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.
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.
Authors: Martin H Voss; Albert Reising; Yuan Cheng; Parul Patel; Mahtab Marker; Fengshen Kuo; Timothy A Chan; Toni K Choueiri; James J Hsieh; A Ari Hakimi; Robert J Motzer Journal: Lancet Oncol Date: 2018-11-08 Impact factor: 41.316
Authors: David A Braun; Yuko Ishii; Alice M Walsh; Eliezer M Van Allen; Catherine J Wu; Sachet A Shukla; Toni K Choueiri Journal: JAMA Oncol Date: 2019-11-01 Impact factor: 31.777
Authors: Daniel Y C Heng; Wanling Xie; Meredith M Regan; Lauren C Harshman; Georg A Bjarnason; Ulka N Vaishampayan; Mary Mackenzie; Lori Wood; Frede Donskov; Min-Han Tan; Sun-Young Rha; Neeraj Agarwal; Christian Kollmannsberger; Brian I Rini; Toni K Choueiri Journal: Lancet Oncol Date: 2013-01-09 Impact factor: 41.316
Authors: Jack V W Bacon; Matti Annala; Maryam Soleimani; Jean-Michel Lavoie; Alan So; Martin E Gleave; Ladan Fazli; Gang Wang; Kim N Chi; Christian K Kollmannsberger; Alexander W Wyatt; Lucia Nappi Journal: Clin Genitourin Cancer Date: 2020-01-08 Impact factor: 2.872
Authors: Dana W Y Tsui; Michael L Cheng; Maha Shady; Julie L Yang; Dennis Stephens; Helen Won; Preethi Srinivasan; Kety Huberman; Fanli Meng; Xiaohong Jing; Juber Patel; Maysun Hasan; Ian Johnson; Erika Gedvilaite; Brian Houck-Loomis; Nicholas D Socci; S Duygu Selcuklu; Venkatraman E Seshan; Hongxin Zhang; Debyani Chakravarty; Ahmet Zehir; Ryma Benayed; Maria Arcila; Marc Ladanyi; Samuel A Funt; Darren R Feldman; Bob T Li; Pedram Razavi; Jonathan Rosenberg; Dean Bajorin; Gopa Iyer; Wassim Abida; Howard I Scher; Dana Rathkopf; Agnes Viale; Michael F Berger; David B Solit Journal: Genome Med Date: 2021-05-31 Impact factor: 11.117
Authors: Andrew W Hahn; David M Gill; Benjamin Maughan; Archana Agarwal; Lubina Arjyal; Sumati Gupta; Jessica Streeter; Erin Bailey; Sumanta K Pal; Neeraj Agarwal Journal: Oncotarget Date: 2017-05-16
Authors: Manuel Caitano Maia; Paulo Gustavo Bergerot; Nazli Dizman; JoAnn Hsu; Jeremy Jones; Richard B Lanman; Kimberly C Banks; Sumanta K Pal Journal: Kidney Cancer Date: 2017-07-26