title: Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study.
abstract: We have tested several biomarkers [dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), thymidylate synthase (TS) and excision cross-complementing gene (ERCC1)] for their prognostic and predictive value in relation to the outcome of chemotherapy in tumour tissues of 556 advanced colorectal cancer (ACC) patients who were randomised between sequential treatment and combination treatment in the CApecitabine, IRinotecan, Oxaliplatin (CAIRO) study. DPD expression showed a statistically significant predictive value for combination treatment with capecitabine plus irinotecan with low versus high values resulting in an improved median progression-free survival (PFS) and median overall survival (OS) of 8.9 (95% confidence interval (CI) 8.3-9.9) versus 7.2 months (95% CI 6.5-8.1, p=0.006), and 21.5 months (95% CI 17.9-26.5) versus 16.9 months (95% CI 13.0-19.1, p=0.04), respectively. In the overall patient population a high OPRT expression in stromal cells was a favourable prognostic parameter for OS, with 21.5 months (95% CI 17.9-27.3) versus 17.2 months (95% CI 15.1-18.6, p=0.036), respectively. A similar effect was observed for PFS. In a multivariate analysis that included known prognostic factors these results remained significant and also showed that a high OPRT expression in tumour cells was an unfavourable prognostic parameter for PFS and OS. In conclusion, in this largest study on capecitabine with or without irinotecan to date we found a predictive value of DPD expression. Our results on the prognostic value of OPRT expression warrant further studies on the role of stromal cells in the outcome of treatments. The divergent results of ours and previous studies underscore the complexity of these biomarkers and currently prevent the routine use of these markers in daily clinical practice.
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Koopman
authors.forename: Sabine
authors.initials: S
authors.lastname: Venderbosch
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.forename: Marjolijn J
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Iris
authors.initials: I
authors.lastname: Nagtegaal
authors.forename: Johan H
authors.initials: JH
authors.lastname: Van Krieken
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Punt
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069287:Capecitabine; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D004268:DNA-Binding Proteins / Q000032:analysis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis; D018572:Disease-Free Survival; D004720:Endonucleases / Q000032:analysis; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D009962:Orotate Phosphoribosyltransferase / Q000032:analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D013939:Thymidine Phosphorylase / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil; D002166:Camptothecin