Rectal mucosal proliferation and risk of colorectal adenomas: results from a randomized controlled trial

Although rectal mucosal labeling index is thought to be a useful surrogate biomarker for colorectal cancer, the ability of the index to predict future neoplasia is unclear. We obtained rectal mucosal biopsies from 333 participants of a randomized controlled chemoprevention trial of calcium supplementation to determine whether labeling index was correlated with concurrent or future colorectal neoplasms. Labeling index was measured using proliferating cell nuclear antigen immunohistochemistry. Adenomas were enumerated at the time of the biopsies (cross-sectional) and 3 years later (prospective). We used logistic regression to test for an association of adenoma occurrence with overall labeling index, the mean proliferative height, and labeling index in the upper 40% of colon crypts. In the cross-sectional analysis, we found indications that higher proliferation was associated with an increase in the prevalence of adenomas. The overall adjusted odds ratios (OR) (95% confidence interval) were 1.14 (0.90-1.45) per % crypt labeling index, OR 1.08 (0.99-1.19) for upper crypt proliferation, and OR 1.07 (1.03-1.12) for proliferative height. In contrast, individuals with higher labeling index at baseline were actually less likely to have adenomas in the prospective analyses: OR 0.80 (0.62-1.02) per % crypt labeling index, OR 0.86 (0.73-1.00) for upper crypt index, and OR 0.97 (0.93-1.01) for proliferative height. Proliferative index does not predict future colorectal neoplasia, although it may be weakly associated with the presence of current adenomas. These results have important implications for the design of future intervention studies. Although it may be attractive to include the measurement of intermediate markers in large controlled trials, until we have more confidence in their performance, we should rely on better proven and more reliable intermediates, such as adenomas.