Impact of germline BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naive prostate cancer


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Abstract

Introduction: 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). Aim: 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. Materials and methods: 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 № 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. Results: 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. Discussion: 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. Conclusion: 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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About the authors

V. B Matveev

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

A. A Kirichek

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: akirdoctor@gmail.com

M. G Filippova

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

A. V Savinkova

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

O. A Khalmurzaev

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

L. N Lyubchenko

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

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