Androgen receptor signaling mechanism in prostate cancer: resistance to antiandrogen therapy and association with DNA repair genes

А.И. Стукань, А.Ю. Горяинова, М.М. Григорян, В.Ф. Кутян, В.С. Жданов, Т.Ю. Семиглазова, Е.Н. Имянитов, A. I. Stukan, A. Goryainova, M. Grigoryan, V. F. Kutyan, V. S. Zhdanov, T. Semiglazova, E. Imyanitov
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引用次数: 1

Abstract

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).
前列腺癌中的雄激素受体信号传导机制:抗雄激素治疗的耐药性及其与DNA修复基因的关系
背景。转移性去势抵抗性前列腺癌仍然是一个复杂的问题,由于患者以前的治疗和有限的选择后续治疗。虽然第二代抗雄激素最初是有效的,但对它们产生耐药性并不罕见。已经描述了依赖于雄激素受体而独立于雄激素受体的机制。特别关注DNA修复基因的突变,特别是参与同源重组修复(HRR)的基因,这可能导致体细胞遗传异常,特别是在进行性转移性疾病中。然而,关于HRR缺陷对前列腺癌抗雄激素治疗效果影响的数据非常有限,这需要额外的临床研究。评估临床、形态学、分子和遗传因素对enzalutamide抗雄激素治疗前列腺癌患者和已知参与HRR和错配修复的DNA修复基因突变的有效性的影响。材料和方法。该研究在第一临床肿瘤药房(克拉斯诺达尔)进行。回顾性分析54例接受enzalutamide抗雄性激素治疗且HRR DNA修复基因(BRCA1、BRCA2、ATM、BARD、BRIP1、CDK12、CHEK1、CHEK2、PALB2、RAD51B、RAD51C、RAD54L、FANCL)种系和体细胞突变和微卫星不稳定状态的前列腺癌患者的临床和形态学参数,进行错配修复缺陷免疫组化检测。采用IBM SPSS Statistics v.22软件进行统计学分析。结果与结论。在54例患者中,17例检测到致病性HRR基因的种系和体细胞突变:BRCA2基因7个突变,CHEK2基因4 -突变,BRCA1基因2 -突变,CDK12基因2 -突变,BRIP1基因1 -突变和ATM基因1 -突变。研究表明,在转移性去势抵抗性前列腺癌患者组中,国际泌尿病理学会(ISUP)的组织学分级G2(总Gleason评分7(3 + 4))与HRR突变的缺失显著相关,G3(总Gleason评分7(4 + 3))与HRR突变相关(30% HR 0.150;95% ci 0.040-0.570;r = 0.005;PSA降低50%,HR 0.039;95% ci 0.006-0.280;r = 0.001;PSA降低bb0 90%, HR 0.116;95% ci 0.036-0.375;* * = 0.000。存在HRR突变,年龄0.05)。Kaplan-Meier曲线显示原发性早期癌组出现去势抵抗的时间有增加的趋势(Breslow = 0.06;Tarone-Ware = 0.062)。亚组分析显示,在阉割抵抗性前列腺癌患者队列中(n = 48),先前接受多西他赛治疗的患者HRR突变缺失比突变患者到psa进展的时间增加(log-rank <0.05)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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