Thymidylate synthase and microsatellite instability in colorectal cancer: implications for disease free survival, treatment response and survival with metastases.

Background: Colorectal cancer (CRC) cell lines displaying microsatellite instability (MSI) are resistant to 5-fluorouracil (5-FU) in vitro, which can be overcome by restoring DNA mismatch repair (MMR) competence. Thymidylate synthase (TS) is inhibited by 5-FU, being another potential mediator of therapeutic resistance to 5-FU. The clinical relevance of these observations remains unclear.

Objective: We examined the expression of TS and two MMR proteins (hMLH1 and hMSH2) in advanced CRC patients, to determine a) their mutual relationship, b) association to therapeutic response and c) impact on disease outcome.

Material And Methods: Tumour samples from 73 patients CRC who were treated in advanced stage with either irinotecan alone or in combination with 5-FU/leucovorin, were analysed for expression of TS, hMLH1 and hMSH2 using immunohistochemistry (IHC).

Results: TS expression was closely correlated with hMLH1 expression (negative-weak/moderate-strong) (p=0.0001). TS-MMR expression was significantly (p=0.029 for whole series; p=0.004 for the 5-FU treated cases) related to response to treatment; tumours with low levels of both TS and MMR responded better (n=14/27, 51.8%) than those with high TS and MMR (n=3/18, 16.6%). Patients with high TS-MMR expression had a significantly longer DFS (47 months vs. 9 months, n=26) than those with low TS-MMR index (p=0.015), while the reverse was true concerning survival with metastases (WMS) (p=0.018) in all the patients (n=73).

Conclusions: The present data suggest that MSI patients with low TS and deficient MMR demonstrate a significantly shorter DFS and longer WMS than patients with high expression of both markers, and they are also more likely to obtain the greatest benefit from 5-FU based chemotherapy.