Clinical Research Papers:

Prospective blinded study of somatic mutation detection in cell-free DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor patients

Seung Tae Kim, Won Suk Lee, Richard B. Lanman, Stefanie Mortimer, Oliver A. Zill, Kyoung-Mee Kim, Kee Taek Jang, Seok-Hyung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Helmy Eltoukhy, Won Ki Kang, Woo Yong Lee, Hee-Cheol Kim, Keunchil Park, Jeeyun Lee and AmirAli Talasaz _

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Oncotarget. 2015; 6:40360-40369. https://doi.org/10.18632/oncotarget.5465

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Seung Tae Kim1,*, Won-Suk Lee2,*, Richard B. Lanman3, Stefanie Mortimer3, Oliver A. Zill3, Kyoung-Mee Kim4,5, Kee Taek Jang5, Seok-Hyung Kim5, Se Hoon Park1, Joon Oh Park1,4, Young Suk Park1, Ho Yeong Lim1, Helmy Eltoukhy3, Won Ki Kang1, Woo Yong Lee6, Hee-Cheol Kim6, Keunchil Park1,4, Jeeyun Lee1,4, AmirAli Talasaz3

1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2Department of Surgery, Gil Medical Center, Gachon University, School of Medicine, Incheon, Korea

3Guardant Health Inc., Redwood City, CA, USA

4The Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea

5Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

6Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Jeeyun Lee, e-mail: [email protected]

AmirAli Talasaz, e-mail: [email protected]

Keywords: cell-free DNA (cfDNA), digital sequencing, genomic test

Received: July 31, 2015     Accepted: September 24, 2015     Published: October 05, 2015


Sequencing of the mutant allele fraction of circulating cell-free DNA (cfDNA) derived from tumors is increasingly utilized to detect actionable genomic alterations in cancer.

We conducted a prospective blinded study of a comprehensive cfDNA sequencing panel with 54 cancer genes. To evaluate the concordance between cfDNA and tumor DNA (tDNA), sequencing results were compared between cfDNA from plasma and genomic tumor DNA (tDNA). Utilizing next generation digital sequencing technology (DST), we profiled approximately 78,000 bases encoding 512 complete exons in the targeted genes in cfDNA from plasma. Seventy-five patients were prospectively enrolled between February 2013 and March 2014, including 61 metastatic cancer patients and 14 clinical stage II CRC patients with matched plasma and tissue samples. Using the 54-gene panel, we detected at least one somatic mutation in 44 of 61 tDNA (72.1%) and 29 of 44 (65.9%) cfDNA. The overall concordance rate of cfDNA to tDNA was 85.9%, when all detected mutations were considered. We collected serial cfDNAs during cetuximab-based treatment in 2 metastatic KRAS wild-type CRC patients, one with acquired resistance and one with primary resistance. We demonstrate newly emerged KRAS mutation in cfDNA 1.5 months before radiologic progression. Another patient had a newly emerged PIK3CA H1047R mutation on cfDNA analysis at progression during cetuximab/irinotecan chemotherapy with gradual increase in allele frequency from 0.8 to 2.1%. This blinded, prospective study of a cfDNA sequencing showed high concordance to tDNA suggesting that the DST approach may be used as a non-invasive biopsy-free alternative to conventional sequencing using tumor biopsy.

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