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?
Authors: Moukas Stefanos , Dohn Merle , Kimmig Rainer , Tewes Mitra , Kolberg Hans-Christian , Kasimir-Bauer Sabine , Keup Corinna 
Published: March 2023

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 &lt; six months) was significantly correlated with decreased progression free survival (PFS) in the CDK4/6i cohort (p-value &lt; 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 &lt; 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 &lt; 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.