The Clinical Pathological Characteristics and Prognostic Relevance of Homologous Recombination Repair Gene Mutations...

Backgrouds: Whether homologous recombination repair (HRR) mutation has a differential effect on the prognosis has not been confirmed by current studies. The purpose of this study was to explore the clinical importance, prognostic value, and frequency of pathogenic changes in HRR genes in patients with ovarian cancer (OC). Methods: We analyze information including HRR mutation and clinical prognosis of OC patients both in our cohort and in the TCGA-OV database. Blood and/or tumor samples from 98 women admitted to Shanghai General Hospital between January 2021 and May 2024, and DNA sequencing was performed on these samples for all patients included in this retrospective study. Testing was performed for HRR mutations, including germline BRCA1/2 mutations, and defects in HRR were defined as detrimental mutations within relevant genes. Comprehensive medical records were gathered for all patients, with a follow-up period recorded for 74 of them. Results: HRR pathway genes, including BRCA1/2, CDK12, RAD54L, RAD51, ATM, MRE11, and BRIP2, are highly expressed in FIGO Stages I-II OCs among 482 patients in the TCGA-OV database, and 95.06% samples presented mutations. The alignment diagram analyzed by logistic and Cox regression was derived to investigate HRR genes on overall survival (OS < 763 days) of OC patients. A total of 98 patients were enrolled in our study, with 70 harboring HRR mutations (HRRmt) and 28 having the HRR wild-type (HRRwt). The predominant pathological type across all four patient groups was high-grade serous adenocarcinoma, with similar prevalence in HRRmt (84.30%) versus HRRwt (75%, p=0.360) and BRCAmt (94.20%) versus BRCAwt (74.60%, p=0.151) groups. Survival prediction data were collected from 74 patients, and the HRRmt group (n = 50) exhibited a numerically longer PFS compared to the HRRwt group (n = 24), with 23 months versus 17 months, respectively. A significant disparity was noted in the percentage of patients administered PARPi medication between the HRRmt and HRRwt groups (58.00% vs. 20.20%; p=0.003). Patients in both the HRRmt group (p=0.049) and the BRCAwt group (p=0.046) receiving PARPi treatment have extended PFS. Significant differences were identified between HRRmt and HRRwt groups in the size of the initial debulking surgery achieving R0 status (p=0.005), low CA125 levels (< 1000 U/mL) at diagnosis (p=0.015), and the use of PARP inhibitors (PARPi) (p=0.024) and antiangiogenic drugs (p < 0.001). For patients with HRR mutations, the use of PARPi significantly impacted PFS (p=0.049), and achieving R0 status (p=0.005) significantly influenced PFS. Conclusions: This study indicates that mutations in the HRR gene possess significant potential as a prognostic marker in OC. Our aim was to comprehensively explore how HRR gene mutations, including but not limited to BRCA, might influence the clinical course and survival of patients, shedding light on potential new avenues for personalized treatment strategies.