Abstracts
2001 Digestive Disease Week

# 336 mRNA Quantitation of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase Can Predict Disease-Free Survival in Stage IIb and III Colon and Stage II and III Rectal Cancer
Marko Kornmann, Karl H. Link, Wolfgang Schwabe, Peter Haeussler, Joern Straeter, Sucan Polat, Peter D. Danenberg, Detlef Behnke, Hans G. Beger, Ulm, Germany, Jena, Germany, Los Angeles,CA

Background: Patients (pts) with UICC stage IIb and III colon and stage II and III rectal cancer (CRC) may receive adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisol. Despite the treatment 30-40% of the patients develop local or distant tumor recurrence. Thymidylate synthase (TS) is a key enzyme in DNA synthesis and targeted by 5-FU, whereas dihydropyrimidine dehydrogenase (DPD) is the key enzyme for the inactivation and catabolism of 5-FU. High intratumoral levels of both enzymes have been associated with 5-FU resistance in advanced colorectal cancer (CRC). Aim: To investigate the value of TS and DPD as a predictive marker for disease-free survival (DFS) in pts with CRC receiving adjuvant 5-FU chemotherapy.

Methods: So far, primary tumor tissue of 348 pts with CRC, which were entered from 1992 to 1999 in our randomized adjuvant trials of colon and rectal cancer (5-FU/levamisol vs. 5-FU/levamisol with folinic acid vs. 5-FU/levamisol with interferon-g), respectively, was used for this retrospective analysis. TS and DPD mRNA quantitation was performed using an reverse transcription polymerase chain reaction technique with b-actin as internal standard.

Results: Neither TS or DPD predicted tumor recurrence nor survival in all 348 pts. However, in the subgroup of pts with tumor recurrence (130/348 = 37%) TS alone predicted DFS. Thus, pts with low TS levels (n = 84) had a median DFS of 19.4 months (range: 3.0-55.7 months) and pts with high TS levels (n = 46) of 11.7 months (range: 1.7-53.1 months; (p < 0.0001). There was also a trend for longer median DFS in pts with low DPD levels, however the difference was statistically not significant.

Conclusion: TS can predict the time to tumor recurrence in pts with CRC receiving adjuvant 5-FU treatment. It is possible that future adjuvant treatment of CRC is performed according to individual TS mRNA levels. Pts with low TS may receive adjuvant 5-FU according to current protocols, whereas pts with high TS may receive other 5-FU regimens or other agents for adjuvant chemotherapy.