Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer
Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer
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DOI：
10.1016/j.clgc.2018.03.006
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发表时间：
2018-08-01
影响因子：
3.2
通讯作者：
Agarwal, Neeraj
中科院分区：
文献类型：
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作者：
Hahn, Andrew W.;Gill, David M.;Agarwal, Neeraj
HSD 3B 1（1245 C）变异体可预测去势敏感性前列腺癌（CSPC）对ADT的反应和去势抵抗性前列腺癌（CRPC）对酮康唑的反应。我们假设DSD 3B 1（1245 C）变体可以预测对醋酸阿比特龙（AA）的反应。在76例转移性CRPC患者中，HSD 3B 1（1245 C）变异不能预测一线AA的反应。背景：HSD 3B 1基因编码酶3 β-羟基类固醇脱氢酶-1（3 β HSD 1），该酶催化肾上腺雄激素前体转化为最有效的雄激素双氢睾酮。最近，在去势敏感性前列腺癌（CSPC）的背景下，HSD 3B 1（1245 C）变异体被证明可预测对药物或手术去势的雄激素剥夺治疗的反应持续时间较短。HSD 3B 1（1245 C）变异还预测了去势抵抗性前列腺癌（CRPC）男性对酮康唑的反应持续时间较长。我们假设，HSD 3B 1（1245 C）变异预测醋酸阿比特龙（AA）治疗的反应，并有助于晚期前列腺癌男性的个性化治疗。方法：临床数据和样本来自犹他州大学前瞻性维护的前列腺癌登记处。进行基因分型。主要研究终点是转移性CRPC男性患者一线AA的无进展生存期。我们进行了预先设定的多变量分析，以评估HSD 3B 1基因型对AA无进展生存期的独立预测价值。结果：纳入了76例接受一线AA治疗的转移性CRPC男性患者。在多变量分析中，HSD 3B 1（1245 C）变异体不能预测一线AA的应答。结论：HSD 3B 1（1245 C）变异不能预测转移性CRPC对一线AA的应答。这一发现可能是由于AA代谢物在雄激素信号传导上同时充当激动剂（3-酮-5 α-阿比特龙）和拮抗剂（Δ 4-阿比特龙）的能力。
The HSD3B1 (1245C) variant is predictive of response to ADT in castration sensitive prostate cancer (CSPC) and to ketoconazole in castration resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant would be predictive of response to abiraterone acetate (AA). In 76 men with metastatic CRPC, the HSD3B1 (1245C) variant was not predictive of response to first-line AA.Background: The HSD3B1 gene encodes the enzyme 3 beta-hydroxysteroid dehydrogenase-1 (3 beta HSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. Methods: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA. Results: Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA. Conclusion: The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5 alpha-abiraterone) and antagonist (Delta 4-abiraterone) on androgen signaling.