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

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 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. 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.

[Impact of PD-L1 status on the long-term outcomes of radical treatment of patients with prostate cancer].

A wide range of variables are associated with poor long-term outcomes of radical treatment in patients with prostate cancer (PCa). Expression of the programmed death-1 ligand 1 (PD-L1) in tumor might be a potential novel marker for PCa. AIM: to evaluate the influence of PD-L1 expression status in tumor cells on long-term results of radical treatment in patients with PCa. MATERIALS AND METHODS: a total of 45 patients with pathologically-proven PCa who undergone radical treatment and followed at N.N. Blokhin National Medical Research Center of Oncology were retrospectively analyzed. In all cases PD-L1 expression in tumor cells was evaluated by immunohistochemical studies of paraffin block sections obtained under direct control of pathologist. Positive expression of PD-L1(+) was defined as expression level in tumor cells more or equal 1%, while hyperexpression was diagnosed when expression level L1 more or equal 5%. RESULTS: PD-L1 expression and hyperexpression in tumor cells were identified in 8 (17.8%) and 6 (13.3%) cases. Median metastasis-free survival in patients with positive PD-L1 expression was 48.918 months (95% CI 42.523-55.313) and was less than in patients with negative PD-L1 expression (68.033 months, 95% CI 48.242- 87.824, p=0.090). Cancer-specific survival in patients with negative PD-L1 expression was significantly longer compared to patients with positive expression (p=0.05) and hyperexpression (p=0.024) of PD-L1 in tumor cells. Multivariate Cox analysis confirmed independent predictive value of positive expression and hyperexpression of PD-L1 in tumor cells for metastasis-free survival (HR 3.461, 95% CI 1.171-10.228, p=0.025, and HR 3.916, 95% CI 1.129-13.591, p=0.032) and cancer-specific survival (HR 7.65, 95% CI 0.69-84.51, p=0.097, and HR 9.73, 95% CI 0.87-108.78, p=0.065). CONCLUSION: According to our study and published data, positive PD-L1 expression in tumor cells is associated with poor prognosis of PCa. Given the lack of association of PD-L1 expression in tumor cells with the routine clinical and pathological characteristics of the disease, it seems reasonable to include the status of PD-L1 expression in the current predictive nomograms for patients with PCa. The results may indicate the potential benefits of developing personalized approaches to PCa treatment, particularly with targeting a PD-L1/PD-1 signaling pathway in tumor cells.

[Rare hereditary syndromes associated with polyposis and the development of malignant tumors].

UNLABELLED: Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome are genetic diseases characterized by gastrointestinal polyps, extraintestinal manifestations, and autosomal dominant inheritance. The carriers of these diseases from early childhood are at risk for neoplasias at different sites, which are symptomatic at various ages. AIM: to study the clinical organ-specific manifestations in patients with FAP and Peutz-Jeghers, genetics update and possibilities of diagnosis, monitoring, and treatment of these diseases. MATERIAL AND METHODS: The authors give the results of their examination and follow-up of children with FAP and Peutz-Jeghers hamartoma-polypous syndrome. In addition, current data from PubMed, Medline (including reviews, original articles and case reports) were used. RESULTS: The main clinical organ-specific signs of multiple tumors in FAP and Peutz-Jeghers syndrome are shown. Data on the assessment of a risk for malignant tumors at various sites in the affected patients and their family members at different ages are provided. Each of these syndromes has a dissimilar genetic foundation. FAP is caused by the germline mutations in the APC gene, Peutz-Jeghers syndrome is by the STK11 gene, which predispose individuals to specifically associated neoplasias and require different follow-up strategies. Information on a phenotype-genotype correlation may serve as a reference point for the possible severity and various manifestations of a disease. An update on the molecular pathogenesis of these diseases is considered. CONCLUSION: Molecular genetic testing of the genes associated with FAP and Peutz-Jeghers syndromes makes it possible to timely recognize family members at high risk, to plan therapeutic strategy and to affect the course of a disease. The joint participation of pediatricians, proctologists, oncologists, morphologists, geneticists, and molecular biologists is essential to timely recognize the carriers of the syndromes and a better prognosis in these patients.