Relationship Between Thymidine Kinase 1 Expression and Trifluridine/Tipiracil Therapy in Refractory Metastatic Colorectal Cancer: A Pooled Analysis of 2 Randomized Clinical Trials.
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.
['Yoshino|Takayuki|T|', 'Yamazaki|Kentaro|K|', 'Shinozaki|Eiji|E|', 'Komatsu|Yoshito|Y|', 'Nishina|Tomohiro|T|', 'Baba|Hideo|H|', 'Tsuji|Akihito|A|', 'Tsuji|Yasushi|Y|', 'Yamaguchi|Kensei|K|', 'Sugimoto|Naotoshi|N|', 'Denda|Tadamichi|T|', 'Muro|Kei|K|', 'Takayama|Tetsuji|T|', 'Esaki|Taito|T|', 'Hamamoto|Yasuo|Y|', 'Moriwaki|Toshikazu|T|', 'Shimada|Yasuhiro|Y|', 'Goto|Masahiro|M|', 'Nakayama|Norisuke|N|', 'Fujii|Hirofumi|H|', 'Tanase|Takanori|T|', 'Ohtsu|Atsushi|A|']
D000368:Aged D000970:Antineoplastic Agents D015179:Colorectal Neoplasms D004338:Drug Combinations D019008:Drug Resistance, Neoplasm D005260:Female D005500:Follow-Up Studies D006801:Humans D008113:Liver Neoplasms D008297:Male D011379:Prognosis D011759:Pyrrolidines D016032:Randomized Controlled Trials as Topic D016879:Salvage Therapy D015996:Survival Rate D013937:Thymidine Kinase D013941:Thymine D014271:Trifluridine D014498:Uracil
Biomarker Overall survival Progression-free survival Disease control rate Next-generation sequencing