TY - JOUR
T1 - Relationship Between Thymidine Kinase 1 Expression and Trifluridine/Tipiracil Therapy in Refractory Metastatic Colorectal Cancer
T2 - A Pooled Analysis of 2 Randomized Clinical Trials
AU - Yoshino, Takayuki
AU - Yamazaki, Kentaro
AU - Shinozaki, Eiji
AU - Komatsu, Yoshito
AU - Nishina, Tomohiro
AU - Baba, Hideo
AU - Tsuji, Akihito
AU - Tsuji, Yasushi
AU - Yamaguchi, Kensei
AU - Sugimoto, Naotoshi
AU - Denda, Tadamichi
AU - Muro, Kei
AU - Takayama, Tetsuji
AU - Esaki, Taito
AU - Hamamoto, Yasuo
AU - Moriwaki, Toshikazu
AU - Shimada, Yasuhiro
AU - Goto, Masahiro
AU - Nakayama, Norisuke
AU - Fujii, Hirofumi
AU - Tanase, Takanori
AU - Ohtsu, Atsushi
N1 - Funding Information:
This investigation was supported by Taiho Pharmaceutical, Tokyo, Japan. The authors wish to thank the participating patients and their families; all the investigators, site staff, and operations staff who participated in the study; Toshihiko Doi, MD, at the National Cancer Hospital East, Japan, for his contribution to the development of the studies; Katsuya Tsuchihara, MD, at the National Cancer Hospital East, Japan, for his contribution to data interpretation; Chikuma Hamada, professor, at the Tokyo University of Science, Japan, for his contribution to the statistical analysis; and Hikari Chiba, Helen Roberton, and Sarah Williams of Edanz Medical Writing for providing medical writing services, which were supported by Taiho Pharmaceutical.
Publisher Copyright:
© 2018 The Authors
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - Biomarker
KW - Disease control rate
KW - Next-generation sequencing
KW - Overall survival
KW - Progression-free survival
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U2 - 10.1016/j.clcc.2018.07.009
DO - 10.1016/j.clcc.2018.07.009
M3 - Article
C2 - 30172759
AN - SCOPUS:85054139925
SN - 1533-0028
VL - 17
SP - e719-e732
JO - Clinical Colorectal Cancer
JF - Clinical Colorectal Cancer
IS - 4
ER -
