Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
Eur Urol. 2017 Jul;72(1):34-42. doi: 10.1016/j.eururo.2017.02.023. Epub 2017 Mar 1.
Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy.
To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA).
DESIGN, SETTING, AND PARTICIPANTS: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced.
Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis.
Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 (n=16) being the most frequent. Patients (n=22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but, after starting ADT, progressed to mCRPC with a median time of 11.8 mo (95% confidence interval [CI] 5.1-18.4). The median time to prostate-specific antigen progression on first-line AR-targeted therapy in the mCRPC setting was 3.3 mo (95% CI 2.7-3.9). Ten out of 11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. A limitation of this study is absence of a formal control cohort for comparison of clinical outcomes.
Patients with mCRPC who have germline DNA repair defects exhibit attenuated responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA, suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.
Patients with metastatic prostate cancer and germline DNA repair defects exhibit a poor response to standard hormonal therapies, but may be prioritized for potentially more effective therapies using a blood test.
最近有研究报道，在转移性去势抵抗性前列腺癌（mCRPC）患者中，有 8-12%存在 DNA 修复基因的种系突变。目前尚不清楚这些突变是否与雄激素受体（AR）靶向治疗的反应差异有关。
确定种系 DNA 修复缺陷的 mCRPC 患者对 AR 靶向治疗的临床反应，并确定是否可以在匹配的循环肿瘤 DNA（ctDNA）中检测到双等位基因 DNA 修复基因缺失。
设计、地点和参与者：我们招募了 319 名 mCRPC 患者，并对 22 个 DNA 修复基因进行了靶向种系测序。在存在有害种系突变的患者中，还对无细胞血浆 DNA 进行了测序。
使用 Kaplan-Meier 分析评估与初始去势治疗（ADT）和随后 mCRPC 治疗相关的前列腺特异性抗原反应和进展。
在 319 名患者中，有 24 名（7.5%）存在有害的种系突变，其中 BRCA2（n=16）最为常见。同源重组相关基因发生突变的患者（n=22）在初始表现时具有异质性，但在开始 ADT 后，中位时间为 11.8 个月（95%置信区间 [CI] 5.1-18.4）进展为 mCRPC。在 mCRPC 背景下，一线 AR 靶向治疗的前列腺特异性抗原进展中位时间为 3.3 个月（95% CI 2.7-3.9）。在可评估的 11 名存在种系 BRCA2 突变的患者中，有 10 名在 ctDNA 中存在完整等位基因的体细胞缺失。本研究的局限性在于缺乏正式的对照队列来比较临床结局。
患有 mCRPC 且存在种系 DNA 修复缺陷的患者对 AR 靶向治疗的反应减弱。ctDNA 中可可靠地检测到双等位基因基因缺失，提示可以通过液体活检优先考虑使用针对有缺陷 DNA 修复的治疗方法来治疗这些患者亚群。
患有转移性前列腺癌和种系 DNA 修复缺陷的患者对标准激素治疗反应不佳，但通过血液检测可能会优先考虑更有效的治疗方法。
