Vascular endothelial growth factor expression, S-phase fraction and thymidylate synthase quantitation in node-positive colon cancer: Relationships with tumor recurrence and resistance to adjuvant chemotherapy

Background: The behaviour of colorectal carcinomas may depend on molecular properties of tumors. In node-positive colon cancer, we assessed the S-phase fraction (SPF) index, the vascular endothelial growth factor (VEGF) expression and the TS levels. The combined analysis of SPF/VEGF was studied for predictivity of recurrent disease, the TS quantitation was related to the efficacy of fluorouracil-based adjuvant chemotherapy. Patients and methods: Consecutive patients with surgically-resected, node-positive colon cancer were studied. Flow cytometry for the SPF and immunohistochemistries for the TS and the VEGF expression were carried out on the primary tumor. Recurrences had to be proven by biopsy or surgery, and they were categorized as early, if occurred within 12 months after surgery, or late if occured 13 months or more. Results: Of 150 evaluable patients, 100 had received fluorouracil-based adjuvant chemotherapy and 50 control patients were untreated. The combined analysis of the VEGF and the SPF showed a strong association between the two markers; 48 patients (32%) had high SPF/VEGF positive tumors and 69 patients (46%) had low SPF/VEGF negative tumors (P < 0.0001). The majority of disease-free patients (73.4%) showed VEGF negative/low SPF tumors (P < 0.0001). Early recurrences occurred more frequently in patients with VEGF positive/high SPF tumors (P < 0.001). In the 100 patients treated with adjuvant chemotherapy, 86% of relapsed patients had TS overexpressing tumors and 69% of disease-free patients had TS negative tumors (P < 0.001). Also, early recurrences occurred more frequently in TS overexpressing tumors (P < 0.0001). Conclusions: Evidence is supported that node-positive colon cancer constitutes a heterogenous disease. Patients with VEGF positive/high SPF tumors showed an unfavourable outcome compared to patients with VEGF negative/low SPF tumors. The efficacy of fluorouracil-based adjuvant chemotherapy may depend on the TS status.