An update of pharmacogenetic analysis of adjuvant rectal cancer patients treated with 5-fluorouracil and pelvic radiation in a phase III intergroup trial (INT-0144, SWOG 9304).

4115 Background: Clinical trials have shown postoperative chemoradiotherapy for adjuvant rectal cancer has improved overall survival and pelvic control. However, the efficacy of chemoradiation therapy may be significantly compromised as a result of individual variations in clinical response and host toxicity. In GI symposium 2008, we have reported our preliminary data suggesting COX-2, IL-8 and TS- 3'UTR gene polymorphisms may help to identify adjuvant rectal cancer patients who are more likely to experience longer survival. Here we explore whether gene-expression levels of genes involved in the critical pathways of cancer progression (i.e., drug metabolism (TS,TP,DPD,GSTP), tumor growth (COX-2, EGFR), angiogenesis (VEGF,IL-8), cell cycle regulation (CyclinD1,P53), and DNA repair (ERCC1,XPD)) may predict the clinical outcome in the same group of rectal cancer patients treated with 5-fluororacil and pelvic radiation.,A total of 105 stage II/III rectal patients from a phase III trial (INT-0144, S9304) of three regimens of 5-fluorouracil and radiation were available for gene-expression assays. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan).,In univariate analysis, we found TS gene expression levels to be significantly associated with overall survival (p=0.04) and progression-free survival (p=0.02). Patients with low TS expression levels showed better overall survival and progression-free survival compared to those with medium or high TS gene expression levels. All other genes we tested did not show significant association with either overall survival or progression free survival.,Future analyses will be expanded to additional patients enrolled in this trial to validate our preliminary data, and to assess whether these markers may identify patients who might selectively benefit from one of the study regimens. [Table: see text].