Prognostic role of thymidine kinase 1 activity in hormone receptor positive metastatic breast cancer. A systematic review and meta-analysis.

INTRODUCTION

Circulating thymidine kinase 1 activity (TKa) is a potential prognostic biomarker in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC); however, results are heterogeneous. In this study we aimed to summarize the current evidence on the prognostic role of circulating TKa in women with HR+ MBC.

METHODS

We conducted a systematic review of PubMed, Embase, and Cochrane CENTRAL databases and abstracts from main international oncology meetings. Phase II-IV clinical trials and prospective observational studies in patients with MBC assessing circulating TK1 levels or TKa and reporting hazard ratios (HRs) for progression-free survival (PFS) and/or overall survival (OS) were included. HRs were pooled using random-effects models (restricted maximum likelihood with Hartung-Knapp adjustment), with heterogeneity quantified by I2 and prediction intervals. The primary study outcome was the association of baseline and on-treatment TKa with PFS and OS. Secondary analyses aimed at exploring the source of heterogeneity.

RESULTS

Eighteen studies, reporting data from nearly 3000 women, were included in the systematic review and 15 studies were meta-analyzed. Patients with HR+ MBC and high baseline TKa showed a significantly higher risk of progression (PFS: HR 1.90; 95% CI 1.57-2.30; p < 0.001) and death (OS: HR 2.48; 95% CI 1.94-3.17; p < 0.001) than those with low TKa. TKa at 2 and 4 weeks on-treatment was also prognostic (2 weeks, PFS: HR 2.76; 95% CI 2.34-3.26; p < 0.001; 4 weeks, HR 2.26; 95% CI 1.93-2.66; p < 0.001). Similar pooled effects were obtained when accounting for different cut-offs, TKa assessment, and sample-type.

CONCLUSION

Pre-treatment high TKa is an adverse prognostic factor in women with HR+ MBC. High on-treatment TKa is also associated with worse outcome, potentially serving as an early signal of treatment resistance. We provide a comprehensive summary of the currently available evidence on the prognostic value of circulating TKa.