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

Abstract

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...

Plasma thymidine kinase 1 activity and outcome of ER+ HER2− metastatic breast cancer patients treated with palbociclib and endocrine therapy

“…Because of these differences in median pTKa across studies and clinical settings, a pTKa threshold should be defined according to treatment history and using a large and homogeneous population, for a better assessment of the prognostic impact of baseline pTKa and pTKa variation. Importantly, chemotherapy having been reported to increase TKa levels [ 26 , 27 ], the early interpretation of the variation could be challenging and this might explain that the variation of pTKa level was not a prognostic factor here. Ongoing large studies like SWOG S0226 (NCT00075764), resistance to first-line therapy with an AI and palbociclib at Johns Hopkins (NCT03439735), and the PYTHIA study (NCT02536742) will address this.…”

Posttranslational Modifications Pattern in Clear Cell Renal Cell Carcinoma

“…More studies are needed for evaluating its role in early or advanced ccRCC. TDH status was used to evaluate the severity of multiple renal and inflammatory diseases (urolithiasis, obstructive uropathy, urinary tract infections, autosomal dominant polycystic disease, acute renal failure, chronic kidney disease, hemodialysis, peritoneal dialysis, renal transplantation) [ 29 , 30 , 31 , 32 , 34 , 35 , 63 , 64 , 65 ].…”

“…Little data about the role of phosphorylation–dephosphorylation in ccRcc in the literature could be found. Kinase- and phosphotransferase-mediated phosphorylation was investigated in some studies by detecting thymidine kinase 1 (TK) and tumor N2 pyruvate kinase (TuM2-PK) activity [ 61 , 62 , 63 ]. TK was considered an enzyme involved in nucleic acids synthesis and an important proliferation marker in tumoral cells [ 64 , 65 ].…”

“…TK-1 was found mostly in serum and it was used in the detection of aggressive tumors and for monitoring the evolution and therapeutic response in patients with solid cancer. Its variation after repeated assessments was considered to show the remission or the relapse of the tumor [ 56 , 61 , 62 , 63 ]. Many tumoral cells are characterized by pyruvate-kinase overproduction [ 66 , 67 , 68 , 69 , 70 ].…”

Thymidine kinase 1 through the ages: a comprehensive review

“…Sera from patients with metastatic breast cancer were measured for total TK activity using the DiviTum assay at baseline (n = 142), 1 month (n = 134), 3 months (n = 122), and 6 months (n = 104) [ 115 ]. Overall, median serum TK activity (sTK) levels were reduced with systemic treatment.…”