title: Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas.
abstract: 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 significant economic and personal impact of chemotherapy provides the impetus for the identification of markers of response for use in guiding patient treatment. However, practical constraints prevent evaluation of all putative markers in a definitive manner. In this study, the enrichment approach was evaluated by examining the expression of a panel of putative response markers in selected patient populations with advanced colorectal cancer (i.e., those demonstrating the best and the poorest clinical response to a standardized 5-fluorouracil/folinic acid chemotherapy regimen). Patients showing a good response had a significantly increased survival when compared with poor responders (P=0.0013). Markers were then ranked for clinical importance based 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 specimens was found to correlate with clinical response of metastatic deposits 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 the 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 approach has allowed prioritization of markers of clinical response on which larger, statistically definitive studies will be performed.
authors.affiliation: Department of Medicine and Therapeutics, University of Aberdeen, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: McKay
authors.forename: C
authors.initials: C
authors.lastname: Lloret
authors.forename: G I
authors.initials: GI
authors.lastname: Murray
authors.forename: P G
authors.initials: PG
authors.lastname: Johnston
authors.forename: R
authors.initials: R
authors.lastname: Bicknell
authors.forename: F Y
authors.initials: FY
authors.lastname: Ahmed
authors.forename: J
authors.initials: J
authors.lastname: Cassidy
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011237:Predictive Value of Tests; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D019714:Tissue Inhibitor of Metalloproteinases; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D002955:Leucovorin