Prognostic significance of thymidylate synthase in colorectal cancer and comparison with DNA ploidy & other clinicopathological parameters

NS Desai MSc, NH Karelia MD, SM Patel PhD, K Shah PhD

Dept. of Pathology, Immunocytometry Division, Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, India

Aim: To investigate the prognostic significance of Thymidylate Synthase (TS), DNA ploidy and S-phase fraction in patients with Colorectal cancer and further correlated with response to therapy. Methods Materials: In this retrospective study, 69 untreated Colorectal cancer patients were enrolled. Immunohistochemical localization was done using Thymidylate Synthase(TS), Neomarker, CA, USA (TS 106) antibody. DNA analysis (DNA aneuploidy and s-phase fraction ) was done on paraffin–embedded section using Flowcytometer.Patients were followed for two years. Results: Out of total 69 patients with Colorectal carcinoma, 57%(39/69)were male, 57% (39/69) had Duke’s stage B patients 32% (22/69) had Duke’s stage C and 9% (6/69) had Duke’s Stage D.30%(21/69) patients died with in follow up period and 55%(38/69)patients received chemotherapy 38%(26/69)tumors were aneuploid and high (>10%) S-phase fraction was documented in 55%(38/69) tumors. While Thymidylate Synthase positivity was observed in 70% (48/69) tumors. Patients with aneuploid tumors had bad prognosis than patients with diploid tumors (P=0.00001). Patients with high S-phase fraction had poor prognosis than patients with low (<10%) S-phase fraction tumors but it was statistically non-significant (P=0.2109). While no such difference was observed amongst patients with TS positive and TS negative tumors (P=8763). Patients with aneuploid tumors had high incidence of S-phase fraction as compared to patients with diploid (P<0.001), while no such difference was observed with TS expression. Patients with diploid and TS positive tumors had good prognosis as compared to patients with aneuploid and TS negative tumors (P<0.001); and patients with anueploid and TS positive tumors(P<0.01). The incidence of aneuploidy was low in Duke’s stage B as compared to Duke’s stage C&D.Patients with Duke’s stage A tumor had low mean S-phase fraction than patients with Duke’s stage B tumors(P<0.05). Similarly significantly more patients with Duke’s stage D died as compared to patients with Duke’s stage B(P<0.05). Patients with Well differentiated tumors had low incidence of aneuploidy as compared to patients with poorly differentiated tumors (P<0.01). Patients with Moderately differentiated tumors had low incidence of aneuploidy as compared to patients with poorly differentiated tumors (P<0.05). Patients with poorly differentiated tumors had bad survival than patients with well differentiated tumors(P<0.01). Conclusion: DNA aneuploidy is an independent prognostic marker in patients with Colorectal cancer while TS expression and S-phase fraction failed as independent prognosticators. Combination of DNA aneuploidy and TS expression may identify those sub groups of patients who may benefit from more aggressive treatment.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 893 (Molecular pathology).