ObjectiveTo investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP‐ribose)‐polymerase (PARPi) as systemic therapy for metastatic castration‐resistant prostate cancer (mCRPC).Patients and methodsOf all HRR‐screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan–Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS.ResultsOf 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia‐telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin‐dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR‐positive vs ‐negative patients. Specifically in hormone‐sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03).ConclusionIncidence of HRR alteration in a clinical real‐world setting is high when using blood‐ and tissue‐based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA‐positive patients with mCRPC with and without PARPi usage vs HRR/BRCA‐negative patients.

中文翻译：

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同源重组修复/乳腺癌 (BRCA) 基因改变对转移性前列腺癌现实环境中生存的影响


目的研究同源重组修复（HRR）的改变，特别是乳腺癌1/2（乳腺癌1/2) 与总生存期 (OS) 相关的基因。此外，探讨抑制聚（ADP-核糖）聚合酶（PARPi）作为转移性去势抵抗性前列腺癌（mCRPC）全身治疗的效果。患者和方法在所有 HRR 筛查的转移性前列腺癌患者中，基线特征为采样。 Kaplan-Meier 估计和多变量 Cox 回归模型预测了 HRR/ 的影响乳腺癌OS 发生 1/2 改变。结果在 196 名符合条件的患者中，61 名 (31%) 存在任何 HRR，40 名 (20%) 存在任何 HRR乳腺癌1/2 改动。在 HRR 改变中，40 次 (66%) vs 6 次 (10%) vs 5 次 (8.2%) vs 4 次 (6.6%) vs 2 次 (3.3%) vs 4 次 (6.6%)乳腺癌1/2 vs 共济失调毛细血管扩张突变激酶（自动提款机) 与检查点激酶 2 (查克2) 与细胞周期蛋白依赖性激酶 12 ( CDK 12) vs Fanconi贫血补充A组(芬卡）与其他突变呈阳性。其中，30% 获得了 PARPi。 HRR 阳性与阴性患者的 OS 存在显着差异。特别是在激素敏感型前列腺癌中，中位 OS 为 63（HRR 阳性） vs 57（HRR 阳性）乳腺癌1/2 正）与 113 个月（HRR 负）（磷≤ 0.01）。在 mCRPC 中，OS 为 42（HRR 阳性）vs 41（HRR 阳性）乳腺癌1/2 阳性）与 70 个月（HRR 阴性）（磷≤ 0.01）。心率和乳腺癌多变量调整后，1/2 的改变与较差的 OS 相关。 最后，mCRPC 患者乳腺癌未接受 PARPi 治疗的 1/2 突变患者的 OS 比接受 PARPi 治疗的患者更差乳腺癌1/2 突变和 PARPi 治疗（中位 OS：33 个月与 48 个月，磷< 0.03)。结论当使用基于血液和组织的测试时，临床现实环境中 HRR 改变的发生率很高。 HRR 患者/乳腺癌改变会产生更差的结果，导致 HRR/ 之间的 OS 存在显着差异乳腺癌‐使用或不使用 PARPi 的 mCRPC 阳性患者与 HRR/乳腺癌‐阴性患者。