Thymidine Kinase 1 Concentration Research Articles

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

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.

Abstract P5-02-50: Do thymidine kinase 1 (TK1) plasma concentration and activity play a role in therapy management of metastatic breast cancer patients treated with CDK4/6 inhibitors?

Abstract Introduction: CDK4/6 is a checkpoint kinase, regulating the transition of the S into the G2 phase of the cell cycle. As a cell transverses through the cell cycle, thymidine kinase 1 (TK1) is expressed and represents a direct marker of proliferative activity.which might indicate therapy efficiency of CDK4/6 inhibitors (CDK4/6i), the first choice of therapy in case no sign of visceral crisis is detected in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients. We here determined whether the activity and/or concentration of TK1 in plasma samples of MBC patients treated with CDK4/6i harbours predictive, monitoring or prognostic value. Methods: Blood of 90 HR+/HER2-MBC patients drawn at baseline of CDK4/6i (Ribociclib/Palbociclib) plus endocrine treatment and 18 HR+/HER2-MBC patients drawn before initiation of endocrine monotherapy (control), as well as available matched blood samples of these patients after six months under TX (n=90), 12/24 months before progression (n=72/24) and at the time of progression (n=52) are available. TK1 concentration in plasma samples was measured by competitive ELISA (ABIN809094, Shanghai BlueGene Biotech Co., LTD, China) and TK1 activity of matched plasma samples by competitive, two-step chemiluminescence immunoassay (REF 310960, Diasorin, Stillwater, US). Statistical analysis was conducted via log-rank test and univariate or multivariate Cox regression. Results: Currently, baseline samples were evaluated for TK1 concentration (n=106) and activity (n=90). The mean value for TK1 activity was 12.69 U/L and the median value was 8.37 U/L in the entire cohort. Values ranged from 0.89 to 79.50 U/L and the standard deviation was determined to be 12.64 U/L, which is similar to the mean value. In contrast to the control group, high TK1 activity (Cut-off: mean or determined by ROC analysis and maximal Youden’s Index for PFS < six months) was significantly correlated with decreased progression free survival (PFS) in the CDK4/6i cohort (p-value < 0.05 in log rank test and univariate Cox regression). In addition, using multivariate Cox regression analysis including clinical parameters (e.g. therapy line, prior chemo- or endocrine therapies, type of CDK4/6i accompanying endocrine therapy, number of sites of metastases, visceral metastases, menopausal status), TK1 activity was found to be an independent marker for PFS.High TK1 activity (Cut-off: mean or determined by ROC analysis and maximal Youden’s Index for PFS < six months or already deceased patients) at baseline was significantly correlated with shorter time from baseline to death in the CDK4/6i cohort (p-value < 0.05 in log rank test and univariate Cox regression) but not in the control cohort. For TK1 concentration analysis, the mean value was 21.76 ng/ml and the median value was 18.57 ng/ml in the entire cohort. Values ranged from 7.35 ng/ml to 46.66 ng/ml and the standard deviation was determined to be 11.16 ng/ml, which is half of the mean value. In contrast to TK1 activity measurements, no significant association of TK1 concentration with PFS or overall survival (OS) was detected in the CDK4/6i cohort. Currently, all remaining samples during the course of treatment are evaluated for TK1 activity and concentration and final statistical analysis of the complete data set will be available at the meeting. Conclusion: Our preliminary results indicate that TK1 activity, in contrast to TK1 concentration, determined before starting CDK4/6 inhibtion could be a suitable predictive and prognostic biomarker for estimating response to treatment. Our final analysis will clarify, whether TK1 could also serve as a monitoring marker during treatment. Citation Format: Stefanos Moukas, Merle Dohn, Rainer Kimmig, Mitra Tewes, Hans-Christian Kolberg, Sabine Kasimir-Bauer, Corinna Keup. Do thymidine kinase 1 (TK1) plasma concentration and activity play a role in therapy management of metastatic breast cancer patients treated with CDK4/6 inhibitors? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-50.

Relationship between thymidine kinase 1 before radiotherapy and prognosis in breast cancer patients with diabetes.

In a retrospective study design, we explored the relationship between serum thymidine kinase 1 (TK1) concentration before radiotherapy and clinical parameters and evaluated the prognostic value of serum TK1 concentration before radiotherapy in breast cancer patients with type 2 diabetes mellitus. The present study finally consisted of 428 breast cancer patients with a mean age of 53.0 years. Compared with low TK1 group, the high TK1 group tended to have larger tumor size (P=0.011) and had more lymph node number (P=0.021). Significant differences were also observed in clinical stages I, II and III (P=0.000). There was no significant difference between TK1 and other clinical parameters. For disease-free survival (DFS), the univariate analysis indicated that the high TK1 increased the risk of poor prognosis (HR = 2.38, 95% CI: 1.64–4.23, P=0.000). The Kaplan–Meier curve indicated the high TK1 group was poorer than that in the low TK1 group (P=0.002). For the overall survival (OS), similar results were found that the high TK1 was related to poor OS (HR = 1.89, 95% CI: 1.34–3.67, P=0.000). The multivariate Cox regression indicated that the TK1 was still associated with DFS (HR = 1.83, 95% CI: 1.22–3.17, P=0.001) and OS (HR = 1.63, 95% CI: 1.19–2.08, P=0.006). The high pretreatment serum TK1 levels in breast cancer patients were associated with poor OS and DFS. TK1 could be a potential predictive factor in differential diagnosis of poor prognosis from all patients.

Thymidine kinase 1 concentration in pleural effusion is a diagnostic marker and survival predictor for malignant pleural effusion.

ObjectiveThymidine kinase 1 (TK1) is a key enzyme in the pyrimidine salvage pathway. Increased TK1 concentration correlates with cell division. TK1 is an emerging biomarker in cancer diagnosis; however, its effectiveness in diagnosis and management for malignant pleural effusion (MPE) is unclear. We evaluated the diagnostic efficiency and prognostic value of pleural effusion TK1 (pTK1) concentration for MPE.MethodsFrom 2013 to 2017, 210 pleural effusion samples were collected from 160 patients diagnosed with MPE and 50 patients diagnosed with benign pleural effusion (BPE). TK1 concentrations in pleural effusion were measured by chemiluminescence dot blot assays. The median follow‐up was 12 months. We constructed a receiver‐operating characteristic (ROC) curve to find the optimal cutoff value for MPE diagnosis. The hazard ratios were estimated using a multivariable Cox proportional hazard model. A nomogram was drawn to illustrate the prognostic characteristics of MPE.ResultsThe TK1 concentration in pleural effusion was significantly higher in MPE than BPE (P < 0.001), and patients with MPE could be distinguished by an optimal cutoff value of 3.10 pmol/L with a sensitivity of 0.894 and a specificity of 0.800. The multivariate analysis suggested that pTK1 concentration was an independent predictor of survival in patients with MPE.ConclusionsThe diagnostic and prognostic prediction of MPE may be improved by measuring pTK1 concentration and utilizing a multivariate nomogram.

Determination of Thymidine Kinase 1 (TK1) Level as a Risk Warning Biomarker to Improve Early Detection of Breast Cancer

Early detection of breast cancer (BC) is a global target to reduce mortality and morbidity also to improve therapeutic and survival outcomes. Currently, mammography is the gold standard in BC diagnosis followed by biopsy when warranted. Thymidine Kinase 1 (TK1) is a proliferative biomarker that succeeded in discovering premalignant transformations of breast cancer before the appearance of any symptoms. This study aimed to provide a non-invasive method to early detect BC by measuring TK1 in sera of women with breast lesions alongside mammography. The study included 271 women divided into five BIRADS categories. Methods and Material: only one blood sample was collected from each woman to detect TK1 concentration, before undergoing mammography and Fine Needle Aspiration Cytology (FNAC) or true cut. Results: TK1 levels were significantly different between BI-RADS categories. It was correlated with clinical stage, histological grade, lymph node metastasis, and vascular invasion. TK1 levels could distinguish between healthy individuals and patients who had breast lesions with a sensitivity and a specificity as follows 91.3 and 87.5%, respectively. Furthermore, this test could discriminate between benign and malignant breast lesions with a sensitivity of 92.5% and a specificity of 91.2%. Conclusion: These findings suggest the determination of TK1 levels as a risk warning biomarker to improve early detection of BC.

Abstract 2618: The thymidine kinase 1 (TK1) protein concentration in sera from Hodgkin lymphoma patients: A marker for cell death and disruption of malignant cells

Abstract TK activity measurements have been used for many years to monitor cancer disease activity. However, what the blood concentrations of TK1 protein reflect is still uncertain. A TK1 immunoassay, the AroCell TK 210 ELISA, has been developed based on specific monoclonal antibodies against the C-terminal region of TK1. We utilized this assay to monitor the blood concentrations of TK1 in a cohort of patients with Hodgkin lymphoma (HL) before and after conventional treatment. TK1 concentrations in serum or plasma were measured using the AroCell TK 210 ELISA. For comparison, a large number of other biomarkers and cells were measured in blood such as C-reactive protein (CRP), Lactate dehydrogenase (LDH), hemoglobin, WBC, platelet counts, erythrocyte sedimentation rates (ESR), albumin, liver enzymes, creatinine. Fifty-eight patients with HL were included before start of treatment. Seventy three percent had the nodular sclerosis subtype and 52% stages I-II and 48% stages III-IV disease. Blood was sampled before treatment, during treatment and twice after completion of treatment. The upper normal TK1 concentration of healthy subjects (n=250) was 0.45 μg/L with a median of 0.25 μg/L (range 0.15-0.66 μg/L) as compared to HL, which was 0.26 μg/L (range 0.03-17 μg/L). The differences in ranges were significant (p&amp;lt;0.0001, F-statistics). Nodular sclerosis patients had higher TK1 levels as compared to the other subtypes (p=0.03). TK1 increased after treatment (p=0.001) in patients with normal concentrations from start i.e. &amp;lt;0.45 μg/L, whereas the concentrations decreased in 5/6 patients with TK1 &amp;gt;0.45 μg/L. TK1 concentrations before start of treatment was correlated to high CRP (p=0.01), low Hemoglobin (p=0.03), high WBC (p&amp;lt;0.001) and high platelet counts (p&amp;lt;0.01), but not to albumin or ESR or any other of the measured biomarkers. In a multivariate regression analysis, TK1 was correlated to LDH as the only independent variable (p&amp;lt;0.0001). In Hodgkin lymphoma patients, serum or plasma concentrations of TK1 may reflect malignant cell death and cell disruption rather than cell proliferation during treatment. Our results and hypothesis may help to interpret TK1 protein measurements as clinical tools in cancer management. Citation Format: Jagarlamudi Kiran Kumar, Staffan Eriksson, Johan Mattsson Ulfstedt, Per Venge, Daniel Molin. The thymidine kinase 1 (TK1) protein concentration in sera from Hodgkin lymphoma patients: A marker for cell death and disruption of malignant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2618.

Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients.

Despite extensive progress in treatment for cancer in recent decades, the early diagnosis for gastric cancer (GC) and colorectal cancer (CRC) remains poor. In this study, we explore the diagnostic value of joint detection of thymidine kinase 1 (TK1), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9) and carbohydrate antigen 72-4 (CA 72-4) in the diagnosis of GC and CRC, and to evaluated the relationship between TK1 expression and clinical pathological characteristics in the patients. Serum TK1, CA 19-9, CA 72-4 and CEA levels were measured in 169 patients with GC, 344 patients with CRC and 75 healthy controls using electro-chemiluminescence. The TK1 concentration was significantly higher in patients with cancer than in healthy controls and patients with clinical stage Ⅲ+Ⅳ had higher TK1 levels than clinical stage Ⅰ+Ⅱ (P<0.05). The levels of TK1 is significantly associated with tumor stage, lymph node metastasis, distant metastasis, tumor differentiation and age (P<0.05). When the tumor markers (TK1, CA 19-9 and CA 72-4) were detected respectively, the area under receiver operating characteristics curve (AUC) of TK1 for three cancers was the highest (0.823-0.895). However, the combination of AUC was higher than that for each tumor marker detected respectively (0.934-0.953), and the Hosmer-Lemeshow test showed an adequate model of calibration (P>0.05). Moreover, the AUCs varied significantly between the combination tests and single biomarker tests (Z test, P<0.01). In conclusion, serum TK1 may be an independent tumor marker for GC and CRC patients, and the combination of TK1, CA 19-9 and CA 72-4 and CEA performed even better. This study suggests that combination detection of four tumor markers may prove to be useful for the diagnosis of GC and CRC.

Abstract 1866: Detection of early-stage lung cancer using a novel ELISA for thymidine kinase 1

Abstract Lung cancer is the number one cause of cancer mortality and early detection will increase the survival of this disease. Thymidine kinase 1 (TK1) is a biomarker indicative of cell proliferation that is elevated in numerous malignancies including lung cancer. TK1 has been found to be elevated early in the development of lung cancer and therefore is an ideal target as an early detection biomarker. We have developed an enzyme-linked immunosorbent assay (ELISA) to detect TK1 in serum. Forty patients with pulmonary nodules and 18 healthy control individuals had serum collected under standard conditions, prior to operative removal of any lesions. All serum samples were analyzed using TK1 radioassay to measure TK1 activity, and TK1 ELISA to measure TK1 concentration. TK1 was significantly elevated in all patients with confirmed lung cancer. This was true even in stage IA, where patients (n=16) had significantly higher TK1 levels than controls. The clearest cut-off was 4.9 nM with an area under the curve of 0.792 for early stage lung cancer. The corresponding sensitivity and specificity was 82.4 and 83.3, respectively. TK1 concentration was a more sensitive and accurate indicator of lung cancer than TK1 activity. Overall, TK1 is significantly elevated in serum of lung cancer patients. This TK1 ELISA is sensitive and specific for detection of lung cancer and further trials with a larger patient base can confirm the potential of this method of detection. Citation Format: Madison K. Ramsden, Melissa M. Alegre, Michael J. Weyant, Daine T. Bennett, Jessica A. Yu, Atif Elnaggar, Richard A. Robison, Kim L. O'Neill. Detection of early-stage lung cancer using a novel ELISA for thymidine kinase 1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1866. doi:10.1158/1538-7445.AM2014-1866

Application value research on the variation of Serum thymidine kinase 1 for breast cancer diagnosis and treatment

Objective To explore the application value of thymidine kinase 1(TK1) for breast cancer diagnosis and treatment.Methods Serum TK1 concentration and positive rate were detected respectively in 205 patients with breast cancer and 150 healthy cases control with western blot-enhanced chemiluminecence.Results TK1 average concentration of patients with breast cancer in untreated group was 2.65 pmol/L; and its positive rate was 67.7％.TK 1 average concentration of healthy control group was 0.96 pmol/L; and its positive rate was 12.7％.There was significant difference(P＜0.001) among groups.The TK1 average concentration and positive rate had significant difference (P＜0.001) among the breast cancer patients in the remission stage of treatment group,the poor prognosis group,and untreated group.Conclusion TK1 has certain value of clinical applications on breast cancer auxiliary diagnosis,curative effect monitoring during treatment,and prognosis estimate. Key words: Thymidine kinase 1 ; Breast cancer; Diagnosis; Treatment

Serum thymidine kinase 1 concentration in Chinese patients with chronic lymphocytic leukemia and its correlation with other prognostic factors

Chronic lymphocytic leukemia (CLL) shows a remarkable heterogeneity, with some patients having an almost normal lifespan, others surviving only several months after diagnosis despite intensive therapy. The aim of this study was to investigate the serum thymidine kinase 1 (TK1) concentration in Chinese patients with CLL and its correlation with well-established other prognostic factors. Enhanced chemiluminescent dot blot assay was performed to measure serum TK1 concentration in 80 CLL patients. The concentration of TK1 was significantly increased in patients with Binet C (P = 0.002), higher levels of serum lactate dehydrogenase (LDH) (P = 0.012) and beta2-microglobulin (beta2-MG) (P = 0.025), unmutated IGHV status (P < 0.001), or higher expression levels of ZAP-70 (P = 0.014) and CD38 (P = 0.018) groups compared to the patients with Binet A, lower levels of serum LDH and beta2-MG, mutated IGHV status, or lower expression levels of ZAP-70 and CD38 groups, respectively. Strong correlation of TK1 level with IGHV mutations (r = 0.412, P < 0.001) or ZAP-70 (r = 0.263, P = 0.024) was observed. According to receiver operating characteristic curve analysis for serum TK1 concentration and IGHV mutational status, area under the curve was 0.757 (P = 0.001) and the optimal cut-off value of serum TK1 concentration level was 1.75 pM, with a 87.8% specificity, a 63.6% sensitivity. It was showed that serum TK1 concentration could be a predictive marker of IGHV mutational status, and might be applied for the assessment of prognosis in patients with CLL.

Serum thymidine kinase 1 is a prognostic and monitoring factor in patients with non-small cell lung cancer

Thymidine kinase 1 (TK1) is a pyrimidine metabolic pathway enzyme involved in salvage DNA synthesis and thus, a cell cycle-dependent marker. We have developed anti-TK1 monoclonal/polyclonal Abs raised against a 15-amino acid synthetic peptide (KPGEAVAARKLFAPQ) corresponding to part of the C-terminus of human TK1. These Abs are useful for both serological and immunohistochemical detection of TK1 in a number of cancer diseases. In this study we examined TK1 concentration in serum (STK1) in 250 preoperative non-small cell lung cancer patients (NSCLC), including 188 non-metastatic (group M0) and 62 metastatic patients (group M1). Serum from 16 healthy individuals was used as controls. The concentration of STK1 of preoperative NSCLC patients was significantly higher than STK1 of healthy individuals (p<0.0001). In group M0, preoperative STK1 concentration was significantly higher in patients of tumour size T2, as compared to tumour size T1 (p=0.042), and in T3-T4, as compared to T1-T2 (p=0.01). No significant difference in STK1 concentration between patients of tumour stage I and stage II (p=0.057) were found, but significantly higher STK1 concentration in patients of stage III, as compared stage I-II (p=0.025). No significant difference of STK1 concentration were found in patients of group M1 concerning tumour size or tumour stage, or between patients with adenocarcinomas (AC) and squamous cell carcinomas (SCC). We studied the changes of STK1 concentration individually one month after operation in metastatic subjects (group M1, n=19) and in tumour-free subjects (group M0, n=38). In the M0 group, the concentration of STK1 one month after operation was significantly decline by 45%, when comparing to concentrations of STK1 preoperative (p<0.001). In the group M1, however, no significant decrease in STK1 concentrations were found one month after operation. We conclude that STK1 has prognostic value and is a reliable marker for monitoring the response to surgery of NSCLC patients.