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Eur Urol. 2017 Jul;72(1):34-42. doi: 10.1016/j.eururo.2017.02.023. Epub 2017 Mar 1.

Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer.

Author information

1
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.
2
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
3
Department of Medical Oncology, British Columbia Cancer Agency, British Columbia, Canada.
4
Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
5
RSM Durham Regional Cancer Centre, Oshawa, Ontario, Canada.
6
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
7
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; Department of Medical Oncology, British Columbia Cancer Agency, British Columbia, Canada.
8
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada. Electronic address: awyatt@prostatecentre.com.

Abstract

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 these mutations 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.

KEYWORDS:

Abiraterone; BRCA2; Castration-resistant prostate cancer; Cell-free DNA; Circulating tumor DNA; DNA repair; Enzalutamide; Liquid biopsy

PMID:
28259476
DOI:
10.1016/j.eururo.2017.02.023
[Indexed for MEDLINE]

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