Assessment of plasma cytokeratin 18 as a potential surrogate marker of treatment efficacy in gastrointestinal malignancy. Free

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Introduction: With the advent of novel targeted therapies, the traditional end-point of tumor response in clinical trials may be less relevant. Greater emphasis will be placed on the measurement of biological responses as potential trial end-points, and this will require reliable biomarkers. Cytokeratin 18 (CK18) is a major component of the intermediate filament of simple epithelial cells and epithelial-derived tumors. It undergoes cleavage by caspases 3, 7 and 9 during apoptosis into proteolytic fragments. The M30 Apoptosense® assay recognizes a neo-epitope of CK18 (CK18Asp396) exposed after caspase-mediated cleavage, but not intact CK18. The M65 ELISA kit measures total soluble CK18 (both caspase-cleaved and uncleaved) and, so, represents epithelial cell death from both apoptosis and necrosis.

Methods: M30 and M65 levels were measured in plasma from 100 healthy controls to determine a normal range (units/liter; U/L) within a population, and compared with M30 values in 40 patients with locally advanced or metastatic gastrointestinal adenocarcinomas. M30 and M65 levels were then determined in patients receiving palliative chemotherapy for locally advanced or metastatic gastrointestinal adenocarcinomas. Multiple blood samples were taken at various time-points throughout their chemotherapy cycles. The fold-increases in M30 and M65 from baseline (pre-chemotherapy) to the maximum value observed during chemotherapy were then calculated for each patient and correlated with clinical outcome.

Results: ThemeanM30values were higher in the cancer patients compared to the normal controls (colorectal cancer 742.7 [95% CI 70.3] U/L, gastric cancer 297.6 [95% CI 141.7] U/L, esophageal cancer 227.9 [95% CI 106.2] U/L, vs. normal controls 165.0 [95% CI 26] U/L). The preliminary results for patients receiving palliative chemotherapy show that higher fold increases in either M30 or M65 observed during treatment appear to be associated with better clinical outcome. The observed fold increase in M65 was significant, 1.6 (95% CI 0.1) vs. 1.0 (95% CI 0.07), p=0.003 when comparing patients with disease stabilization/response vs. disease progression.

Conclusions: The results show that assessment of changes in plasma CK18 may be a potential surrogate marker of treatment efficacy in gastrointestinal malignancy. This study is currently ongoing and the full results will be reported.