Background: After neoadjuvant chemotherapy of breast cancer pathologic complete response (pCR) indicates a favorable prognosis. Among non-selected patients, pCR is, however, achieved in only 10–30%. Early evaluation of tumour response to treatment would facilitate individualized therapy, with ineffective chemotherapy interrupted or changed. The methodology for this purpose is still limited. Tumour imaging and analysis of macromolecules, released from disrupted tumour cells, are principal alternatives. Objective: To investigate whether a metric of cell-loss, defined as the ratio between serum concentration of thymidine kinase1 (sTK1, ng x ml^− 1) and tumour volume, can be used for early prediction of pathologic response. Methods: One hunred four women with localized breast cancer received neoadjuvant epirubicin/docetaxel in 6 cycles, supplemented with bevacizumab in cycles 3–6. The cell-loss metric was established at baseline (n = 104), 48 h after cycle 2 (n = 104) and prior to cycle 2 (n = 57). The performance of the metric was evaluated by association with pathologic tumour response at surgery 4 months later. Results: Treatment caused a rise in sTK1, a reduction in tumour volume and a marked increase in the cell-loss metric. Patients were subdivided into quartiles according to the baseline cell-loss metric. For these groups, baseline means were 0.0016, 0.0042, 0.0062, 0.0178 units. After subtraction of baselines, means for the quartiles 48 h after treatment 2 were 0.002, 0.011, 0.030 and 0.357 units. pCR was achieved in 24/104, their distribution in the quartiles (11, 11, 23 and 46%) differed significantly (p = 0.01). In 80 patients with remaining tumour, tumour size was inversely related to the metric (p = 0.002). In 57 patients studied before treatment 2, positive and negative predictive values of the metric were 77.8 and 83.3%, compared to 40.5 and 88.7% 48 h after treatment 2. Conclusion: A cell-loss metric, based on serum levels of TK1, released from disrupted tumour cells, and tumour volume, reveal tumour response early during neoadjuvant treatment. The metric reflect tumour properties that differ greatly between patients and determine the sensitivity to cytotoxic treatment. The findings point to the significance of cell loss for tumour growth rate. The metric should be considered in personalized oncology and in the evaluation of new therapeutic modalities. Trial registration: PROMIX (Clinical Trials.gov NCT000957125).

Background: Thymidine kinase 1 (TK1) recycles DNA before cell division. We do not know if baseline blood concentrations of TK1 predict death in prostate cancer within 30 years.Our objective is to determine if there is an association between baseline levels of TK1 and future prostate cancer‐specific mortality.Methods: With a “proof of concept” approach, we performed a nested case–control study among 1782 individuals screened for prostate cancer between 1988 and 1989. The concentration of TK1 was measured in frozen serum from 330 men, 36 of whom have died of prostate cancer.The primary endpoint was prostate cancer‐specific mortality and outcomes after 30 years were analyzed using logistic regression modeling odds ratios (Ors).Results: The estimated OR (adjusted for age) for dying from prostate cancer among the men who had a TK1 value in the upper tertile was 2.39 (95% confidence interval 1.02–5.63). The corresponding OR, regardless of the cause of death, was 2.81 (1.24–6.34).Conclusions: High levels of TK1 predicts death in prostate cancer within 30 years of follow‐up.

Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988–1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.

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.

Background: After neoadjuvant chemotherapy of breast cancer pathologic complete response (pCR) indicates a favourable prognosis. Among non-selected patients, pCR is, however, achieved in only 10-30%. Early evaluation of tumour response to treatment would facilitate individualized therapy, with ineffective chemotherapy interrupted or changed. The methodology for this purpose is still limited. Tumour imaging and analysis of macromolecules, released from disrupted tumour cells, are principal alternatives. Objective: To investigate whether a metric of cell-loss, defined as the ratio between serum concentration of thymidine kinase1 (sTK1, ng x ml-1) and tumour volume, can be used for early prediction of pathologic response. Methods: 104 women with localized breast cancer received neoadjuvant epirubicin/docetaxel in 6 cycles, supplemented with bevacizumab in cycles 3-6. The cell-loss metric was established at baseline (n=104), 48h after cycle 2 (n=104) and prior to cycle 2 (n=57). The performance of the metric was evaluated by association with pathologic tumour response at surgery 4 months̴ later.Results: Treatment caused a rise in sTK1, a reduction in tumour volume and a marked increase in the cell-loss metric. Patients were subdievided into quartiles according to the baseline cell-loss metric. For these groups, baseline means were 0.0016, 0.0042, 0.0062, 0.0178 units. After subtraction of baselines, means for the quartiles 48h after treatment 2 were 0.002, 0.011, 0.030 and 0.357 units. pCR was achieved in 24/104, their distribution in the quartiles (11%, 11%, 23% and 46% ) differed significantly (p=0.01).In 80 patients with remaining tumour, tumour size was inversely related to the metric (p=0.002). In 57 patients studied before treatment 2, positive and negative predictive values of the metric were 77.8% and 83.3%, compared to 40.5% and 88.7% 48h after treatment 2. Conclusion: A cell-loss metric, based on serum levels of TK1, released from disrupted tumour cells, and tumour volume, reveal tumour response early during neoadjuvant treatment. The metric reflect tumour properties that differ greatly between patients and determine the sensitivity to cytotoxic treatment. The findings point to the significance of cell loss for tumour growth rate. The metric should be considered in personalized oncology and in the evaluation of new therapeutic modalities.