Plasma thymidine kinase activity (TKa) as a novel prognostic biomarker in metastatic melanoma.
Authors: Helgadottir Hildur , Svedman Fernanda Costa , Jalsenius Marie , Hoiom Veronica , Rotstein Samuel , Brage Suzanne Egyhazi , Grozman Vitali , Söderdahl Fabian , Ny Lars , Bergqvist Mattias 
Published: June 2021

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Background: In the recent decade, new effective immunotherapies and targeted therapies have emerged for the treatment of disseminated melanoma. However, a considerable fraction of patients does not respond or get lasting effects and the treatments also have significant side effects. Biomarkers can contribute with more knowledge on prognosis and the efficacy of these therapies in different patients. In other cancer types, the plasma activity of the enzyme thymidine kinase (TKa), has been demonstrated as a marker of tumor stage and prognosis. The TK enzyme is part of a reaction chain to introduce thymidine into the DNA strand. TK thereby has a key function in DNA-synthesis, -repair and cell division. Dividing cells release TK during mitotic exit and TK can thus be detected in the blood. This study is the first to investigate plasma TKa as a potential biomarker in melanoma patients. Methods: Plasma samples were collected within five days prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with immunotherapy (anti-CTLA-4 and/or anti-PD-1) or targeted therapy (BRAF±MEK inhibitors). Plasma TKa levels were determined using the DiviTum TKa ELISA assay (Biovica, Sweden). TKa levels were correlated with the patients’ baseline criteria, response rate (RR), progression free survival (PFS) and overall survival (OS). Results: Among the 124 study patients, the median TKa was 50 Du/L (range < 20-3491 Du/L). Significantly higher plasma TKa levels were found in patients with ECOG performance status ≥1 vs. 0-1 ( P< 0.001), M1c-d vs. M1a-b disease ( P< 0.001), ≥3 vs. 1-2 affected organs ( P= 0.002) or elevated vs. non-elevated LDH ( P< 0.001). In the patients treated with immunotherapy (n = 86) the RR was 63.2% vs. 37.9% in those with low ( < 60 Du/L) vs. high TKa ( P= 0.024). The median PFS and OS was 19.9 and > 60 months in those with low TKa vs. 12.6 and 18.5 months in those with high TKa (HR for PFS: 1.73 (95% CI, 1.01-2.97), P= 0.044 and HR for OS: 2.16 (95% CI, 1.17-3.98), P= 0.011). In the patients treated with BRAF±MEK inhibitor (n = 38) a similar trend was observed, with shorter PFS and OS in those with high TKa, but the differences were not statistically significant. Conclusions: In this first study on plasma TKa in melanoma patients, high pretreatment TKa was significantly associated with poor baseline factors and poor response and survival in immunotherapy treated patients. Currently, plasma LDH is the only non-clinical factor that is routinely used as a prognostic marker in melanoma. Several other candidate markers have been described, such as PD-L1 tumor immunohistochemistry, tumor mutational burden, gut microbiome and circulating tumor DNA. Compared to these assays, TKa measured with DiviTum is a simpler, ELISA based test for a single plasma marker. TKa is hence a novel and interesting marker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease.