Personalized Medicine and Imaging Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer ArunA.Azad, StanislavV. Volik,AlexanderW.Wyatt,AnneHaegert, StephaneLeBihan,

Purpose: Although novel agents targeting the androgen– androgen receptor (AR) axis have altered the treatment paradigm ofmetastatic 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 1⁄4 29), enzalutamide (n 1⁄4 19), or other agents (n 1⁄4 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 1⁄4 0.02, c). 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 1⁄4 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 1⁄4 0.013, c) and shorter time to radiographic/clinical progression (P1⁄4 0.010, Cox proportional hazards regression). Conclusions:ARgene aberrations in cfDNAare associatedwith resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogatingmechanisms of therapeutic resistance in mCRPC. Clin Cancer Res; 21(10); 2315–24. 2015 AACR.