Multi-level evidence that circulating CK18 is a biomarker of tumour burden in colorectal cancer

• Published in: British journal of cancer 2012-10, Vol.107 (9), p.1518-1524
• Main Authors: Greystoke, A, Dean, E, Saunders, M P, Cummings, J, Hughes, A, Ranson, M, Dive, C, Renehan, A G
• Format: Article
• Language: English
• Subjects: 631/67/1857; 692/699/67/1504/1885; 692/700/1750; Apoptosis; Apoptosis - physiology; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - blood; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cell death; Chemotherapy; Clinical medicine; Clinical trials; Colonoscopy; Colorectal cancer; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Cross-Sectional Studies; Cytokeratin; Drug Resistance; Enzymes; Epidemiology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Keratin-18 - blood; Male; Medical prognosis; Medical research; Medical sciences; Metastasis; Middle Aged; Molecular Diagnostics; Molecular Medicine; Oncology; Pharmacodynamics; Prognosis; Prospective Studies; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Surgery; Survival analysis; Testicular cancer; Tumor Burden; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.416

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.