Comprehensive profiling of the androgen receptor in liquid biopsies from castration-resistant prostate Ccncer reveals novel intra-AR structural variation and splice variant expression patterns

Background Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7negative. Objective To investigate if a comprehensive liquid biopsybased AR profile may improve patient stratification in the context of second-line endocrine therapy. Design, setting, and participants Peripheral blood was collected from patients with CRPC (n = 30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Outcome measurements and statistical analysis Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Results and limitations Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.42414.41; p = 0.0105). Six out of 17 poor responders were AR-V7negative, but four carried other AR perturbations.

Publication year:2017

Keywords:A1 Journal article

BOF-keylabel:yes

BOF-publication weight:10

CSS-citation score:4

Authors:International

Authors from:Higher Education

Accessibility:Open