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Prostate cancer (PCa) is one of the most common malignant tumor in men. Significant advances have been made in the early detection and treatment of localized PCa, but metastatic castration-resistant PCa (mCRPC) remains one of the most challenging problems to treat in oncology. To improve treatment outcomes for patients at this stage of the disease, it is necessary to develop personalized therapy options based on the definition of biological predictors. In mCRPC, mutations in DNA repair genes are detected in ~23 % of patients with mCRPC. Detection of these mutations in patients with PCa has important clinical relevance. PCa with mutations in DNA repair genes may be sensitive to poly(ADP-ribose)-polymerase (PARP) inhibitors. Several studies II and III phase have demonstrated the effectiveness of PARP inhibitors with a high objective response rate in the treatment of mCRPC in patients with mutations in the DNA repair genes, which is definitely a more personalized approach to treatment. Identification of hereditary mutations in DNA repair genes is an important prognostic factor for the proband's relatives (for both men and women), which can later be used for genetic counseling of patients and the application of strategies to reduce the risk of malignant diseases.
Prostate cancer (PCa) is one of the most common malignant tumor in men. Significant advances have been made in the early detection and treatment of localized PCa, but metastatic castration-resistant PCa (mCRPC) remains one of the most challenging problems to treat in oncology. To improve treatment outcomes for patients at this stage of the disease, it is necessary to develop personalized therapy options based on the definition of biological predictors. In mCRPC, mutations in DNA repair genes are detected in ~23 % of patients with mCRPC. Detection of these mutations in patients with PCa has important clinical relevance. PCa with mutations in DNA repair genes may be sensitive to poly(ADP-ribose)-polymerase (PARP) inhibitors. Several studies II and III phase have demonstrated the effectiveness of PARP inhibitors with a high objective response rate in the treatment of mCRPC in patients with mutations in the DNA repair genes, which is definitely a more personalized approach to treatment. Identification of hereditary mutations in DNA repair genes is an important prognostic factor for the proband's relatives (for both men and women), which can later be used for genetic counseling of patients and the application of strategies to reduce the risk of malignant diseases.
Background. Prostate cancer is the most common malignant condition among oncological diseases of the genitourinary tract, which occupies the second place in male mortality from malignant neoplasms. At the same time, population of patients with prostate cancer is heterogeneous: in some patients, the disease does not require active treatment, while in others it progresses rapidly with the formation of metastatic castration-resistant prostate cancer. Therefore, the search for new predictive markers remains relevant.Objective. Analysis of the prognostic significance of the loss of heterozygosity of PTEN, RB1, TP53, BRCA1 and BRCA2 genes in patients with localized and locally advanced prostate cancer.Materials and methods. The study included 52 patients with prostate cancer, 31 (59.6 %) of whom had a localized form (T1-2N0M0), and 21 (40.4 %) - locally advanced (T3a-bN0/1M0). All patients underwent radical prostatectomy, followed by genotyping of postoperative and biopsy specimens to determine genetic alterations in the studied genes. Detection of deletions in the studied genes was carried out using the method of multiplex ligation-dependent probe amplification.Results. In 13 (25.0 %) patients in the postoperative specimen was detected deletion of PTEN gene, in 6 (11.5 %) - deletion of RB1 gene, and in 1 (1.9 %) - deletion of BRCA2 gene. At the same time, patients with loss of PTEN heterozygosity were more likely to have perineural invasion (p = 0.01) and lymph node involvement (p = 0.0003). Deletion of RB1 gene is associated with more frequent detection of high-grade tumors (p = 0.013), cribriform growth component (p = 0.002), and invasion of the periprostatic tissue (p = 0.005).Conclusion. Detection of loss of heterozygosity of PTEN and RB1 genes is a promising tool for clarifying the prognosis of the disease, which in the future will allow more accurately stratify patients into risk groups for biochemical relapse.
Background. Metastatic castration-resistant prostate cancer remains a complex problem due to patients' previous treatments and limited selection of subsequent therapies. While 2nd generation antiandrogens are initially effective, resistance to them is not an exceptional event. Mechanisms depending on androgen receptor and independent of it have been described. A special focus is on mutations in DNA repair genes, particularly genes involved in homologous recombination repair (HRR) as a possible cause of somatic genetic abnormalities specifically in progressive metastatic disease. However, data on the effect of the HRR defect on the effectiveness of antiandrogen therapy for prostate cancer are very limited, which requires additional clinical studies.Aim. To evaluate the effect of clinical, morphological, molecular and genetic factors on the effectiveness of enzalutamide antiandrogen therapy in patients with prostate cancer and known mutations in DNA repair genes involved in HRR and mismatch repair.Materials and methods. The study was performed at the Clinical Oncological Dispensary No. 1 (Krasnodar). Retrospective analysis of clinical and morphological parameters of 54 patients with prostate cancer who received enzalutamide antiandrogen therapy and with known status of germ line and somatic mutations of HRR DNA repair genes (BRCA1, BRCA2, ATM, BARD, BRIP1, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD54L, FANCL) and microsatellite instability in immunohistochemical determination of mismatch repair deficit was performed. Statistical analysis was performed using IBM SPSS Statistics v.22 software.Results and conclusion. In 17 of 54 patients, pathogenic germline and somatic mutations of HRR genes were detected: 7 mutations in BRCA2 gene, 4 - in CHEK2, 2 - in BRCA1, 2 - in CDK12, 1 - in BRIP1 and 1 - in ATM. It was shown that in the group of patients with metastatic castration-resistant prostate cancer, histological grade per the International Society of Urological Pathology (ISUP) G2 (total Gleason score 7 (3 + 4)) is significantly associated with the absence of HRR mutation, and grade G3 (total Gleason score 7 (4 + 3)) was associated with HRR mutations (р <0.05). Increase in prostate-specific antigen (PSA) level/biochemical progression 12-16 weeks after enzalutamide therapy start was significantly associated with metastatic castration-resistant prostate cancer without HRR mutations (р <0.05). In case of tumor response to enzalutamide therapy, decrease in PSA level did not depend on the age of disease onset, differentiation grade, primary advancement, previous docetaxel treatment, and presence of HRR mutation. Cox multivariate regression test showed that prescription of docetaxel before enzalutamide increased the risk of PSA-progression (hazard ratio (HR) 5.160; 95 % confidence interval (CI) 1.549-17.189; р = 0.008) and radiographic progression (HR 5.161; 95 % CI 1.550-17.187; р = 0.008). Progression risk decreased with increased level of PSA decrease 12-16 weeks after enzalutamide therapy start: for PSA decrease >30 % HR 0.150; 95 % CI 0.040-0.570; р = 0.005; for PSA decrease >50 % HR 0.039; 95 % CI 0.006-0.280; р = 0.001; for PSA decrease >90 % HR 0.116; 95 % CI 0.036-0.375; р = 0.000. Presence of HRR mutation, age <58 years, primary metastatic disease and poorly differentiated morphology did not affect duration without PSA-progression (p >0.05). Kaplan-Meier curves showed a trend towards increased time to development of castration resistance in the group of primary early cancer (Breslow р = 0.06; Tarone-Ware р = 0.062). Subgroup analysis showed that in the cohort of patients with castration-resistant prostate cancer (n = 48), absence of HRR mutation in patients who previously received docetaxel therapy increases time to PSA-progression compared to patients with mutations (log-rank р <0.05).
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