed paraffin-embedded samples.
• Classification of variants and assessment of HRD status using Myriad MyChoice CDx.

Main Results:

• 151 pathogenic/likely pathogenic variants were identified in 81 samples from 92 patients.
• PARPi-sensitizing variants were found in HRD-negative patients with clinical benefit, and resistance variants in HRD-positive patients with poor outcomes.
• Truncating BRCA1 variants in exon 11 correlated with improved PFS when niraparib was combined with bevacizumab.

Conclusions:

• PARPi response in AOC is complex and influenced by genetic alterations beyond HRD status.
• Somatic variant analysis offers potential for identifying novel biomarkers for PARPi therapy.
• Further research into BRCA1 exon 11 variants and combination therapies is warranted for precision oncology in AOC.