Background

Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.

Objective

To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations.

Design, setting, and participants

We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide.

Outcome measurements and statistical analysis

We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses.

Results and limitations

Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations.

Conclusions

Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations.

Patient summary

Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.

中文翻译：

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一线阿比特龙和恩杂鲁胺的转移性去势抵抗性前列腺癌男性生殖细胞DNA修复基因突变和结果。

背景

遗传性DNA修复基因突变在晚期前列腺癌患者中比以前认为的更为普遍，但是其临床意义尚不完全清楚。

客观的

目的调查接受下一代激素治疗（NHT）的转移性去势抵抗性前列腺癌（mCRPC）男性生殖系DNA修复基因改变的临床意义，尤其着重于BRCA / ATM突变。

设计，设置和参与者

我们从172名mCRPC患者的白细胞DNA中询问了50个致病或可能致病的种系突变基因，这些患者开始用阿比特龙或enzalutamide一线NHT治疗。

成果测量和统计分析

我们评估了种系DNA修复基因突变状态对≥50％和≥90％PSA反应，PSA无进展生存期（PSA-PFS），临床/放射学无进展生存期（PFS）和总体生存期（OS）的影响）。使用倾向评分加权多变量Cox回归分析调整生存结局。

结果与局限性

在包括的172名mCRPC患者中，男性的种系突变（在任何DNA修复基因中）在12％（22/172）的男性中发现，种系BRCA / ATM突变特别在5％（9/172）的男性中发现。在未经校正的分析中，相对于PSA-PFS（危险比[HR] 0.47；p  = 0.061），PFS（HR 0.50；p），具有生殖系BRCA / ATM突变（对无突变）的男性，一线NHT的结局更好。 = 0.090）和OS（HR 0.28; p  = 0.059）。在倾向评分加权多变量分析，结果均优于在人与种系BRCA / ATM突变相对于PSA-PFS（HR 0.48,95％置信区间[CI] 0.25-0.92; p  = 0.027），PFS（HR 0.52， 95％CI 0.28–0.98;p  = 0.044）和OS（HR 0.34，95％CI 0.12–0.99；p  = 0.048），但非BRCA / ATM种系突变的男性则不然（所有p  > 0.10）。这些结果需要前瞻性验证，我们的结论受到少数BRCA / ATM突变患者（n  = 9）的限制。

结论

一线NHT的结果在具有种系BRCA / ATM突变（相对于无突变）的mCRPC患者中似乎更好，但对于其他非BRCA / ATM种系突变的患者则没有。

病人总结

患有转移性去势抵抗性前列腺癌且在BRCA1 / 2和ATM中具有种系突变的患者可以从阿比特龙和恩杂鲁胺治疗中受益。