Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer

Abstract

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.

Sequential Use of Androgen Receptor Axis-targeted Agents in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Retrospective Analysis With 3-Year Follow-up

“…10,17 Additionally, there have been particular pathogenic missense mutations in the ligand-binding domain of AR known to be associated with a worse PSA response and PFS depending on the specific ARTA used. 10,17,18 These findings are promising and should be further validated in future studies. However, screening these gene alterations might not be useful in determining whether to use ABI or ENZ, because resistance mechanisms for ARTAs are similar for ABI and ENZ.…”

“…Genetic alterations detected in circulating tumor DNA will be of help in determining treatment choice for patients with CRPC, 10,17,18 although it is yet to be widely available in real-world clinical practice. Alterations in driver genes including TP53, RB1, PTEN, and AR have been reported to predict unfavorable survival in patients with CRPC.…”

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…In three cohorts of patients—CTC - , CTC + /AR7 - , and CTC + /AR-V7 + —outcomes were best for the CTC - cohort, intermediate for CTC + /AR-V7 - patients, and worse for CTC + /AR-V7 patients [226]. Other recent studies have confirmed the clinical utility of AR-V7 detection in ct-DNA as a biomarker for treatment of CRPC [227,228]. Finally, recent studies have also shown that the testing of AR-V7 mRNA in circulating tumor cells may provide an AR-V7-positive and AR-V7 negative score in a clinically acceptable time range and may provide a guide for the choice of the optimal treatment [229].…”

Clinical utility of emerging biomarkers in prostate cancer liquid biopsies

“…It is reasonable to suggest that AR copy number gain evolves during treatment leading to cross-resistance between next generation ARTAs. Sumiyoshi et al reported that AR aberrations were only associated with poor response to abiraterone, but not to enzalutamide [101]. Recent data suggest that patients with AR gain should be treated with docetaxel [102].…”