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. 2025 Mar 25;15(1):10347.
doi: 10.1038/s41598-025-95114-7.

Thymidine kinase 1 concentration and activity in metastatic breast cancer under CDK4/6 inhibitor therapy

Stefanos Ioannis Moukas  1 , Merle Dohn  2 , Catrin Lehnerdt  3 , Anja Welt  3 , Hans-Christian Kolberg  4 , Oliver Hoffmann  2 , Rainer Kimmig  2 , Sabine Kasimir-Bauer  2 , Corinna Keup  2
Affiliations

Thymidine kinase 1 concentration and activity in metastatic breast cancer under CDK4/6 inhibitor therapy

Stefanos Ioannis Moukas et al. Sci Rep. .

Abstract

We investigated whether TK1 concentration or activity in the blood, drawn at baseline and under therapy, might have value for therapy management in 110 hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (mBC) patients treated with CDK4/6 inhibitors (CDK4/6i) and/or endocrine therapy (ET). TK1 concentration and activity were not significantly correlated with each other in matched samples. In the CDK4/6i cohort at baseline, high TK1 concentration and activity were significantly associated with a decreased PFS and primary resistance. Longitudinal sampling revealed a higher variability of TK1 concentration under therapy compared to TK1 activity that was reduced during therapy. Elevated TK1 activity after six months of CDK4/6i and an increase in TK1 concentration from baseline to six months under CDK4/6i significantly correlated with a decreased PFS. These results indicate a possible value of TK1 concentration and activity before and during CDK4/6i for HR+/HER2- mBC patients to guide treatment that warrants further investigation.

Keywords: Breast cancer; Longitudinal studies; Neoplasm metastasis; Palbociclib; Precision medicine; Prognosis; Progression-free survival; Ribociclib; Thymidine kinase 1.

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Conflict of interest statement

Declarations. Competing interests: S.M. received honoraria for lectures from MSD, and Roche and support for travel from Johnson&Johnson, Intuitive Surgical and Distalmotion. A.W. received support for travel and honoraria for lectures from Roche, Eisai, Novartis, Pfizer, Lilly, Iomedica, Interplan, MSD, MCI, RCC and Menarini Stemline. A.W. participated on a Data Safety Monitoring Board of Iomedico and partipated in Advisory Boards of MSD, Roche, Novartis, Pfizer, Seagen, Lilly, Menarini Stemline and P. Fabre. A.W. participated the steering committee of the Breast Cancer and Gynecological Cancer Track of the AIO (Arbeitsgemeinschaft Internistische Onkologie) of the DKG (Deutsche Krebsgesellschaft) and was a member in the Consensus Conference Update S3-Guideline Breast Cancer of the DKG (Deutsche Krebsgesellschaft). H.-C.K. declares financial and non-financial support from Pfizer, Seagen, Novartis, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, TEVA, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lilly, SurgVision, Onkowissen, Gilead, Daiichi Sankyo, Stemline, Tesaro and MSD and owns stock of Theraclion SA. O.H. declares financial support from Eli Lilly, Roche, AstraZeneca, Amgen, Pfizer, Eisai, Gilead, Hexal, MSD, Novartis, Seagen und Daiichi Sankyo and Alpinion. O.H. is auditor for OnkoZert on behalf of the DKG (Deutsche Krebsgesellschaft). R.K. declares financial and non-financial support from Intuitive Surgical, Medtronic, Avatera, CMR Surgical, Active Surgical, Cava Robotics, Novocure, Medicaroid, GSK, MSD, Astra-Zeneca. S.K.-B. is a consultant for QIAGEN and was the PI for two independent research grants sponsored by Pfizer Pharma GmbH. C.K. received support for travel expenses from QIAGEN and was involved in the conduction of two independent research grants sponsored by Pfizer Pharma GmbH. All other authors declare no financial or non-financial competing interests.

Figures

Fig. 1
Fig. 1
TK1 concentration versus TK1 activity. Matched samples (n = 253) of the entire HR+/HER2- mBC cohort are visualized with TK1 activity [U/L] in a log10 scale. Spearman test showed no significant correlation between concentration and activity (r = 0.06302, p = 0.318).
Fig. 2
Fig. 2
TK1 concentration and activity at baseline in relation to PFS or response in the CDK4/6i treated patients. High TK1 concentration at baseline (Cut-off: 17.53ng/mL) significantly correlated with PFS in the CDK4/6i cohort in the log-rank analysis (A) and uni-, as well as multivariate Cox regression (B) and was also significantly more prevalent in Non-Responders (C, fisher exact, two-sided). Similarly, high TK1 activity at baseline (Cut-off: 11.05U/L) significantly correlated with PFS in the CDK4/6i cohort in the log-rank analysis (D) and uni-, as well as multivariate Cox regression (E) and was also significantly more prevalent in Non-Responders (F, fisher exact, two-sided).
Fig. 3
Fig. 3
TK1 concentration (A + B) and activity (C + D) under therapy in the entire cohort. Boxes range from the first to the third quartile, the line within the boxes represents the median, the whiskers represent 1.5x of the interquartile range (IQR), the single dots represent samples exceeding the 1.5x IQR (Tukey format). Significant increase in TK1 concentration from baseline to the progressive disease time point and from six months after therapy start to three months before the progressive disease time point, but a significant decrease from three months before the progressive disease time point in the entire cohort (unmatched samples, Mann-Whitney U test, A). Scatterplot of the absolute difference in TK1 concentration from baseline to six months after therapy start (matched samples n = 42, B) shows an equal distribution of increased and decreased values. Significant increase in TK1 activity from baseline to six months after therapy start and from three months before the progressive disease to the time point of progressive disease (unmatched samples, Mann-Whitney U test, C). Scatterplot of the absolute difference in TK1 activity from baseline to six months after therapy start (matched samples n = 69, D) shows the majority of patients with decreased values.
Fig. 4
Fig. 4
TK1 activity after six months under therapy (A + B) and concentration dynamics from baseline to six months under therapy (C + D) significantly correlated with PFS in the CDK4/6i cohort.
Fig. 5
Fig. 5
TK1 concentration and activity at different time points in the CDK4/6i cohort with relation to OS. Baseline TK1 activity significantly correlated with OS in the CDK4/6i cohort (A). TK1 concentration after six months of CDK4/6i was related to OS (B). Increase in TK1 concentration from baseline to six months after therapy start significantly correlated with a decreased OS in the CDK4/6i cohort (C). TK1 activity at the progressive time point significantly correlated with OS in the CDK4/6i cohort (D).
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