Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy |
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| Institution: | 1. Department of Oncology;2. Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore;3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston;4. Department of Cancer Biology;5. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville;6. Department of Therapeutic Radiology;7. Section of Medical Oncology, Department of Internal Medicine, Yale University School of Medicine, New Haven;8. Department of Radiation Oncology, University of California, Los Angeles;9. Department of Pathology, University of California, San Francisco;10. Mayo Clinic, Rochester, USA;1. National Research Centre for the Working Environment, Copenhagen DK-2100, Denmark;2. Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada;3. Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde, Denmark;4. Department of Micro- and Nanotechnology, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark;5. Nanologica AB, SE-114 28 Stockholm, Sweden;6. Veneto Nanotech SCpA, ECSIN — European Centre for the Sustainable Impact of Nanotechnology, I-45100 Rovigo, Italy;7. Laboratory of Nanobiotechnology, National Institute for Research and Development in Microtechnologies, 077190 Bucharest, Romania;8. European Commission Joint Research Centre Institute for Environment and Sustainability, I-21027 Ispra, VA, Italy;9. National Food Institute, Technical University of Denmark, Søborg, Denmark;10. Department of Public Health, University of Copenhagen, DK-1014 Copenhagen K, Denmark |
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| Abstract: | BackgroundCirculating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome.Patients and methodsPatients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m2) and cetuximab (500 mg/m2) q2w in a prospective phase II trial. The study was conducted prior to implementation of KRAS as selection criteria. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA, and KRAS mutations were quantified by an in-house qPCR method. Results are presented according to REMARK.ResultsOne-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis (Hazard Ratio (HR) = 2.98 (95% CI 1.53–5.80, p = 0.001) and 2.84 (1.46–5.53, p = 0.002), for OS and PFS, respectively). Combining the information of total cell free DNA levels and plasma KRAS mutation status, produced an additional prognostic effect.ConclusionThe value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue. |
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| Keywords: | Plasma KRAS cfDNA Cetuximab Metastatic colorectal cancer Prognosis |
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