Purpose: According to the CAO-/ARO-/AIO-94 trial of the German Rectal Cancer Study Group, pre-operative 5-fluorouracil (5-FU)-based long-term chemoradiotherapy (CT/RT) is recommended for patients with rectal cancer UICC stage II/III. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison to adjuvant CT/RT. We assessed the impact of standardized pre-operative CT/RT and intratumoural mRNA levels and polymorphisms of the TS gene on histopathological tumour regression.
Patients and methods: 40 patients with rectal cancer UICC stage II/III, receiving pre-operative 5-FU-based CT/RT followed by standardized surgery, including total mesorectal excision, were investigated. TS gene expression and TS polymorphisms of surgical specimens were correlated with the grade of histopathological tumour regression (0-4). Patients achieved regression grades 2-4 were determined as responders.
Results: TS polymorphisms (5'-28bp repeat+G/C SNP and TS1494del6) could be determined in 39/40 (97.5%) and in 38/40 (95%) patients, respectively. Quantification of TS mRNA expression was successful in 36/40 (90%) patients. There was a highly significant linkage disequilibrium between 5'- and 3'-TS polymorphisms (p=0.0013). Interestingly, the majority of patients (82.1%) with 5'-TS genotypes known to be associated with low mRNA expression (2R/2R, 2R/3RC, 3RC/3RC) also possessed the TS1494del6 +6bp/+6bp genotype correlating with high TS mRNA expression. TS1494del6 polymorphism was significantly associated with TS mRNA expression. Patients with TS1494del6 -6bp/-6bp or -6bp/+6bp genotypes showed significantly lower mean TS mRNA expression with 0.55 (range:0.33;0.84) as compared to +6bp homozygotes with a mean expression of 0.90 (range:0.20;1.91) (p=0.025). Furthermore, all patients with TS 3'-UTR -6bp/-6bp or -6bp/+6bp genotype (11/11) were responders as compared to only 20/26 (77%) of patients with TS 3'-UTR +6bp/+6bp genotype (p=0.082). TS 5'-polymorphisms were not associated with neither tumour regression nor gene expression.
Conclusion: Our data suggest that the TS1494del6 polymorphism may be an important predictor for histopathological tumour regression in UICC II/III rectal cancer patients receiving neoadjuvant 5-FU-based CT/RT.