Abstract
You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (MP24)1 Sep 2021MP24-15 CLINICAL UTILITY OF DETECTING LOW-FREQUENCY CELL-FREE DNA VARIANTS IN CASTRATION-RESISTANT PROSTATE CANCER Kei Mizuno, Shusuke Akamatsu, Takayuki Sumiyoshi, Takayuki Goto, Takashi Kobayashi, Akihiro Fujimoto, Takatsugu Okegawa, and Osamu Ogawa Kei MizunoKei Mizuno More articles by this author , Shusuke AkamatsuShusuke Akamatsu More articles by this author , Takayuki SumiyoshiTakayuki Sumiyoshi More articles by this author , Takayuki GotoTakayuki Goto More articles by this author , Takashi KobayashiTakashi Kobayashi More articles by this author , Akihiro FujimotoAkihiro Fujimoto More articles by this author , Takatsugu OkegawaTakatsugu Okegawa More articles by this author , and Osamu OgawaOsamu Ogawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002015.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Plasma cell-free DNA (cfDNA) testing is emerging as a tool for precision medicine in castration-resistant prostate cancer (CRPC). However, circulating cell-free tumor DNA (ctDNA) is highly diluted by cfDNA from non-cancer cells, complicating its detection and analysis. Recently, we developed a bioinformatics pipeline, called “eVIDENCE”, which analyze molecular barcoded sequencing data and can detect low-frequency variants with high sensitivity and specificity. In this study, we examined genomic landscape of ctDNA in CRPC patients and analyzed the relevance between the findings and the clinical course. We also investigated genomic profiling of lymphocyte DNA in the same cohort to detect clonal hematopoiesis of indeterminate potential (CHIP)-associated alterations. METHODS: A total of 103 CRPC patients who were eligible for abiraterone of enzalutamide were enrolled. We extracted cfDNA and lymphocyte DNA from the blood. We then performed targeted sequencing of cfDNA and germline DNA using our custom panel targeting 88 genes. The sequencing data were analyzed using eVIDNECE and detected variants with the variant allele frequency (VAF) of ≥0.1%. Somatic variants detected in both cfDNA and matched lymphocyte DNA were considered as CHIP-associated variants. We also assessed the relevance between genomic ctDNA alterations and clinicopathological features. RESULTS: We detected 542 variants across the 103 cfDNA samples, and 191 were pathogenic variants. Of the 191, 89 (46.6%) showed VAF of <1% (0.16–0.98%); the most commonly mutated genes were TP53 (11%), AR (9.9%), and KMT2C (7.3%). The median ctDNA fraction was 1.9%, and 8 samples with the ctDNA fraction of <2% had TP53 and/or ATM pathogenic variants. Defects in ATM and BRCA2 and TP53 defects were both associated with early progression independently of clinical prognostic factors (p=0.002 and 0.047, respectively). In addition, we detected “deleterious” CHIP-associated variants in ATM (n= \7), BRCA1 (n=1) and CHEK2 (n=3). CONCLUSIONS: Defects in ATM and BRCA2 and TP53 aberrations were significantly associated with poor clinical outcomes. Some pathogenic variants in ATM and TP53 genes were detected in the samples with the ctDNA fraction of <2%, indicating the clinical utility of detecting low-frequency variants in cfDNA. However, cfDNA variants contain CHIP-associated alterations, most frequently in ATM, which require attention when considering eligibility of poly(ADP-ribose) polymerase (PARP) inhibitors based on cfDNA analysis. Source of Funding: This study was supported by a research grant provided by AstraZeneca © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e417-e418 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kei Mizuno More articles by this author Shusuke Akamatsu More articles by this author Takayuki Sumiyoshi More articles by this author Takayuki Goto More articles by this author Takashi Kobayashi More articles by this author Akihiro Fujimoto More articles by this author Takatsugu Okegawa More articles by this author Osamu Ogawa More articles by this author Expand All Advertisement Loading ...
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