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

Journal Article


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.

Publication Date


  • 2012

Citation


  • Greystoke, A., Dean, E., Saunders, M. P., Cummings, J., Hughes, A., Ranson, M., . . . Renehan, A. G. (2012). Multi-level evidence that circulating CK18 is a biomarker of tumour burden in colorectal cancer.. British journal of cancer, 107(9), 1518-1524. doi:10.1038/bjc.2012.416

Web Of Science Accession Number


Start Page


  • 1518

End Page


  • 1524

Volume


  • 107

Issue


  • 9

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.

Publication Date


  • 2012

Citation


  • Greystoke, A., Dean, E., Saunders, M. P., Cummings, J., Hughes, A., Ranson, M., . . . Renehan, A. G. (2012). Multi-level evidence that circulating CK18 is a biomarker of tumour burden in colorectal cancer.. British journal of cancer, 107(9), 1518-1524. doi:10.1038/bjc.2012.416

Web Of Science Accession Number


Start Page


  • 1518

End Page


  • 1524

Volume


  • 107

Issue


  • 9