Preoperative Serum Thymidine Kinase Activity as Novel Monitoring, Prognostic, and Predictive Biomarker in Pancreatic Cancer

Felix, Klaus; Hinz, Ulf; Dobiasch, Sophie; Hackert, Thilo; Bergmann, Frank; Neumüller, Magnus; Gronowitz, Simon; Bergqvist, Mattias; Strobel, Oliver

doi:10.1097/mpa.0000000000000966

Cited by 7 publications

(10 citation statements)

References 34 publications

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“…Regarding survival, high sTK1 level was an independent prognostic factor for both PFS and OS in patients with newly diagnosed MBC. These results support previous studies reporting impaired survival in patients with high TK1 levels in different malignancies [11][12][13] . When evaluating sTK1 levels during therapy as a tool for monitoring treatment in MBC we found that the median cut-off of initial sTK1 level was relevant for correlation to both PFS and OS at follow-up time points at 3 and 6 months.…”

Section: Discussionsupporting

confidence: 92%

Serial evaluation of serum thymidine kinase activity is prognostic in women with newly diagnosed metastatic breast cancer

Larsson

Bendahl

Aaltonen

et al. 2020

Sci Rep

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The rapid development of new therapies in metastatic breast cancer (MBC), entails a need for improved prognostic and monitoring tools. Thymidine kinase 1 (TK1) is involved in DNA synthesis and its activity correlates to outcome in cancer patients. The aim of this study was to evaluate serum TK1 activity (sTK1) levels in MBC patients as a tool for prognostication and treatment monitoring. 142 women with MBC scheduled for 1 st line systemic treatment were included in a prospective observational study. sTK1 was measured at baseline (BL) and at 1, 3 and 6 months and correlations to progression-free and overall survival (PFS, OS) evaluated. High sTK1 levels (above median) correlated to worse PFS and OS at BL, also after adjusting for other prognostic factors. sTK1 levels were significantly associated with PFS and OS measured from follow-up time points during therapy. Changes from 3 to 6 months during therapy significantly correlated to PFS and OS, whereas early changes did not. We could demonstrate sTK1 level as an independent prognostic factor in patients with newly diagnosed MBC. Changes in sTK1 levels from 3 to 6 months correlated to PFS and OS. Future studies of sTK1 are warranted to further define its clinical utility. Breast cancer is the most common malignant disease in women and although the 5-year survival is approaching 90%, 20-30% of women with initially local disease will develop metastatic disease 1. Even though treatment regimens have improved, the median survival in women with metastatic breast cancer (MBC) is approximately 2 years and the 5-year survival is only 25% 2. MBC is generally an incurable disease and therapy is focused on symptom palliation, extending survival and improving quality of life 2. Monitoring treatment response in MBC remains a clinical challenge and current guidelines suggest a combination of imaging, clinical assessment and in addition application of serum tumor markers if initially elevated 2-4. Imaging is golden standard for tumor response evaluations in patients with measurable disease 5. However, studies report that 10-40% of MBC patients have non-measurable disease 6,7. There is a clinical need for better tools to improve prognostication and therapy monitoring in MBC. Blood-borne markers are gaining attention since they carry real-time information on tumor progression and are easily evaluated in a simple blood test. Thymidine Kinase 1 (TK1) has been proposed as a marker of cell proliferation. The main function of TK1 is involvement in nucleotide metabolism with a fundamental role in DNA synthesis, essential for cell proliferation 8-10. In patients with different tumor types, TK1 activity has been shown to carry prognostic information and potential in tumor monitoring 11-14. In breast cancer, high TK1 activity in blood has been associated with worse prognosis 15. Serum TK1 activity (sTK1) level has been proposed as a prognostic marker in MBC patients during endocrine therapy (ET) and as an indicator for early response in these patients 16,17. Furthermore, it has been suggeste...

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Section: Discussionsupporting

confidence: 92%

Serial evaluation of serum thymidine kinase activity is prognostic in women with newly diagnosed metastatic breast cancer

Larsson

Bendahl

Aaltonen

et al. 2020

Sci Rep

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“…60 In humans, preoperative measurements of TK1 activity with the DiviTum assay provide prognostic information in primary breast, lung, and renal cancers. 64,77,78 The DiviTum assay provides valuable clinical information in the treatment and management of chronic lymphocytic leukemia. 62 Consequently, the DiviTum method is valuable to encourage further investigation in veterinary patients.…”

Section: Discussionmentioning

confidence: 99%

“…Samples were run in batches depending on the number of samples and transported in ice pack by express/overnight service. Analysis of TK1 activity was determined by a refined enzyme‐linked immunosorbent assay (ELISA), the DiviTum assay (Biovica International, Uppsala, Sweden), according to the manufacturer's instructions (http://biovica.com/), as previously described . Serum was added to reaction mixture, containing bromodeoxyuridine (BrdU), in a 96‐well ELISA titer plate.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of serum thymidine kinase 1 activity as a biomarker for treatment effectiveness and prediction of relapse in dogs with non‐Hodgkin lymphoma

Boyé

Floch

Serres

et al. 2019

Veterinary Internal Medicne

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Background Serum thymidine kinase 1 (sTK1) activity is closely correlated with DNA synthesis. Objectives Evaluate sTK1 activity as a biomarker for treatment response and early detection of relapse in dogs with lymphoma. Animals Ninety‐seven client‐owned dogs with naive or relapsed lymphoma and 23 healthy dogs. Methods Prospective study. Serum TK1 activity measured by refined ELISA‐based method (DiviTum assay, Biovica International) before treatment, at clinical response, and every 4 weeks until relapse or last follow‐up. Results Serum TK1 activity was ≤20 Du/L in 96% (22/23) of healthy dogs. Pretreatment sTK1 activity was >20 Du/L in 88% (85/97) dogs with lymphoma. At clinical response, sTK1 activity was significantly lower in dogs with complete (CR, n = 36) versus partial (PR, n = 29) response ( P < .0001). Sensitivity (Se) and specificity (Sp) of sTK1 activity for detecting nonfully responders were 76% and 100%, respectively, with cutoff of 119.5 Du/L (AUC, 0.90; 95%‐CI, 0.81‐0.98; P < .0001). In dogs with CR, a 5‐fold increase in sTK1 activity at a 4‐week interval predicted relapse at the subsequent 4‐week assessment with a Se 50% and Sp 94% (AUC, 0.72; 95%‐CI, 0.55‐0.90; P = .02). An increase of sTK1 activity (>2.7‐fold value measured at clinical response) predicted relapse at subsequent 4‐week assessment with a Se 61% and Sp 88% (AUC, 0.79; 95%‐CI, 0.64‐0.95; P = .004). Conclusions and Clinical Importance Monitoring sTK1 activity could help to detect complete responders and early disease progression in dogs with lymphoma.

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“…The median TKa was 42 Du/L (range <20-1787 Du/L), while, as a reference, in 123 healthy subjects, the median TKa value was <20 Du/L (Biovica data on file). In a cohort of preoperative pancreatic cancer patients, the median TKa value was 40 Du/L, and in a cohort of preoperative renal cell cancer patients, the median TKa was 38 Du/L [12,14]. Further, in a cohort of non-small cell lung cancer patients, the median TKa was 129 Du/L before the start of systemic treatment, whereas in a cohort of breast cancer patients, the pre-treatment TKa was 57 Du/L in patients with locoregional disease and 101 Du/L in patients with visceral metastasis [15,18].…”

Section: Discussionmentioning

confidence: 97%

“…Further, elevated TK enzyme activity has been measured in blood samples from cancer patients and is associated with tumor proliferation and tumor burden [8]. Circulating levels of TKa, measured with the DiviTum assay, have been shown to be associated with disease stage, prognosis, and treatment efficacy in several cancer types, including breast, lung, pancreatic, and renal cell cancer [9][10][11][12][13][14][15]. This study is the first to analyze TKa levels in the plasma of melanoma patients.…”

Section: Introductionmentioning

confidence: 99%

Plasma Thymidine Kinase Activity as a Novel Biomarker in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibitors

Svedman

Jalsenius

Höiom

et al. 2022

Cancers

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Background. Immune checkpoint inhibitors (ICI) are effective in fractions of patients with disseminated melanoma. This study is the first to analyze the plasma activity of thymidine kinase (TK), an enzyme involved in DNA synthesis and repair, as a biomarker in melanoma patients. Methods. Plasma samples were collected prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with ICI (anti-CTLA-4 and/or anti-PD-1). Plasma TK activity (TKa) levels were determined using the DiviTum TKa ELISA assay. TKa levels were correlated with patients’ baseline characteristics, response rate (RR), progression-free survival (PFS), and overall survival (OS). Results. In the 90 study patients, the median TKa level was 42 Du/L (range <20–1787 Du/L). A significantly higher plasma TKa was found in patients with ECOG performance status ≥1 (p = 0.003), M1c-d disease (p = 0.015), and elevated lactate dehydrogenase levels (p < 0.001). The RR was 63.2% and 30.3% in those with low or high TKa, respectively (p = 0.022). The median PFS was 19.9 and 12.6 months in patients with low or high TKa, respectively (hazard ratio (HR) 1.83 (95% CI, 1.08–3.08), p = 0.024). The median OS was >60 months and 18.5 months in patients with low or high TKa, respectively (HR: 2.25 (95% CI, 1.25–4.05), p = 0.011. Conclusions. High pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients. TKa is hence a novel and interesting plasma biomarker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease.

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Preoperative Serum Thymidine Kinase Activity as Novel Monitoring, Prognostic, and Predictive Biomarker in Pancreatic Cancer

Abstract: Pancreatic ductal adenocarcinomas reveal a significant increase in S-TK activity, which is associated with overall survival, especially in early tumor stages. Serum thymidine kinase 1 activity may be a useful parameter for monitoring nTx efficacy.

Cited by 7 publications

References 34 publications

Serial evaluation of serum thymidine kinase activity is prognostic in women with newly diagnosed metastatic breast cancer

Serial evaluation of serum thymidine kinase activity is prognostic in women with newly diagnosed metastatic breast cancer

Evaluation of serum thymidine kinase 1 activity as a biomarker for treatment effectiveness and prediction of relapse in dogs with non‐Hodgkin lymphoma

Plasma Thymidine Kinase Activity as a Novel Biomarker in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibitors

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