Purpose: Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Methods: Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Results: Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Conclusions: Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.

中文翻译：

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高危或转移性前列腺癌患者的种系 DNA 损伤修复变异和预后


目的：某些 DNA 修复基因中的有害种系变异是发展为侵袭性前列腺癌的危险因素。目的是量化他们在前列腺癌诊断后的预后影响。方法： 主要具有欧洲血统的前列腺癌男性患者来自四个队列，并进行了长期随访。评估了 26 个 DNA 修复基因中的致病性或可能致病性种系变异与高危、局部前列腺癌的无转移生存期以及转移性去势敏感性前列腺癌 （mCSPC） 和转移性去势抵抗性前列腺癌 （mCRPC） 的总生存期的关系。结果： 在最初诊断为非转移性前列腺癌的 3,525 例患者中，2,594 例患有高危局限性前列腺癌，入组时 mCSPC 为 429 例，mCRPC 为 502 例。BRCA2 变异携带者在高危局限性前列腺癌中的无转移生存期 （风险比 [HR] 1.01,95% 置信区间 [CI] 0.69， 1.46） 或 mCSPC （HR 0.46， 95% CI 0.14， 1.45） 或 mCRPC （HR 0.60， 95% CI 0.31， 1.17） 与 DNA 修复变异的非携带者相比。在另外 868 例新发转移性 （M1） 前列腺癌患者中，BRCA2 变异携带者的总生存率往往较差 （HR 1.59,95% CI 1.01,2.51）。BRCA2 预后关联不能用放疗、PARP 抑制剂或铂类治疗来解释。其他基因的结果精度有限，因为变异不太常见。结论： 在最初诊断为非转移性肿瘤并接受治疗的高危或转移性前列腺癌患者中，BRCA2 中的种系 DNA 修复变异不会带来明显更差的预后。