Molecular determinants of efficacy for 5-FU-based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy-related genes.
5-Fluorouracil (5-FU)-based regimens remain a cornerstone in the treatment of colorectal cancer (CRC). However, the attendant toxicity prevents these regimens from reaching maximum therapeutic potential. In this retrospective analysis, we examined the pretreatment expression of 18 genes in archival tumor bank samples from patients with advanced CRC to determine if one or more of the selected genes showed promise as either a prognostic or predictive marker of 5-FU-based treatment outcomes. One hundred and forty-four CRC patient samples (collected from 1983 to 2004) were analyzed via real-time PCR for gene expression. Univariate analyses were used to correlate gene expression with efficacy and time-to-event variables. Low thymidine phosphorylase (TP), dihydrofolate reductase, dihydropyrimidine dehydrogenase (DPD), excision repair cross-complementing 1 (ERCC1) and thymidylate synthase gene expression were associated with better time-to-progression in the entire population. Low TP, DPD and ERCC1 expression were independently associated with improved overall survival. Low TP gene expression was also predictive of response. This study suggests that TP gene expression in particular is a predictive as well as a prognostic biomarker for advanced CRC patients. Gene panels assessing pretreatment TP, DPD, ERCC1, dihydrofolate reductase and thymidylate synthase gene expression may help improve the therapeutic potential of 5-FU- or other novel antifolate-based regimens. Further analysis of the prognostic or predictive value of these genes in prospective trials in CRC patients seems warranted.
Gustavsson
Bengt
B
Department of General Surgery, Göteborg University, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden. bengt.gustavsson@vgregion.se
Kaiser
Christopher
C
Carlsson
Göran
G
Wettergren
Yvonne
Y
Odin
Elisabeth
E
Lindskog
Elinor Bexe
EB
Niyikiza
Clet
C
Ma
Doreen
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis*; D012189:Retrospective Studies; D013939:Thymidine Phosphorylase / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil