Thymidine Kinase as a Proliferative Marker: Clinical Relevance in 1,692 Primary Breast Cancer Patients

Abstract

PURPOSE: To assess the prognostic value of thymidine kinase (TK), an enzyme involved in the DNA synthesis salvage pathway, relative to other prognostic factors in primary breast cancer. PATIENTS AND METHODS: This retrospective study involved 1,692 patients with operable breast cancer treated in six institutions (median follow-up, 82 months). Among the 857 node-negative patients, 135 received adjuvant chemotherapy (fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, etoposide, and cisplatin [FEC]). TK was assayed in cytosol with a quantitative radioenzymatic technique. Disease-specific survival (DSS), local recurrence-free interval (LRI), and distant-relapse-free interval (DRI) were investigated. RESULTS: High TK levels were associated with large tumor size, high histologic grade, and steroid hormone receptor negativity. Univariate analysis of the entire data set showed that high TK levels were related to shorter DSS (P < 10-5), LRI (P < 10-3), and DRI (P < 10-5). In time-dependent Cox models, high TK levels remained an independent predictor of the three outcomes, both in the overall population and in node-negative patients, although its prognostic value decreased over time. In node-negative patients, the introduction of an interaction term in multivariate analysis suggested that chemotherapy was more efficacious for patients who had tumors with high TK contents. In node-positive patients, high TK levels were related only to an increased risk of LRI. CONCLUSION: High TK values are an important risk factor in node-negative patients and seem to be associated with a beneficial effect of adjuvant FAC or FEC in patients who received adjuvant chemotherapy. The rationale of chemotherapy for patients with slowly proliferating tumors has to be discussed from a risk-benefit point of view.