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

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

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.

Publication types

  • Validation Study

MeSH terms

  • Aged
  • Androgen Antagonists / adverse effects
  • Androgen Antagonists / therapeutic use*
  • Antineoplastic Agents, Hormonal / adverse effects
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Circulating Tumor DNA / blood
  • Circulating Tumor DNA / genetics
  • DNA Mutational Analysis
  • DNA Repair*
  • Disease Progression
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Kallikreins / blood
  • Kaplan-Meier Estimate
  • Liquid Biopsy
  • Loss of Heterozygosity*
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Phenotype
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Time Factors
  • Treatment Outcome

Substances

  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • Kallikreins
  • kallikrein-related peptidase 3, human
  • Prostate-Specific Antigen