Association of baseline fecal and plasma bile acids with colorectal adenoma recurrence and high-grade dysplasia in a phase III trial of colorectal adenoma recurrence
Authors: Denise M. Laronde, Lewei Zhang, Catherine F. Poh, Greg Hislop, Scott Durham, Nhu Le, P. Michele Williams, Pamela J. Gardner, Allan Hovan, Ken Berean, John Hay, Miriam P. Rosin
Journal: Cancer Research (2006)

1433  Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Secondary bile acids (BA), in particular deoxycholic acid (DCA), promote colorectal adenomas (CRA) and CRC. Ursodeoxycholic acid (UDCA), the 7Β-epimer of chenodeoxycholic acid, has been shown to inhibit colorectal carcinogenesis in animal models and in individuals at increased risk of CRC. The precise mechanisms by which UDCA prevents CRC are unknown, but one potential mechanism is that UDCA alters the bile acid profile and reduces exposure of the colorectum to harmful effects of secondary BAs. We previously published results of a phase III trial of UDCA on CRA recurrence in 1285 subjects. The major findings were a non-significant 12% reduction in adenoma recurrence and a significant 39% reduction (p=0.03) in recurrence of adenomas with high-grade dysplasia (HGD). As part of this study we collected 72-hr fecal and plasma samples for BA analysis at baseline and 3 years of intervention on a subset of subjects, although in this analysis we focus only on the association of baseline BAs and risk of CRA recurrence in the placebo group. The median concentrations of UDCA and DCA in the aqueous fecal fraction were 0 μM/L (mean 39.7 ± SD 101.1) and 297.3 μM/L (mean 373.4 ±296.0) and in the plasma were 0.8 μM/L (mean 1.2 ± 1.5) and 0.9 μM/L (mean 1.0 ± 0.8). Spearman correlation coefficients for UDCA and DCA in aqueous fecal and plasma samples were 0.26 and 0.08, respectively. While previous small cross-sectional studies found unconjugated serum DCA to be associated with presence of CRAs, we found no association between unconjugated plasma DCA levels in the placebo group (N=78) and CRA recurrence at year 3 (p=0.09). In contrast, plasma UDCA levels were associated with reduced CRA recurrence –tertile of plasma UDCA and % adenoma recurrence : tertile 1 (0-0.5 μM/L), -76.9%, %; tertile 2 (0.5-1.2 μM/L), 65.4%, %; and tertile 3 (1.2-11.7 μM/L), 50.0% (p=0.04 for trend). The recurrence of adenomas with HGD was also significantly reduced with higher plasma UDCA (tertile 1—50.5%, tertile 2—26.9%, and tertile 3—20.0%, p=0.023 for trend). None of the baseline fecal BAs (N=365) from the placebo group were significantly associated with CRA recurrence or recurrence of CRAs with HGD. In conclusion, although previous studies have shown serum DCA to be higher in individuals with CRAs compared to controls, our study shows no association of baseline fecal or plasma DCA levels and risk of CRA recurrence. In contrast, baseline plasma but not fecal UDCA levels were associated with reduced risk of both CRA recurrence and recurrence of CRAs with HGD. These results complement those of the original phase III trial and further support a role of UDCA as a chempreventive agent for those at risk of CRC. Results also suggest that plasma UDCA may be a marker of reduced risk of CRA recurrence and recurrence of CRAs with HGD.