Relationship Between Thymidine Kinase 1 Expression and Trifluridine/Tipiracil Therapy in Refractory Metastatic Colorectal Cancer: A Pooled Analysis of 2 Randomized Clinical Trials

Takayuki Yoshino, Kentaro Yamazaki, Eiji Shinozaki, Yoshito Komatsu, Tomohiro Nishina, Hideo Baba, Akihito Tsuji, Yasushi Tsuji, Kensei Yamaguchi, Naotoshi Sugimoto, Tadamichi Denda, Kei Muro, Tetsuji Takayama, Taito Esaki, Yasuo Hamamoto, Toshikazu Moriwaki, Yasuhiro Shimada, Masahiro Goto, Norisuke Nakayama, Hirofumi FujiiTakanori Tanase, Atsushi Ohtsu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

No predictive biomarker to indicate the clinical benefit of trifluridine/tipiracil (FTD/TPI) has been identified. Individual patient data from 329 patients from 2 randomized placebo-controlled trials were analyzed to determine the relationship between thymidine kinase 1 (TK1) expression and FTD/TPI efficacy in refractory metastatic colorectal cancer. Patients with high TK1 expression showed an improvement in overall survival when treated with FTD/TPI. Background: High thymidine kinase 1 (TK1) activity increases the incorporation of trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer. Patients and Methods: Individual patient data from 2 randomized placebo-controlled trials were analyzed. We measured TK1 protein expression in tumor tissue samples and its relationship with FTD/TPI clinical efficacy using overall survival (OS), progression-free survival, and disease control rate. Results: This study comprised 329 patients (FTD/TPI, 224; placebo, 105). FTD/TPI significantly improved OS versus placebo in the high-expression (cutoff ≥ 15%) TK1 group (median OS, 7.8 vs. 6.8 months; hazard ratio = 0.65; 95% confidence interval, 0.46-0.93; P =.018). The low-expression (cutoff < 15%) TK1 group experienced a smaller OS benefit (9.3 vs. 7.4 months; hazard ratio = 0.88; 95% confidence interval, 0.63-1.23; P =.45). For patients who received placebo, the high-expression TK1 group had a slightly worse prognosis than the low-expression TK1 group. The tendency of FTD/TPI efficacy concerning progression-free survival and disease control rate was not similar to that concerning OS between groups. Conclusion: Patients with high TK1 expression showed an improvement in OS when treated with FTD/TPI. Further investigations are warranted to confirm this relationship.

Original languageEnglish
Pages (from-to)e719-e732
JournalClinical Colorectal Cancer
Volume17
Issue number4
DOIs
Publication statusPublished - 2018 Dec

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Keywords

  • Biomarker
  • Disease control rate
  • Next-generation sequencing
  • Overall survival
  • Progression-free survival

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology

Cite this

Yoshino, T., Yamazaki, K., Shinozaki, E., Komatsu, Y., Nishina, T., Baba, H., Tsuji, A., Tsuji, Y., Yamaguchi, K., Sugimoto, N., Denda, T., Muro, K., Takayama, T., Esaki, T., Hamamoto, Y., Moriwaki, T., Shimada, Y., Goto, M., Nakayama, N., ... Ohtsu, A. (2018). Relationship Between Thymidine Kinase 1 Expression and Trifluridine/Tipiracil Therapy in Refractory Metastatic Colorectal Cancer: A Pooled Analysis of 2 Randomized Clinical Trials. Clinical Colorectal Cancer, 17(4), e719-e732. https://doi.org/10.1016/j.clcc.2018.07.009