Matti Annala1, Werner J Struss2, Evan W Warner2, Kevin Beja2, Gillian Vandekerkhove2, Amanda Wong2, Daniel Khalaf3, Irma-Liisa Seppälä4, Alan So2, Gregory Lo5, Rahul Aggarwal6, Eric J Small6, Matti Nykter4, Martin E Gleave2, Kim N Chi7, Alexander W Wyatt8. 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.
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.
Authors: Emmanuel S Antonarakis; Changxue Lu; Brandon Luber; Chao Liang; Hao Wang; Yan Chen; John L Silberstein; Danilo Piana; Zhao Lai; Yidong Chen; William B Isaacs; Jun Luo Journal: Eur Urol Date: 2018-02-10 Impact factor: 20.096
Authors: Julie L Boyle; Andrew W Hahn; Ashley L Kapron; Wendy Kohlmann; Samantha E Greenberg; Timothy J Parnell; Craig C Teerlink; Benjamin L Maughan; Bing-Jian Feng; Lisa Cannon-Albright; Neeraj Agarwal; Kathleen A Cooney Journal: JCO Precis Oncol Date: 2020-03-04