Synapse - Matched molecular profiling of cell-free DNA and tumor tissue in patients with advanced clear cell renal cell carcinoma

Matched molecular profiling of cell-free DNA and tumor tissue in patients with advanced clear cell renal cell carcinoma Journal Article

Authors:	Kotecha, R. R.; Gedvilaite, E.; Ptashkin, R.; Knezevic, A.; Murray, S.; Johnson, I.; Shapnik, N.; Feldman, D. R.; Carlo, M. I.; Shah, N. J.; Dunigan, M.; Huberman, K.; Benayed, R.; Zehir, A.; Berger, M. F.; Ladanyi, M.; Tsui, D. W. Y.; Motzer, R. J.; Lee, C. H.; Voss, M. H.
Article Title:	Matched molecular profiling of cell-free DNA and tumor tissue in patients with advanced clear cell renal cell carcinoma
Abstract:	PURPOSE The clinical utility of cell-free DNA (cfDNA) as a biomarker for advanced clear cell renal cell carcinoma (ccRCC) remains unclear. We evaluated the validity of cfDNA-based genomic profiling in a large cohort of patients with ccRCC with matched next-generation sequencing (NGS) from primary tumor tissues. MATERIALS AND METHODS We performed paired NGS of tumor DNA and plasma cfDNA using the MSK-IMPACT platform in 110 patients with metastatic ccRCC. Tissues were profiled for variants and copy number alterations with germline comparison. Manual cross-genotyping between cfDNA and tumor tissue was performed. Deep sequencing with a higher sensitivity platform, MSK-ACCESS, was performed on a subset of cfDNA samples. Clinical data and radiographic tumor volumes were assessed to correlate cfDNA yield with treatment response and disease burden. RESULTS Tumor tissue MSK-IMPACT testing identified 582 genomic alterations (GAs) across the cohort. Using standard thresholds for de novo variant calling in cfDNA, only 24 GAs were found by MSK-IMPACT in cfDNA in 7 of 110 patients (6%). With manual cross-genotyping, 210 GAs were detectable below thresholds in 74 patients (67%). Intrapatient concordance with tumor tissue was limited, including VHL (31.6%), PBRM1 (24.1%), and TP53 (52.9%). cfDNA profiling did not identify 3p loss because of low tumor fractions. Tumor volume was associated with cfDNA allele frequency, and VHL concordance was superior for patients with greater disease burden. CONCLUSION cfDNA-based NGS profiling yielded low detection rates in this metastatic ccRCC cohort. Concordance with tumor profiling was low, even for truncal mutations such as VHL, and some findings in peripheral blood may represent clonal hematopoiesis. Routine cfDNA panel testing is not supported, and its application in biomarker efforts must account for these limitations. (c) 2022 by American Society of Clinical Oncology
Journal Title:	JCO Precision Oncology
Volume:	6
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2022-01-01
Start Page:	e2200012
Language:	English
ACCESSION:	WOS:000975488400032
DOI:	10.1200/po.22.00012
PROVIDER:	wos
PMCID:	PMC9489165
PUBMED:	35797508
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding author is MSK author Martin H Voss --Source: Wos