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.
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.


METHODS
Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m(2)) and cetuximab (500 mg/m(2)) 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.


CONCLUSIONS
The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue.
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Oncology, Vejle Hospital, Vejle, Denmark. Electronic address: Spindler@hafnet.dk.
Karen-Lise Garm
KL
Spindler
Department of Biochemistry, Vejle Hospital, Vejle, Denmark.
Niels
N
Pallisgaard
Department of Oncology, Vejle Hospital, Vejle, Denmark.
Ane Lindegaard
AL
Appelt
Department of Biochemistry, Vejle Hospital, Vejle, Denmark.
Rikke Fredslund
RF
Andersen
Department of Oncology, Copenhagen University Hospital at Herlev, Herlev, Denmark.
Jakob V
JV
Schou
Department of Oncology, Copenhagen University Hospital at Herlev, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Dorte
D
Nielsen
Department of Oncology, Odense University Hospital, Odense, Denmark.
Per
P
Pfeiffer
Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
Mette
M
Yilmaz
Department of Oncology, Copenhagen University Hospital at Herlev, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Julia S
JS
Johansen
Department of Pathology, Copenhagen University Hospital at Herlev, Herlev Denmark.
Estrid V
EV
Hoegdall
Department of Oncology, Vejle Hospital, Vejle, Denmark.
Anders
A
Jakobsen
Department of Oncology, Copenhagen University Hospital at Herlev, Herlev, Denmark.
Benny V
BV
Jensen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D016612:Paraffin Embedding / Q000379:methods; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016707:Tissue Fixation / Q000379:methods
D004273:DNA, Neoplasm; C117307:KRAS protein, human; D000077146:Irinotecan; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002166:Camptothecin
Cetuximab; Metastatic colorectal cancer; Plasma KRAS; Prognosis; cfDNA