Logistic regression model of the clinical response to 5-fluorouracil based chemotherapy for metastatic colorectal cancer patients.

Several genes have been involved in drug resistance but none are currently used in the drug decision process. To address this problem, mRNA levels were measured for the 5-fluorouracil metabolism-related genes, thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumor samples of 40 patients with synchronous metastatic colon cancer by quantitative RT-PCR. Drug response and overall survival were also obtained for each patient. A logistic regression model was defined to calculate a response predicting score (RPS) with gene expression levels. This RPS split responders from non- responders as, at the best statistical threshold (0.35), the area of receiver operating characteristic (ROC) curve established with this method was 0.82 and sensitivity and specificity were respectively 100 % and 65.4 %. Furthermore patients with scores above 0.35 tended to have better overall survival than those with a score less than 0.35 (p=0.09). Colorectal cancer is the second most common cancer in developed countries and is diagnosed at a metastatic stage in 20% of all cases (1). Several genes have been suspected to play a role in resistance to chemotherapy drugs (2), the most cited for 5-fluorouracil (5-FU) are thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) but many more have been implicated (3, 4). A metaanalysis showed that TS seems to confer a hazard ratio of 1.74 for overall survival (OS) and that RT- PCR methods quite consistently give a positive link between TS overexpression and negative drug response (5). Nevertheless, the usefulness of these markers, including TS, is still questionable as the thresholds or cut-off values are difficult to define and the decision to select one drug over another based on a threshold value has not been validated (4). In this study, an attempt was made to analyse mRNA levels of 3 genes (TS, TP, DPD) in colon tumors and bioclinical parameters in such a way as to predict clinical outcomes such as objective response rate (ORR), progression free survival (PFS) and OS based on these values. Furthermore, the ethical possibility of "tailoring" chemotherapy was investigated, so that in the future, 5-FU would not be proposed for patients likely to be non- responders (6). A retrospective study was performed on a population of 40 metastatic colon cancer patients diagnosed with at least one measurable metastatic site and with a precise clinical follow-up. After surgical removal of the primary tumor site, relative mRNA levels were determined by quantitative RT-PCR in a tumor sample. Thereafter, a statistical model was defined to describe the relationship between gene expression and response to chemotherapy.