期刊
EUROPEAN UROLOGY
卷 72, 期 1, 页码 34-42出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.eururo.2017.02.023
关键词
BRCA2; Circulating tumor DNA; Cell-free DNA; Liquid biopsy; Enzalutamide; Abiraterone; Castration-resistant prostate cancer; DNA repair
资金
- Prostate Cancer Canada through Movember Discovery Grants [D2015-06, D2014-13]
- Movember Rising Star in Prostate Cancer research program
- CCSRI Innovation Grant [702837]
- Emil Aaltonen Foundation
- Academy of Finland [269474]
- Stand Up to Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0812]
- Terry Fox New Frontiers Program Project grant [TFF116129]
- Cancer Foundation Finland sr [170133, 150112, 140147] Funding Source: researchfish
Background: 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 thesemutations associate with differential response to androgen receptor (AR)-directed therapy. Objective: 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. Outcome measurements and statistical analysis: 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. Results and limitations: 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. Conclusions: 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. Patient summary: 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. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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