Multi-level evidence that circulating CK18 is a biomarker of tumour burden in colorectal cancer.
Greystoke, Alastair Saunders, Mark P Cummings, Jeffrey Hughes, A Ranson, Malcolm R
Greystoke, Alastair
Saunders, Mark P
Cummings, Jeffrey
Hughes, A
Ranson, Malcolm R
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Abstract
Background:Circulating total cytokeratin 18 (tCK18) and/or caspase cleaved cytokeratin 18 (cCK18) (measured by M65 and M30 enzyme-linked immunosorbent assays (ELISAs), respectively) are used as pharmacodynamic (PD) biomarkers of epithelial cell death in clinical trials. Having validated these ELISAs, we assessed their utility in colorectal cancer (CRC).Methods:We applied the assays in several settings: 53 controls; 97 patients undergoing surgery and 74 patients with metastatic CRC undergoing chemotherapy (55 first line; 56 patients with repeated sampling through chemotherapy). Prognostic significance was evaluated using Kaplan-Meier life tables and Cox models; PD utility was assessed by analysis of repeated measures.Results:Median cCK18 and tCK18 levels were elevated in patients with cancer (both P=0.0001), and among cancer patients, there were increasing trends from early to advanced stages (both P(trends)=0.0001). Increasing tCK18 predicted for reduced survival after surgery with curative intent (adjusted hazard ratio (HR) for doubling in concentration 1.77, 95% CI: 1.04, 3.01) and after first-line chemotherapy in metastatic disease (adjusted HR per doubling in concentration=1.78, 95% CI: 1.37, 2.30). In patients with progressive disease during chemotherapy, repeated sampling revealed profiles with high baselines and progressive upwardly increases after cycle 1.Conclusion:This study provides evidence for cytokeratin 18 (CK18) as a prognostic and PD biomarker in patients with CRC and supports continued deployment of circulating CK18 in biomarker-enhanced trials.
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Date
2012-10-23
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Multi-level evidence that circulating CK18 is a biomarker of tumour burden in colorectal cancer. 2012, 107 (9):1518-24 Br J Cancer