Role of thymidylate synthase (TS) polymorphisms (SNPs) as a potential prognostic factor in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (preCh-RT).

Abstract

e14080 Background: Neoadjuvant concomitant fluoropyrimidine-based chemotherapy plus radiotherapy is considered a standard approach for LARC. SNPs of TS, the target for fluoropyrimidines, are recognized prognostic factors in colon cancer. The aim of this study was to evaluate the role of TS SNPs in LARC patients (pts) treated with preCh-RT. Methods: Between November 2001 and March 2009, 110 consecutive pts with stage II/III LARC were treated with neoadjuvant RT (5,040 cGy) plus fluoropyrimidine-based chemotherapy (ci 5FU:69 pts; capecitabine:41pts). Patients underwent surgery 6-8 weeks after pre Ch-RT. DNA was extracted from paraffin embedded biopsies. TS1494del6 and 5′-28bp repeat +G/C SNP polymorphisms were determined. Results: 67% were men and median age was 67 years. ypT stage was: ypT0 10%, ypT1 3%, ypT2 27%, ypT3 58% and ypT4 2%; 32% had positive nodes. Median follow-up was 45 months and relapses occurred in 20% of patients. SNPs could be determined in 98% of pt: -6bp/-6bp 10%, - 6bp/+6bp 39%, +6bp/+6bp 51% and 2R/2R 72%, 2R/3R 21%, 3R/3R 6%. The grade of pathological tumor regression was not associated with SNPs. Distant or locoregional disease relapses occurred in 40% of -6bp/-6bp pts (5FU: 42.9%; capectabine: 33.3%), 22% of patients -6bp/+6bp or +6bp/+6bp (5FU: 25.2%; capecitabine: 15.8%). The difference in disease- free survival (DFS) between the first and the second groups was statistically significant (p=0.049).Equally, a significant difference was found between -6bp/-6bp pts treated wit 5FU vs capecitabine (35m vs 16m). No relation between 5′-28bp repeat +G/C SNP polymorphism and DFS was found. Conclusions: In LARC our data suggest that the choice between 5FU or capecitabine could depends of the knowledge of TS1494del6 status.