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

• Published in: Scientific reports 2019-03, Vol.9 (1), p.4030-4030, Article 4030
• Main Authors: Sumiyoshi, Takayuki, Mizuno, Kei, Yamasaki, Toshinari, Miyazaki, Yu, Makino, Yuki, Okasho, Kosuke, Li, Xin, Utsunomiya, Noriaki, Goto, Takayuki, Kobayashi, Takashi, Terada, Naoki, Inoue, Takahiro, Kamba, Tomomi, Fujimoto, Akihiro, Ogawa, Osamu, Akamatsu, Shusuke
• Format: Article
• Language: English
• Subjects: 45; 45/23; 45/77; 692/4025/1752; 692/4028/67/1857; Aged; Aged, 80 and over; Androgen receptors; Androgens; Androstenes - pharmacology; Androstenes - therapeutic use; Animals; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Biomarkers; Biomarkers, Tumor - blood; Castration; Cell Line, Tumor; Cell-Free Nucleic Acids - blood; Cell-Free Nucleic Acids - drug effects; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - genetics; Gene Dosage; Humanities and Social Sciences; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; multidisciplinary; Mutation; Patients; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Phenylthiohydantoin - therapeutic use; Precision medicine; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - therapy; Receptors, Androgen - genetics; Science; Science (multidisciplinary); Treatment Outcome
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-40719-y

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.