Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-Receptor-Positive Breast Cancer

SIMPLE SUMMARY: Chemotherapy before surgery (NAC) is an option for high-risk breast cancer (BC) patients. Pathologic complete response (pCR) predicts long-term outcome and has become a surrogate biomarker for survival. pCR is, however, reached in only <10% of hormone-receptor-positive (ER+) patients and is of limited prognostic value. Biomarkers able to predict outcome early during NAC would facilitate individualized therapy with the possibility to adjust or interrupt an ineffective therapy. Here, it is shown that differential response of the serum concentration of thymidine kinase 1, an enzyme involved in the DNA synthesis and released from the tumor into the blood, 48 h after the first cycle of NAC, predicts long-term outcome in localized advanced ER+/HER2-BC. The different reactions to chemotherapy could be used to guide this process early during NAC and utilized to identify mechanisms of tumor sensitivity that could provide a prediction of long-term outcome prior to chemotherapy. ABSTRACT: Pathologic complete response (pCR) predicts the long-term outcome of neoadjuvantly treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers enabling adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether changes in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1–4 and in an additional 77 patients before and 48 h after treatment 1. Treatment resulted in a 2-fold increase of sTK1 before and a 3-fold increase 48 h after the cycles, except for the first cycle, where half of the patients reacted with a significant decrease and the other half with an increase of sTK1. In Kaplan–Meier estimates of ER+ patients divided by the median of the post/pre-treatment sTK1 ratio at the first treatment cycle, OS was 97.7% and 78% (p = 0.005), and DFS was 90.7% and 68% (p = 0.006), respectively. Thus, the response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for the guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.