Elevated thymidine kinase 1 in serum following neoadjuvant chemotherapy predicts poor outcome for patients with locally advanced breast cancer

Abstract

Patients with locally advanced breast cancer (LABC) commonly have an unfavorable prognosis. A molecular predictor for the identification of at-risk patients is urgently required. Thymidine kinase 1 in serum (S-TK1) is an enzyme involved in the synthesis of DNA precursors. In studies using immunohistochemistry, it was reported to be a more useful proliferation marker than Ki-67 in breast, lung and colorectal carcinoma. In the present study, we extended the research of prior breast carcinoma studies by postulating that in patients with LABC, overexpression of S-TK1 following neoadjuvant chemotherapy predicts cancer outcome. An experimental design consisting of 48 patients with LABC was prospectively constructed and analyzed. All patients received neoadjuvant chemotherapy and definitive surgical therapy. Study homogeneity was maintained by standardized treatment, surveillance and compliance protocols. The S-TK1 concentration was detected using the anti-TK1 chicken IgY antibody, using a dot-blot immuno-assay. After a median follow-up of 30 months, the results indicated a statistically significant trend (unadjusted). Patients with high S-TK1 overexpression had a significantly higher incidence of recurrence (P=0.006) and cancer death (P= 0.0128) than those with low S-TK1 overexpression. A multivariate analysis provided identical results. The hazards ratio for developing recurrence in patients with higher S-TK1 expression was 6-7 times higher than the hazards ratio in patients with lower expression. In conclusion, our results indicate that a high S-TK1 concentration in sera from LABC patients receiving neoadjuvant chemotherapy is predictive of cancer outcome.

Figure 1.

TK1 overexpression in LABC specimens. Note that TK1 overexpression was observed in varying degrees in breast cancer specimens.

Figure 2.

Influence of TK1 overexpression on disease-free survival for LABC patients who were treated with neoadjuvant chemotherapy. This Kaplan-Meier survival curve compares the disease-free survival, based on the degree of TK1 overexpression, in LABC patients who underwent neoadjuvant chemotherapy. Note that patients whose tumors had a high TK1 concentration in their serum had a worse disease-free survival when compared to those whose tumors had low serum TK1 concentration (P=0.003).

Figure 3.

Influence of TK1 overexpression on overall survival for LABC patients who were treated with neoadjuvant chemotherapy. This Kaplan-Meier survival curve compares the overall survival, based on the degree of TK1 overexpression, in LABC patients who underwent neoadjuvant chemotherapy. Note that patients whose tumors had high TK1 concentration in serum had a relatively worse overall survival when compared to those whose tumors had low TK1 concentration although there were no significant differences.