HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer
HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer
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DOI：
10.1001/jamaoncol.2017.3159
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发表时间：
2018-04-01
期刊：
影响因子：
28.4
通讯作者：
Sharifi, Nima
中科院分区：
文献类型：
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作者：
Almassi, Nima;Reichard, Chad;Sharifi, Nima
重要性HSD 3B 1（1245 C）种系变异体编码3 β-羟基类固醇脱氢酶同工酶1的功能获得性错义（3 β HSD 1）导致性腺外前体合成双氢睾酮增加，并预测更快进展为去势抵抗性前列腺癌（CRPC）。基因型可预测转移性CRPC. ORGN患者对非甾体17 α-羟化酶/17，20-裂解酶（CYP 17 A1）抑制的性腺外雄激素消融的临床反应设置.和参与者在加州大学进行了一项1998年6月至2012年12月期间接受酮康唑治疗的转移性CRPC男性的观察性研究，San弗朗西斯科.在转移性CRPC男性患者中使用非甾体CYP 17 A1抑制剂酮康唑进行性腺外雄激素消融.主要结局和指标分析的主要终点是酮康唑治疗的持续时间和疾病进展的时间按HSD 3B 1基因型分层。疾病进展定义为生化或放射学进展，分别使用前列腺癌工作组3和实体瘤疗效评价标准（RECIST）第1.1版定义。Kaplan-Meier分析用于估计治疗时间和疾病进展时间。趋势的对数秩检验被用来比较结果的HSD 3B 1 genotype.Results一个总共90名男性（中位数[四分位数范围]年龄，61.5 [55.3-67.0]岁）转移性CRPC被纳入分析，有足够的数据来确定酮康唑治疗的持续时间和疾病进展的时间，分别在88和81例患者。中位治疗持续时间随遗传性HSD 3B 1（1245 C）变异等位基因数量增加而增加：0个变异等位基因为5.0个月（95%CI，3.4-10.4）; 1个为7.5个月（95%CI，4.9-19.2）; 2个为12.3个月（95%CI，1.8-未达到）（趋势总体比较，P = 0.01）。中位无进展生存期也随遗传的HSD 3B 1（1245 C）变异等位基因数量增加而增加：5.4个月（95% CI，3.7-7.5）0个变异等位基因; 9.7个月（95%CI，5.6-32.9）; 15.2个月（95% CI，7.8-未达到）2（趋势的总体比较，P = .03）结论和相关性HSD 3B 1（1245 C）变异等位基因的遗传，其是对去势抵抗的预测性生物标志物，也是对用非甾体CYP 17抑制剂进行性腺外雄激素消除的敏感性的预测性生物标志物。这些发现标志着前列腺癌患者治疗分层的可能途径。
IMPORTANCE The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3 beta-hydroxysteroid dehydrogenase isoenzyme 1 (3 beta HSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC).OBJECTIVE To determine whether the HSD3B1(1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17a-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC.DESIGN. SETTING. AND PARTICIPANTS An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco.EXPOSURES Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC.MAIN OUTCOMES AND MEASURES The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype.RESULTS A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1(1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1(1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03)CONCLUSIONS AND RELEVANCE Inheritance of the HSD3B1(1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17Alinhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.