Prediction of Overall Survival by Thymidine Kinase 1 Combined with Prostate-Specific Antigen in Men with Prostate Cancer

Abstract

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.

Keywords: PSA; biomarker integration; prediction; prostate cancer; survival; thymidine kinase 1.

Figure 1

Overview of the function of thymidine kinase 1 in the DNA synthesis. (a) TK1 and cell cycle, (b) TK1 concentration during cell cycle, (c) transformation of thymidine* (Thd) to deoxythymidine—monophosphate.

Figure 2

Last follow-up in relation to the time of the diagnosis in 271 men with prostate cancer, detected by screening 1988/89 and during 30 years of follow-up. Red symbols: alive, black symbols: deceased. On the right side, number of prostate cancers in relation to the actual number of the initial 1782 men.

Figure 3

Overall survival by Kaplan–Meier estimates in 175 men with prostate cancer, (a) according to the median concentration of PSA (b), according to the median concentration of TK1, (c) according to TK1 + PSA. 1. TK1 < 0.25 + PSA < 3.8 ng/ml, 2. TK1 < 0.25 + PSA > 3.8 ng/ml, 3. TK1 > 0.25 + PSA < 3.8 ng/ml, 4. TK1 > 0.25 + PSA > 3.8 ng/ml. Abbreviations: PSA = prostate-specific antigen, TK1 = thymidine kinase 1.

Figure 4

Overall survival of 175 men with prostate cancer stratified by quartiles of age at screening and median TK1 concentration: (a) Kaplan–Meier estimates of TK1 concentrations < 0.25 ng/ml; (b) Weibull-transformed Kaplan–Meier estimates of TK1 concentrations < 0.25 ng/ml; (c) Kaplan–Meier estimates of TK1 concentrations > 0.25 ng/ml; (d) Weibull-transformed Kaplan–Meier estimates of TK1 concentrations > 0.25 ng/ml.

Figure 5

Survival probability of 175 men with prostate cancer stratified by age and TK1 below and above the median. The survival probability was calculated from Weibull-transformed Kaplan–Meier estimates. The shattered line shows the survival probability of age alone.

Figure 6

Influence of TK1 concentration on survival probability of 175 men with prostate cancer stratified by age. The survival probability was calculated from Weibull-transformed Kaplan–Meier estimates. The shattered line shows the survival probability of age alone.

Figure 7

Influence of PSA concentration on survival probability of 175 men with prostate cancer stratified by age. The survival probability was calculated from Weibull-transformed Kaplan–Meier estimates. The shattered line shows the survival probability of age alone.

Figure 8

Survival probability of 175 men with prostate cancer stratified by age and different cut-off values of TK1 concentration in combination with PSA below and above 3.0 ng/ml.