Abstract 67P
Background
Pathogenic BRCA1/2 mutations currently serve as the main biomarker of homologous recombination deficiency (HRD) for PARP inhibitor (PARPi) selection, which have also been reported to correlate with the efficacy of platinum (Pt) chemotherapy. However, patients without BRCA1/2 alterations can also present HRD phenotype through other mechanisms and might benefit from PARPi or Pt chemotherapy.
Methods
HRD score of tumor samples from 199 patients (Cohort I: ovarian, breast, pancreatic, prostate, and uterine cancers) were evaluated by targeted next-generation sequencing (NGS) (GeneseeqPrime® HRD). A cohort of 416 independent solid tumor patients (Cohort II) were further analyzed for exploring HRD score distribution, while another cohort of 84 high-grade serous ovarian cancer patients (Cohort III) who received Pt chemotherapy were analyzed for investigating the predictive value of HRD score in treatment efficacy.
Results
HRD score, combining loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale station transitions (LST), of Cohort I ranges from 0 to 107, 32% of which harbor BRCA1/2-deficiency (pathogenic mutations with LOH, ≥2 pathogenic mutations, or homozygous deletion). HRD score ≥ 38 was defined as HRD-positive that accounts for approximately 95% of the BRCA1/2-deficient cases. In Cohort II, 14% of them were BRCA1/2-deficient with a median HRD score of 67 which was significantly higher than that of the BRCA1/2-sufficient ones (28; p<0.001). In BRCA1/2-wildtype subgroup, 37% of patients have HRD scores≥38 (51%, 42%, and 8% for ovarian, breast, and pancreatic cancers). In Cohort III, patients with a platinum-free interval (PFI) of over 6 months (Pt-sensitive) have significantly higher HRD scores than Pt-resistant patients (median: 55 vs 34, p=0.04). In BRCA1/2-wildtype patients, a significantly longer PFS was observed when HRD≥38 than those with HRD<38 (median: 17.8 vs 11.8 months, p=0.04).
Conclusions
Our study reported an HRD evaluation pipeline based on targeted NGS in diverse cancer types, and HRD≥38 was chosen to define HRD-positive status, which correlates with better clinical outcomes of Pt-chemotherapy.
Legal entity responsible for the study
Fudan University Shanghai Cancer Center.
Funding
Has not received any funding.
Disclosure
Y. Ma, R. Liu, Q. Ou, H. Bao, X. Wu: Financial Interests, Personal, Full or part-time Employment: Nanjing Geneseeq Technology Inc.. All other authors have declared no conflicts of interest.