Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer.

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, χ(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, χ(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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 10 Pg. 2315-24 (May 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25712683 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Androstenes
• Biomarkers, Tumor
• DNA, Neoplasm
• Receptors, Androgen
• Taxoids
• Docetaxel
• abiraterone

Topics

• Aged
• Aged, 80 and over
• Androstenes (pharmacology, therapeutic use)
• Biomarkers, Tumor (blood)
• DNA Copy Number Variations
• DNA Mutational Analysis
• DNA, Neoplasm (blood)
• Disease-Free Survival
• Docetaxel
• Drug Resistance, Neoplasm
• High-Throughput Nucleotide Sequencing
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation, Missense
• Neoplasm Metastasis
• Neoplastic Cells, Circulating
• Proportional Hazards Models
• Prostatic Neoplasms, Castration-Resistant (blood, drug therapy, genetics, mortality)
• Receptors, Androgen (genetics)
• Taxoids (pharmacology, therapeutic use)