Androgen receptor gene aberrations in circulating cell-free DNA: Biomarkers of therapeutic resistance in castration-resistant prostate cancer

Arun A. Azad, Stanislav V. Volik, Alexander W. Wyatt, Anne Haegert, Stephane Le Bihan, Robert H. Bell, Shawn A. Anderson, Brian McConeghy, Robert Shukin, Jenny Bazov, Jack Youngren, Pamela Paris, George Thomas, Eric J. Small, Yuzhuo Wang, Martin E. Gleave, Colin C. Collins, Kim N. Chi

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Abstract

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, χ2). 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, χ2) 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.

Original languageEnglish (US)
Pages (from-to)2315-2324
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number10
DOIs
StatePublished - May 15 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Azad, A. A., Volik, S. V., Wyatt, A. W., Haegert, A., Le Bihan, S., Bell, R. H., Anderson, S. A., McConeghy, B., Shukin, R., Bazov, J., Youngren, J., Paris, P., Thomas, G., Small, E. J., Wang, Y., Gleave, M. E., Collins, C. C., & Chi, K. N. (2015). Androgen receptor gene aberrations in circulating cell-free DNA: Biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clinical Cancer Research, 21(10), 2315-2324. https://doi.org/10.1158/1078-0432.CCR-14-2666