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Immunohistochemical Quantitation of Thymidylate Synthase Expression in Colorectal Cancer Metastases Predicts for Clinical Outcome to Fluorouracil-Based Chemotherapy

From the Department of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Department of Pathology, E.O. Ospedali Galliera, Genova, and University of Udine, Udine, Italy; and Wadsworth Center, New York State Department of Health, Albany, NY.

Address reprint requests to C. Aschele, MD, Divisione di Oncologia Medica, Azienda Ospedaliera di Padova, Via Giustiniani 2, 35128 Padova, Italy; email c.aschele{at}galliera.it 16132, Genova, Italy; email aschele@hp380.ist.unige.it.

PURPOSE: To determine whether immunohistochemical thymidylate synthase (TS) quantitation predicts for clinical outcome in patients with advanced colorectal cancer treated by fluorouracil (FUra)-based chemotherapy.

PATIENTS AND METHODS: TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 48 patients homogenously treated by bolus FUra plus methotrexate alternating with continuous-infusion FUra plus leucovorin. These measurements were retrospectively correlated with patient characteristics and clinical outcome.

RESULTS: A significant correlation was found between intratumoral TS expression and all the parameters of clinical outcome analyzed. In patients whose tumors had low (n = 27) and high (n = 21) TS levels, the overall response rates were 67% and 24%, respectively (P = .003). The percentage of tumor shrinkage after chemotherapy was linearly related to TS immunoreactivity (r = .56, P = .00004), and its mean values were 65% and 14% with low and high TS levels, respectively (P = .0001). By logistic regression analysis, low TS expression was the single best predictor of response to chemotherapy (relative probability, 5.0). In patients with low and high TS expression, the median time to progression was 9.6 months v 6.2 months (P = .005) and the median survival time 18.4 months v 15.4 months (P = .02), respectively. Two- and 3-year survival rates were 41% v 15% and 19% v 0% (P = .02), respectively.

CONCLUSION: In this cohort of homogenously treated patients, intratumor TS content was a major predictor of clinical outcome. Immunohistochemical TS quantitation provides a convenient, low-cost technique for identifying patients unresponsive to TS inhibitors who may be candidates for alternative chemotherapy regimens.

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