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. 2021 Apr;6(2):100076.
doi: 10.1016/j.esmoop.2021.100076. Epub 2021 Mar 10.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

A Matikas  1 , K Wang  2 , E Lagoudaki  3 , B Acs  4 , I Zerdes  2 , J Hartman  4 , E Azavedo  5 , J Bjöhle  6 , L Carlsson  7 , Z Einbeigi  8 , I Hedenfalk  9 , M Hellström  2 , T Lekberg  10 , N Loman  11 , A Saracco  12 , A von Wachenfeldt  13 , S Rotstein  6 , M Bergqvist  14 , J Bergh  10 , T Hatschek  10 , T Foukakis  10
Affiliations

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

A Matikas et al. ESMO Open. 2021 Apr.

Abstract

Background: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate.

Methods: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models.

Results: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04).

Conclusion: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Keywords: TK1 kinetics; breast cancer; longitudinal; neoadjuvant chemotherapy; prognosis; thymidine kinase 1.

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Conflict of interest statement

Disclosure JH was former member of the advisory board at Visiopharm A/S, has obtained speaker's honoraria or advisory board remunerations from Roche, Novartis, AstraZeneca, Eli Lilly, Pfizer and Merck Sharp & Dohme, is co-founder and shareholder of Stratipath AB and has received institutional research grants from Cepheid and Novartis. MB is employee of Biovica International and holds stock/stock options in the company; SR holds stock/stock options in Biovica International; JB reports that his institution (Karolinska Institutet and/or Karolinska University Hospital) has received research grants from AstraZeneca, Amgen, Bayer, Roche, Merck, Pfizer and Sanofi-Aventis. No personal payments. Payment from UpToDate for two chapters in breast cancer prediction paid to Asklepios Medicine HB; TH: institutional grants from Roche Sweden and Pfizer Sweden, personal fees from Roche, Pfizer and Novartis; TF: institutional grants from Roche and Pfizer and personal fees from Novartis, Pfizer, Roche and UpToDate. All other authors have declared no conflicts of interest. Data sharing Gene expression data are available at the Gene Expression Omnibus (GEO) database under accession number GSE87455. Further data that support the findings of this study are available from the corresponding author upon reasonable request.

Figures

Figure 1
Figure 1
Gene set enrichment analysis of baseline tumor gene expression associated with serum TK1 and tumor Ki67, respectively. FDR, false discovery rate; GEX, gene expression; NES, normalized enrichment score; TK1, thymidine kinase 1.
Figure 2
Figure 2
(A) Boxplot of TK1 over time and (B) mean and 95% confidence interval of log10-transformed TK1 at each timepoint. TK1, thymidine kinase 1.
See this image and copyright information in PMC

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