title: Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer.
abstract: 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).
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Struss
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Evan W
authors.initials: EW
authors.lastname: Warner
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beja
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Gillian
authors.initials: G
authors.lastname: Vandekerkhove
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, British Columbia, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Khalaf
authors.affiliation: Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
authors.forename: Irma-Liisa
authors.initials: IL
authors.lastname: Seppälä
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: So
authors.affiliation: RSM Durham Regional Cancer Centre, Oshawa, Ontario, Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Lo
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Aggarwal
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: 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.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.affiliation: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada. Electronic address: awyatt@prostatecentre.com.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D000074141:Circulating Tumor DNA / Q000097:blood / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D000073890:Liquid Biopsy; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010641:Phenotype; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Abiraterone; BRCA2; Castration-resistant prostate cancer; Cell-free DNA; Circulating tumor DNA; DNA repair; Enzalutamide; Liquid biopsy