Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer.

Abstract

PURPOSE:

Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from patients with CRPC and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%.

EXPERIMENTAL DESIGN:

This prospective, multicenter cohort study enrolled patients with CRPC eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pretreatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF ≥0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied.

RESULTS:

One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious ATM, BRCA2, and TP53 variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in ATM or BRCA2 [HR, 2.52; 95% confidence interval (CI), 1.24-5.11; P = 0.0091] and TP53 (HR, 3.74; 95% CI, 1.60-8.71; P = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable.

CONCLUSIONS:

Detecting low-frequency ctDNA variants with a VAF <1% is important to identify clinically informative genomic alterations in CRPC.

• Authors: Kei Mizuno, Takayuki Sumiyoshi, Takatsugu Okegawa, Naoki Terada, Satoshi Ishitoya, Yu Miyazaki, Takahiro Kojima, Hiromichi Katayama, Naohiro Fujimoto, Shingo Hatakeyama, Masaki Shiota, Koji Yoshimura, Yoshiyuki Matsui, Shintaro Narita, Hiroaki Matsumoto, Ryoma Kurahashi, Hidenori Kanno, Katsuhiro Ito, Hiroko Kimura, Yuki Kamiyama, Takuro Sunada, Takayuki Goto, Takashi Kobayashi, Hitoshi Yamada, Norihiko Tsuchiya, Tomomi Kamba, Hideyasu Matsuyama, Tomonori Habuchi, Masatoshi Eto, Chikara Ohyama, Akihiro Ito, Hiroyuki Nishiyama, Hiroshi Okuno, Toshiyuki Kamoto, Akihiro Fujimoto, Osamu Ogawa, Shusuke Akamatsu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 22 Pg. 6164-6173 (11 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34526361 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Cell-Free Nucleic Acids

Topics

• Biomarkers, Tumor (genetics, therapeutic use)
• Cell-Free Nucleic Acids (genetics)
• Cohort Studies
• Humans
• Male
• Prospective Studies
• Prostatic Neoplasms, Castration-Resistant (diagnosis, drug therapy, genetics)