Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 10, Pages 2315-2324Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-2666
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Funding
- Movember Global Action Plan (GAP)
- BC Cancer Foundation
- CIHR/Terry Fox Foundation New Frontiers Program [TFF-116129]
- Stand Up to Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0812]
- CJ Martin Biomedical Overseas Fellowship from the National Health and Medical Research Council
- Coalition to Cure Prostate Cancer Young Investigator Award
- Movember Foundation
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Purpose: Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients. Experimental Design: Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR. Results: On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, chi(2)). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline >= 30% (P = 0.013, chi(2)) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression). Conclusions: AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC. (C)2015 AACR.
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