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

被引：10

作者：

Yoshino, Takayuki ^{[1
]}

Yamazaki, Kentaro ^{[2
]}

Shinozaki, Eiji ^{[3
]}

Komatsu, Yoshito ^{[4
]}

Nishina, Tomohiro ^{[5
]}

Baba, Hideo ^{[6
]}

Tsuji, Akihito ^{[7
,8
]}

Tsuji, Yasushi ^{[9
]}

Yamaguchi, Kensei ^{[10
]}

Sugimoto, Naotoshi ^{[11
]}

Denda, Tadamichi ^{[12
]}

Muro, Kei ^{[13
]}

Takayama, Tetsuji ^{[14
]}

Esaki, Taito ^{[15
]}

Hamamoto, Yasuo ^{[16
,17
]}

Moriwaki, Toshikazu ^{[18
]}

Shimada, Yasuhiro ^{[19
]}

Goto, Masahiro ^{[20
]}

Nakayama, Norisuke ^{[21
]}

Fujii, Hirofumi ^{[22
]}

Tanase, Takanori ^{[23
]}

Ohtsu, Atsushi ^{[1
]}

机构：

[1] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, 6-5-1 Kashiwanoha, Kashiwa, Chiba 2778577, Japan

[2] Shizuoka Canc Ctr, Div Gastrointestinal Oncol, Shizuoka, Japan

[3] Japanese Fdn Canc Res, Dept Gastroenterol Canc, Inst Hosp, Tokyo, Japan

[4] Hokkaido Univ Hosp, Dept Canc Chemotherapy, Sapporo, Hokkaido, Japan

[5] Natl Hosp Org, Dept Gastrointestinal Med Oncol, Shikoku Canc Ctr, Matsuyama, Ehime, Japan

[6] Kumamoto Univ, Grad Sch Med Sci, Dept Gastroenterol Surg, Kumamoto, Japan

[7] Kochi Hlth Sci Ctr, Dept Clin Oncol, Kochi, Japan

[8] Kobe City Med Ctr Gen Hosp, Dept Clin Oncol, Kobe, Hyogo, Japan

[9] Tonan Hosp, Dept Med Oncol, Sapporo, Hokkaido, Japan

[10] Saitama Canc Ctr, Dept Gastroenterol, Ina, Saitama, Japan

[11] Osaka Int Canc Inst, Dept Med Oncol, Osaka, Japan

[12] Chiba Canc Ctr, Div Gastroenterol, Chiba, Japan

[13] Aichi Canc Ctr Hosp, Dept Clin Oncol, Nagoya, Aichi, Japan

[14] Univ Tokushima, Dept Gastroenterol & Oncol, Tokushima, Japan

[15] Natl Hosp Org, Dept Gastrointestinal & Med Oncol, Kyushu Canc Ctr, Fukuoka, Japan

[16] Tochigi Canc Ctr, Dept Chemotherapy, Utsunomiya, Tochigi, Japan

[17] Keio Univ, Dept Internal Med, Sch Med, Tokyo, Japan

[18] Univ Tsukuba, Div Gastroenterol, Tsukuba, Ibaraki, Japan

[19] Natl Canc Ctr, Gastrointestinal Oncol Div, Tokyo, Japan

[20] Osaka Med Coll Hosp, Canc Chemotherapy Ctr, Osaka, Japan

[21] Kanagawa Canc Ctr, Dept Gastroenterol, Yokohama, Kanagawa, Japan

[22] Jichi Med Univ Hosp, Dept Clin Oncol, Shimotsuke, Tochigi, Japan

[23] Taiho Pharmaceut Co Ltd, Tokyo, Japan

来源：

CLINICAL COLORECTAL CANCER | 2018年 / 17卷 / 04期

关键词：

Biomarker; Disease control rate; Next-generation sequencing; Overall survival; Progression-free survival; PHASE-III TRIAL; ANTITUMOR-ACTIVITY; DOUBLE-BLIND; COMBINATION ANTIMETABOLITE; THYMIDYLATE SYNTHASE; TAS-102; MONOTHERAPY; 1ST-LINE THERAPY; OXALIPLATIN; PLACEBO; CHEMOTHERAPY;

D O I：

10.1016/j.clcc.2018.07.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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, D antitumor activity is likely to increase in patients with high tumoral TM activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relaionship 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. (C) 2018 The Authors. Published by Elsevier Inc.

引用

页码：E719 / E732

页数：14

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