HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer
HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer
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DOI：
10.1001/jamaoncol.2019.6496
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发表时间：
2020-04-01
期刊：
影响因子：
28.4
通讯作者：
Sharifi, Nima
中科院分区：
文献类型：
--
作者：
Hearn, Jason W. D.;Sweeney, Christopher J.;Sharifi, Nima
肾上腺限制性HSD 3B 1（1245 A）等位基因限制性腺外双氢睾酮合成，而肾上腺允许性HSD 3B 1（1245 C）等位基因增加性腺外双氢睾酮合成。回顾性研究表明肾上腺素允许等位基因（其在白色男性中的频率最高）与去势抵抗性前列腺癌（CRPC）的早期发生之间存在关联。E3805化学激素治疗与雄激素消融治疗前列腺癌广泛性疾病的随机试验（CHAARTED）是一项在新诊断的转移性前列腺癌男性中进行去势联合或不联合多西他赛治疗的大型、多中心、III期试验。从2006年7月28日至2012年12月31日，790例患者接受了随机分组，其中527例有可用的DNA样本。在这项研究中，在475例接受E3805 CHAARTED治疗的白色男性中回顾性确定了HSD 3B 1种系基因型，并通过基因型分析了临床结局。数据分析从2006年7月28日至2018年10月17日进行。干预男性被随机分为去势加多西他赛，75 mg/m2，每3周一次，共6个周期或单独去势。根据基因型将研究组的患者合并，以评估与基因型相关的总体结局。结果：在475例有DNA样本的白色男性中，270例（56.8%）患者遗传了肾上腺素允许基因型（>= 1个HSD 3B 1 [1245 C]等位基因）。平均（SD）年龄为63（8.7）岁。在患有肾上腺允许型与肾上腺限制型低容量疾病的男性中，2年时无CRPC的比例降低：51.0%（95% CI，40.9%-61.2%）vs 70.5%（95% CI，60.0%-80.9%）（P = 0.01）。在肾上腺允许基因型的低容量疾病患者中，5年总生存率也更差：57.5%（95% CI，47.4%-67.7%）vs 70.8%（95% CI，60.3%-81.3%）（P = 0.03）。CRPC的风险比为1.89（95% CI，1.13-3.14; P = .02），死亡的风险比为1.74（95% CI，1.01-3.00; P = .045）。基因型和高容量疾病患者的预后之间没有相关性。基因型之间没有相互作用，并从docetaxel.CONCLUSIONS和RELEVANCE遗传的肾上腺允许的HSD 3B 1基因型与早期去势抵抗和较短的总生存率在男性低容量转移性前列腺癌，并可能有助于确定男性更有可能受益于升级雄激素受体轴抑制超出性腺睾酮抑制。
IMPORTANCE The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).OBJECTIVE To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data.DESIGN, SETTING, AND PARTICIPANTS The E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.INTERVENTIONS Men were randomized to castration plus docetaxel, 75mg/m(2), every 3 weeks for 6 cycles or castration alone.MAIN OUTCOMES AND MEASURES Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype.RESULTS Of 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (>= 1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5%(95% CI, 47.4%-67.7%) vs 70.8%(95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.CONCLUSIONS AND RELEVANCE Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.