Journal
CANCER DISCOVERY
Volume 7, Issue 9, Pages 1006-1017Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0261
Keywords
-
Categories
Funding
- Movember [Movember/PCUKCEO13-2-002]
- Prostate Cancer Foundation (PCF) [20131017]
- Prostate Cancer UK [PCUK PG12-49]
- Stand Up To Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant [20131017, SU2C-AACR-DT0712, 20131017-1]
- Cancer Research UK
- Experimental Cancer Medicine Centre grant funding from Cancer Research UK
- Department of Health
- Biomedical Research Centre [ECMC CRM064X]
- Cancer Research UK [C12540/A12829, C12540/A13230, C1491/A9895, C1491/A15955]
- AstraZeneca
- National Institute for Health Research Cancer Research Network
- Prostate Cancer Foundation (PCF) Young Investigator Award [PCF-16-YOUN11]
- Prostate Cancer UK-Medical Research Council Fellowship [MR/M003272/1]
- Prostate Cancer Foundation of Australia
- Prostate Cancer UK PhD Studentship [TLD-S15-006]
- Medical Research Council Fellowship [MR/M018618/1]
- MRC [MR/M003272/1, MR/M018318/1] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [SGL014\\1015] Funding Source: researchfish
- Cancer Research UK [25237, 24439, 14276, 20447, 13230, 12829] Funding Source: researchfish
- Medical Research Council [MR/M003272/1, MR/M018318/1] Funding Source: researchfish
Ask authors/readers for more resources
Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06-0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (chi(2) P < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer. SIGNIFICANCE: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with second hit mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. (C) 2017 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available