Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas

A wide range of tumor response is seen amongst patients with the same stage of colorectal cancer, even with the use of uniform chemotherapy. The signi ficant economic and personal impact of chemotherapy provides the impetus fo r the identification of markers of response for use in guiding patient trea tment. However, practical constraints prevent evaluation of all putative ma rkers in a definitive manner. In this study, the enrichment approach was ev aluated by examining the expression of a panel of putative response markers in selected patient populations with advanced colorectal cancer (i.e., tho se demonstrating the best and the poorest clinical response to a standardiz ed 5-fluorouracil/folinic acid chemotherapy regimen). Patients showing a go od response had a significantly increased survival when compared with poor responders (P=0.0013), Markers were then ranked for clinical importance bas ed on differences in expression between the two groups. This allows for the relatively rapid and inexpensive investigation of multiple markers, using defined patient groups. Bcl-2 overexpression in primary colorectal tumor sp ecimens was found to correlate with clinical response of metastatic deposit s to chemotherapy (P=0.044), as did the site of the primary tumor (P=0.011) . However, no clear association was observed between response status and th e other examined factors (p53, PCNA, TP, MMPs 1, 2 or 9, TIMPs 1 or 2, TS, Dukes' stage at initial diagnosis, histological grade, sex or age). This ap proach has allowed prioritization of markers of clinical response on which larger, statistically definitive studies will be performed.