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

• Published in: European journal of cancer (1990) Vol. 51; no. 17; pp. 2678 - 2685
• Main Authors: Spindler, Karen-Lise Garm, Pallisgaard, Niels, Appelt, Ane Lindegaard, Andersen, Rikke Fredslund, Schou, Jakob V, Nielsen, Dorte, Pfeiffer, Per, Yilmaz, Mette, Johansen, Julia S, Hoegdall, Estrid V, Jakobsen, Anders, Jensen, Benny V
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2015
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Cetuximab; Cetuximab - administration & dosage; cfDNA; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; DNA, Neoplasm - blood; DNA, Neoplasm - genetics; Female; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; Male; Metastatic colorectal cancer; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Metastasis; Outcome Assessment (Health Care) - methods; Outcome Assessment (Health Care) - statistics & numerical data; Paraffin Embedding - methods; Plasma KRAS; Prognosis; Proportional Hazards Models; Prospective Studies; Proto-Oncogene Proteins p21(ras) - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Tissue Fixation - methods; Prognosis; Plasma KRAS; Cetuximab; cfDNA; Metastatic colorectal cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2015.06.118

Abstract Background Circulating 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 methods Patients 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. Results One-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. Conclusion The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue.