Synapse - Utility of serial cfDNA NGS for prospective genomic analysis of patients on a phase I basket study

Utility of serial cfDNA NGS for prospective genomic analysis of patients on a phase I basket study Journal Article

Authors:	Smyth, L. M.; Reichel, J. B.; Tang, J.; Patel, J. A. A.; Meng, F.; Selcuklu, D. S.; Houck-Loomis, B.; You, D.; Samoila, A.; Schiavon, G.; Li, B. T.; Razavi, P.; Piscuoglio, S.; Reis-Filho, J. S.; Taylor, B. S.; Baselga, J.; Solit, D. B.; Hyman, D. M.; Berger, M. F.; Chandarlapaty, S.
Article Title:	Utility of serial cfDNA NGS for prospective genomic analysis of patients on a phase I basket study
Abstract:	PURPOSE Cell-free DNA (cfDNA) analysis offers a noninvasive means to access the tumor genome. Despite limited sensitivity of broad-panel sequencing for detecting low-frequency mutations in cfDNA, it may enable more comprehensive genomic characterization in patients with sufficiently high disease burden. We investigated the utility of large-panel cfDNA sequencing in patients enrolled to a Phase I AKT1-mutant solid tumor basket study. METHODS Patients had AKT1 E17K-mutant solid tumors and were treated on the multicenter basket study (ClinicalTrials.gov identifier: NCT01226316) of capivasertib, an AKT inhibitor. Serial plasma samples were prospectively collected and sequenced using exon-capture next-generation sequencing (NGS) analysis of 410 genes (Memorial Sloan Kettering [MSK]-Integrated Molecular Profiling of Actionable Cancer Target [IMPACT]) and allele-specific droplet digital polymerase chain reaction (ddPCR) for AKT1 E17K. Tumor DNA (tDNA) NGS (MSK-IMPACT) was also performed on available pretreatment tissue biopsy specimens. RESULTS Among 25 patients, pretreatment plasma samples were sequenced to an average coverage of 504x. Somatic mutations were called in 20/25 (80%), with mutant allele fractions highly concordant with ddPCR of AKT1 E17K (r(2) = 0.976). Among 17 of 20 cfDNA-positive patients with available tDNA for comparison, mutational concordance was acceptable, with 82% of recurrent mutations shared between tissue and plasma. cfDNA NGS captured additional tumor heterogeneity, identifying mutations not observed in tDNA in 38% of patients, and revealed oncogenic mutations in patients without available baseline tDNA. Longitudinal cfDNA NGS (n = 98 samples) revealed distinct patterns of clonal dynamics in response to therapy. CONCLUSION Large gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations. (C) 2021 by American Society of Clinical Oncology
Journal Title:	JCO Precision Oncology
Volume:	5
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2021-01-08
Start Page:	6
End Page:	16
Language:	English
ACCESSION:	WOS:000636553200002
DOI:	10.1200/po.20.00184
PROVIDER:	wos
PMCID:	PMC8232437
PUBMED:	34250397
Notes:	Sadan Duygu Selcuklu's name appears as Duygu S. Selcuklu on the original publication -- Article -- Source: Wos