Enumeration and targeted analysis of KRAS, BRAF and PIK3CA mutations in CTCs captured by a label-free platform: Comparison to ctDNA and tissue in metastatic colorectal cancer
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Evelyn Kidess-Sigal1,2,*, Haiyan E. Liu3,*, Melanie M. Triboulet2, James Che3, Vishnu C. Ramani2, Brendan C. Visser2, George A. Poultsides2, Teri A. Longacre4, Andre Marziali5, Valentina Vysotskaia6, Matthew Wiggin5, Kyra Heirich2, Violet Hanft2, Ulrich Keilholz7, Ingeborg Tinhofer8, Jeffrey A. Norton2, Mark Lee9, Elodie Sollier-Christen3, Stefanie S. Jeffrey2
1Department of Medicine, Division of Hepatology and Gastroenterology, Charité University Hospital, Berlin, Germany
2Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
3Vortex BioSciences, Inc., Menlo Park, CA, USA
4Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
5Boreal Genomics, Vancouver, BC, Canada
6Counsyl Inc., San Francisco, CA, USA
7Comprehensive Cancer Center Charité, Berlin, Germany
8Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany
9GRAIL, Redwood City, CA, USA
*These authors have contributed equally to this work
Stefanie S. Jeffrey, email: [email protected]
Keywords: colorectal cancer, circulating tumor cells, circulating tumor DNA, liquid biopsy, Vortex
Received: June 30, 2016 Accepted: October 26, 2016 Published: November 15, 2016
Treatment of advanced colorectal cancer (CRC) requires multimodal therapeutic approaches and need for monitoring tumor plasticity. Liquid biopsy biomarkers, including CTCs and ctDNA, hold promise for evaluating treatment response in real-time and guiding therapeutic modifications. From 15 patients with advanced CRC undergoing liver metastasectomy with curative intent, we collected 41 blood samples at different time points before and after surgery for CTC isolation and quantification using label-free Vortex technology. For mutational profiling, KRAS, BRAF, and PIK3CA hotspot mutations were analyzed in CTCs and ctDNA from 23 samples, nine matched liver metastases and three primary tumor samples. Mutational patterns were compared. 80% of patient blood samples were positive for CTCs, using a healthy baseline value as threshold (0.4 CTCs/mL), and 81.4% of captured cells were EpCAM+ CTCs. At least one mutation was detected in 78% of our blood samples. Among 23 matched CTC and ctDNA samples, we found a concordance of 78.2% for KRAS, 73.9% for BRAF and 91.3% for PIK3CA mutations. In several cases, CTCs exhibited a mutation that was not detected in ctDNA, and vice versa. Complementary assessment of both CTCs and ctDNA appears advantageous to assess dynamic tumor profiles.
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