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

Takayuki Sumiyoshi,Takahiro Inoue,Tomomi Kamba,Takayuki Goto,Shusuke Akamatsu,Kei Mizuno,Yuki Makino,Xin Li,Akihiro Fujimoto,Kosuke Okasho,Noriaki Utsunomiya,Naoki Terada,Yu Miyazaki,Toshinari Yamasaki,Takashi Kobayashi,Osamu Ogawa

doi:10.1038/s41598-019-40719-y

Takayuki Sumiyoshi, Takahiro Inoue + Show 14 more

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https://doi.org/10.1038/s41598-019-40719-y

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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.

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The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded
copy numbers (CN) analysis in cell-free DNA (cfDNA) has been performed by several methods; array comparative genomic hybridization, generation sequencing (NGS), real time PCR and dPCR8–13,17
We showed that androgen receptor gene (AR) amplification could be detected by digital PCR (dPCR) even when VCaP genomic DNA (gDNA) was diluted to 1.0%

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Introduction

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. 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. The primary mechanism underlying CRPC is reactivation of the AR pathway This includes de novo androgen synthesis by cancer cells, AR gene (AR) amplification and mutations, and generation of truncated splice variants lacking the ligand binding domain (LBD)[1,2]. In PCa, several groups have recently shown the association of AR amplification and mutations in plasma cfDNA with poor responses to abiraterone and enzalutamide in patients with CRPC8–12. We established a robust method to analyze the AR copy number (CN) and mutations in plasma cfDNA by combined use of digital PCR (dPCR) and multiplex PCR based target sequencing. We analyzed the AR status of Japanese patients with CRPC to evaluate the utility of cfDNA as a novel biomarker

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