Prognostic significance of germline mutations in DNA homologous recombination repair genes in patients with primary metastatic prostate cancer

Background. Since recently, hereditary and somatic defects in DNA homologous recombination repair (HHR) genes have been considered as promising prognostic and predictive markers for prostate cancer. However, despite the growing evidence of their prognostic significance, these biomarkers are not included in the standard prognostic classifications for primary hormone-sensitive metastatic prostate cancer (mPCa).Aim. To assess the frequency of germline HHR DNA mutations in the Belarusian population of patients with primary mPCa and to evaluate the prognostic significance of this biomarker for long-term mPCa treatment outcomes.Materials and methods. The study included 97 patients with primary mPCa, aged between 45 and 88 years (median age 66 years) who had their HHR DNA mutation status determined from venous blood samples. Next-generation sequencing was used for genetic analysis. All patients received standard initial treatment including androgen deprivation and docetaxel chemotherapy. Cox univariate and multivariate regression analyses were conducted for major prognostic factors and genetic status and overall survival (OS) as the endpoint. The total cohort was split into three prognostic groups.Results. Рathogenic germline HHR DNA mutations were found in 16 patients (16.5 %; 95 % CI 9–24 %). The median OS and progression-free survival in the overall group were 31 months (95 % CI 25–38 months) and 15 months (95% CI 10–19 months), respectively. In the multivariate analysis with stepwise exclusion, the final model included two independent prognostic factors: HHR DNA mutation status (p = 0.028) and alkaline phosphatase (ALP) level (p 0.001). Based on pre-treatment ALP levels and HHR DNA mutation status, patients were categorized into groups with favorable, intermediate, and unfavorable prognosis, with median OS of 46 months, 31 months, and 18 months, respectively (p 0.0001).Conclusion. In patients with primary mPCa, the frequency of germline HHR DNA mutations was 16.5 %. In the multivariate analysis, HHR DNA mutations statistically significantly correlated with OS. We developed prognostic classification of primary mPCa based on pre-treatment ALP levels and HHR DNA mutation status.