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

Matikas, Alexios; Wang, K.; Lagoudaki, Eleni; Ács, Balázs; Zerdes, Ioannis; Hartman, Johan; Azavedo, Edward; Bjöhle, Judith; Carlsson, Lena; Einbeigi, Zakaria; Hedenfalk, Ingrid; Hellström, Mats; Lekberg, Tobias; Loman, Niklas; Saracco, Ariel; Wachenfeldt, Anna von; Rotstein, Samuel; Bergqvist, Mattias; Bergh, Jonas; Hatschek, Thomas; Foukakis, Theodoros

doi:10.1016/j.esmoop.2021.100076

Cited by 6 publications

(7 citation statements)

References 48 publications

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“…Furthermore, we observed an increase in sTK1 even after short exposure to neoadjuvant treatment, similar to our previous findings on HER2-negative breast cancer treated with chemotherapy [ 11 ], and in contrast with available data on neoadjuvant endocrine-treated disease [ 10 ]. This could be due to following explanations: (1) Effective targeted treatment induces cancer cell death, cytosolic TK1 is then released into the bloodstream; (2) Effective chemotherapy inhibits de novo dTMP synthesis pathway, and salvage pathway is effectively activated, leading to more TK1 uptake, thus more exocytosis/exosome TK1 is detected in the blood[ 18 ].…”

Section: Discussionsupporting

confidence: 92%

“…The study employed the ELISA-based DiviTum® TKa assay (Biovica, Sweden) to determine the enzymatic activity of sTK1 in serum samples. The assay was performed on two aliquots of approximately 1 mL serum for each timepoint, following the manufacturer's instructions and as previously described [ 11 ]. Briefly, the serum samples were mixed with a reaction buffer and incubated with a 96-well microtiter plate.…”

Section: Methodsmentioning

confidence: 99%

“…A recent study demonstrated the utility of serum TK1 activity for monitoring responses to neoadjuvant CDK4/6i in early HR + BC patients[ 10 ]. In addition, we have previously shown that serial measurement of serum TK1 activity during neoadjuvant chemotherapy (NACT) might provide long-term prognostic information[ 11 ]. However, there is currently limited data regarding the utility of TK1 as a predictive or prognostic marker in HER2-positive BC.…”

Section: Introductionmentioning

confidence: 99%

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The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial

Zhu,

Zerdes,

Matikas

et al. 2024

Breast Cancer Res Treat

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Background Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown. Methods In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated. Results No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis. Conclusion sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation. Trial registration ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial

Zhu,

Zerdes,

Matikas

et al. 2024

Breast Cancer Res Treat

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“…In the same patients of the PROMIX trial, the TK1 activity was measured (40). The mean TK1 activity was reported to increase from about 30 units at baseline to about 200 units 48 h following cycle 1.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-receptor-positive Breast Cancer

Tribukait¹

2021

Preprint

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Complete pathologic response (pCR) predicts the long-term outcome of neoadjuvant treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers able to guide adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether shifts in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1-4 and in a total of 131 patients before and 48h after cycle 1. The prognostic significance of the results was evaluated by log-rank tests of Kaplan–Meier estimates. Treatment resulted in a 2-fold increase of sTK1 before and 3-fold increase 48h after the cycles, except for the first cycle, where half of patients reacted with a decrease (post/pre sTK1- ratio <1.12) and the other half reacted with an increase (ratio >1.12). OS rates in ER+ patients with ratios of >1.12 and <1.12 were 97.7% and 78% (p=0.005), respectively, and DFS rates were 90.7% and 68% (p=0.006), respectively. Thus, response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.

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“…In the same patients of the PROMIX trial, TK1 activity was also measured [ 38 ]. The mean TK1 activity was reported to increase from about 30 units at baseline to about 200 units 48 h following cycle 1.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-Receptor-Positive Breast Cancer

Tribukait

2021

Cancers

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Pathologic complete response (pCR) predicts the long-term outcome of neoadjuvantly treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers enabling adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether changes in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1–4 and in an additional 77 patients before and 48 h after treatment 1. Treatment resulted in a 2-fold increase of sTK1 before and a 3-fold increase 48 h after the cycles, except for the first cycle, where half of the patients reacted with a significant decrease and the other half with an increase of sTK1. In Kaplan–Meier estimates of ER+ patients divided by the median of the post/pre-treatment sTK1 ratio at the first treatment cycle, OS was 97.7% and 78% (p = 0.005), and DFS was 90.7% and 68% (p = 0.006), respectively. Thus, the response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for the guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.

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

Cited by 6 publications

References 48 publications

The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial

The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial

Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-receptor-positive Breast Cancer

Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-Receptor-Positive Breast Cancer

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