Abstract
BACKGROUND: Homologous recombination deficiency (HRD) is a molecular biomarker for administrating PARP inhibitor (PARPi) or platinum-based (Pt) chemotherapy. The most well-studied mechanism of causing HRD is pathogenic BRCA1/2 mutations, while HRD phenotype is also present in patients without BRCA1/2 alterations, suggesting other unknown factors. METHODS: The targeted next-generation sequencing (GeneseeqPrime® HRD) was used to evaluate the HRD scores of 199 patients (Cohort I). In Cohort II, a total of 85 Pt-chemotherapy-treated high-grade serous ovarian cancer (HGSOC) patients were included for investigating the role of HRD score in predicting treatment efficacy. The concurrent genomic features analyzed along HRD score evaluation were studied in a third cohort with 416 solid tumor patients (Cohort III). RESULTS: An HRD score ≥ 38 was predefined as HRD-positive by analyzing Cohort I (range: 0-107). Over 95% of the BRCA1/2-deficient cases of Cohort I were HRD-positive under this threshold. In Cohort II, Pt-sensitive patients have significantly higher HRD scores than Pt-resistant patients (median: 54 vs. 34, p = 0.031) and a significantly longer PFS was observed in HRD-positive patients (median: 548 vs. 343 days, p = 0.003). Furthermore, TP53, NCOR1, and PTK2 alterations were enriched in HRD-positive patients. In Cohort III, impaired homologous recombination repair pathway was more frequently observed in HRD-positive patients without BRCA1/2 pathogenic mutations. The alteration enrichment of TP53, NCOR1, and PTK2 observed in Cohort II was also validated by the ovarian subgroup in Cohort III. CONCLUSIONS: Using an in-house HRD evaluation method, our findings show that overall HRR gene mutations account for a significant part of HRD in the absence of BRCA1/2 aberrations, and suggest that HRD positive status might be a predictive biomarker of Pt-chemotherapy.