PURPOSE Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms. EXPERIMENTAL DESIGN Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue. RESULTS During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60-0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19-0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95-1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever (n = 10) versus never users (n = 103). CONCLUSIONS Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.

中文翻译：

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服用他汀类药物与降低PTEN无效和致命性前列腺癌的风险有关。

目的他汀类药物与侵袭性前列腺癌的风险较低相关，但致死性前列腺癌的研究尚未深入，其作用机制尚不清楚。我们在《健康专业人员追踪研究》（HPFS）中前瞻性地检查了他汀类药物和致死性前列腺癌的风险，测试了与分子亚型的关联，并整合了基因表达谱以鉴定推定的机制。实验设计我们的研究包括1990年无癌症的44,126名男性患者，其后直至2014年的前列腺癌发病率均以双年度问卷记录他汀类药物的使用。我们使用多变量Cox回归，通过临床上显着疾病的测量以及ERG和PTEN状况，全面检查了他汀类药物与前列腺癌风险之间的关联。在探索性分析中，年龄调整后的基因集富集分析确定了在肿瘤和邻近正常前列腺组织中富集的他汀类药物相关途径。结果在随访的24年中，诊断出6,305例前列腺癌，其中801例（13％）是致命的（诊断时转移或随访期间转移/致命）。相对于从不/过去使用，当前他汀类药物的使用与致死性前列腺癌的风险呈负相关[HR，0.76; 95％置信区间（CI），0.60-0.96]，但不是整体疾病。我们发现与PTEN无效的癌症（HR，0.40; 95％CI，0.19-0.87）的风险呈反比，而与PTEN完整的癌症（HR，1.18; 95％CI，0.95-1.48; P异质性= 0.01）则无显着相关性。 。协会没有因ERG而异。他汀类药物的正常前列腺组织中的炎症和免疫途径丰富（n = 10），而从未使用过（n = 103）。结论分子肿瘤分类确定PTEN和炎症/免疫激活是将他汀类药物与较低致死性前列腺癌风险联系起来的潜在机制。这些发现支持潜在的因果关系，并可以为他汀类临床试验选择相关的生物标志物。