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

Karen Lise Garm Spindler*, Niels Pallisgaard, Ane Lindegaard Appelt, Rikke Fredslund Andersen, Jakob V. Schou, Dorte Nielsen, Per Pfeiffer, Mette Yilmaz, Julia S. Johansen, Estrid V. Hoegdall, Anders Jakobsen, Benny V. Jensen

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

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.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Cancer
Vol/bind51
Udgave nummer17
Sider (fra-til)2678-2685
Antal sider8
ISSN0959-8049
DOI
StatusUdgivet - 2015
Udgivet eksterntJa

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