Abstract
as shown in previous studies, mutations in the BRCA1/2 and CHEK2 genes are associated with worsened long-term results of the definitive treatment for localized prostate cancer (PCa). to evaluate the prognostic value of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with metastatic PCa (mPCa), receiving hormonal therapy in the first-line systemic treatment. A total of 76 patients with mPCa receiving hormonal therapy with luteinizing hormone-releasing hormone analogue (LHRHa) in N.N. Blokhin National Medical Research Center of Oncology were recruited in our prospective study. All patients were genotyped for germline mutations in the BRCA1/2 and CHEK2 genes by real-time polymerase chain reaction using a set "OncoGenetics" (LLC "Research and Production Company DNA-Technology", Russia, registration certificate No 2010/08415) and the Sanger sequencing using a set "Beckman Coulter enomeLab GeXP". In addition, a histologic grade and volume of metastatic disease were evaluated. Pathogenic and possibly pathogenic mutations in the BRCA2 and CHEK2 gene were identified in 19 (25%) patients. No cases of BRCA1 mutations were detected. Median time to castration resistance was significantly lower in BRCA2 and CHEK2 mutation carriers (7.93 mo, 95% confidence interval (CI) 2.62-13.25), than in non-carriers (48,66 mo, 95% CI 31.05-68.26, p<0,001). Cox analysis confirmed three independent unfavorable prognostic factors. The results of our study and other publications have confirmed limited efficacy of standard approach to treatment hormone-sensitive mPCa in germline mutation BRCA2 and CHEK2 carriers. However, the main objective of studies was to assess the survival rates in these patients at the stage of castration-resistant mPCa. Our results demonstrated that germline BRCA2 and CHEK2 mutations are independent unfavorable predictors in patients with mPCa which are associated with decreased time to castration resistance (HR 3.04, 95% CI 1.63-5.66, p<0.001), particularly in subgroup with low volume metastatic disease (HR 4.59, 95% CI 2.06-10.22, p<0,001). An evaluation of a prognostic value of mutations in other DNA repair genes requires additional research.
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