Expression of dUTP nucleotidohydrolase (dUTPase) and thymidylate synthase (TS) in stage III colon cancer patients treated with either bolus 5-FU or infusional 5-FU in the adjuvant setting: Results of a translational study of the PETACC-2 trial.

Abstract

417 Background: Pts with stage III colon cancer have been treated with either infusional 5-FU or bolus 5- FU in the adjuvant setting (PETACC-2 trial). DUTPase and TS demonstrated potential as predictive markers for 5-FU efficacy in pts with advanced colorectal cancer. Here we aimed to explore whether TS or dUTPase protein levels may predict recurrence of disease for stage III colon pts treated with 5-FU. Methods: Tumor (T) blocks of 324 pts were analyzed for protein expression of dUTPase and TS. For analysis monoclonal antibodies DUT415 and TS106 were used. T were evaluated by two investigators as follows. Only nuclear staining for both, TS and dUTPase, was analyzed. If tumor cells (TC) showed a nuclear dUTPase expression in >10% of cells, the sample was scored positive. Positive nuclear staining for >20% of TC, when using the TS antibody, determined a positive sample. Results: Analysis for dUTPase was successful in 308 samples (95.1%, 308/324). 263 out of those 308 pts showed a positive dUTPase expression (85.3%). 297/324 samples (91.7%) could be evaluated for TS. In the TS group 62.3% (185/297) showed a positive expression for TS protein. In 281 cases analyses were successful for both TS and dUTPase. We observed a significant association between dUTPase and TS expression with a majotity of 71.4% (172/241) dUTPase positive T also being positive for TS as compared to 32.5% (13/40) of dUTPase negative T that showed positivity for TS protein expression (p< 0.0001). Of pts with dUTPase positive T 64.7% showed no recurrence of disease as compared to 44.7% of those with dUTPase negative T 5 years after completion of therapy (HR 0.61 [95% CI 0.36, 1.03], p=0.06). No associations between TS and DFS were observed. Both TS and dUTPase expression did not correlate with OS in this patient cohort. Conclusions: High TS protein levels appeared to be significantly correlated with high protein levels of dUTPase in stage III colon cancer pts. Neither dUTPase nor TS protein levels appeared to be significantly associated with DFS or OS of stage III colon cancer pts that received adjuvant chemotherapy with 5-FU. No significant financial relationships to disclose.