A prospective pharmacogenetic study of 5FU/LV in high-risk stage II and III colon cancer patients

Abstract

2067 Background: The promoter of thymidylate synthase (TS) has a variable number of tandem repeats (VNTR) polymorphism and a single nucleotide polymorphism (SNP) within the VNTR region. The VNTR have been associated with toxicity of TS inhibitors in retrospective studies. The TS SNP has not been studied with respect to toxicity from TS inhibitors. The TS SNP has been suggested to abolish activity of the USF-1 enhancer located in the 2nd tandem repeat of the VNTR. The combined effect of the VNTR and SNP means that pts will have 2, 3 or 4 USF-1 enhancers in the TS promoter. We hypothesized that the number of enhancers would predict pts at risk for Gr 3/4 mucositis and diarrhea and have undertaken a prospective pharmacogenetic study of TS polymorphisms in colon cancer pts treated with 5-fluoruracil (5FU)/leucovorin (LV). Methods: Pts were treated with 5FU/LV (425mg/m2/20mg/m2) daily for 5 ds every 4 wks. Pts had blood drawn wkly for hematologic toxicity in cycle 1. Pts were assessed for mucositis and diarrhea according NCI CTC 2.0. Blood for genotyping was obtained prior to treatment. Results: Thus far 56 out of 104 pts have been enrolled, 28 pts have been genotyped and 27 are evaluable for toxicity. Patient characteristics: median age 60.5 yrs (range 39–76), 11F/16M, Stage III 23, Stage II 4. The observed toxicities were: diarrhea (37%, Gr 1; 22%, Gr 2; 11%, Gr 3; 4%, Gr 4) and mucositis (59%, Gr 1; 22%, Gr 2; 4%, Gr 3). Frequencies of 2 tandem repeat (TSER*2) and 3 tandem repeat (TSER*3) polymorphisms were respectively 0.38 and 0.62. Patients were genotyped for the C to G SNP at position 12 in the 2ndrepeat of TSER*3, 38% of TSER*3 had a G at position 12 (TSER*3G), and 62% of TSER*3 had a C at position 12 (TSER*3C). The frequency of Gr 3/4 mucositis/diarrhea was 4/12 (33%) in pts with 2 enhancers (TSER*2/TSER*2 or TSER*3G/TSER*3G) vs. 1/15 (7%) in patients with 3 or 4 enhancers (TSER*3C/TSER*3C, TSER*3C/TSER*3G, TSER*3C/TSER*2), (p=0.14, Fisher's exact test). There was no difference in hematologic toxicity between the two groups. Conclusions: Our early results suggest the TS SNP may be a critical determinant of toxicity in pts treated with 5FU/LV. No significant financial relationships to disclose.