Japanese Foundation for Cancer Research, Tokyo, Japan
Mitsukuni Suenaga , Tetsuo Mashima , Naomi Kawata , Shingo Dan , Takeru Wakatsuki , Eiji Shinozaki , Takashi Ichimura , Mariko Ogura , Daisuke Takahari , Hiroki Osumi , Yumiko Ota , Keisho Chin , Hiroyuki Seimiya , Kensei Yamaguchi , Toshiharu Yamaguchi
Background: Trifluridine (FTD) incorporation into DNA is the main anti-tumor mechanism of action of TAS-102. We performed preclinical analysis and translational validation study to identify the candidate cytokines for TAS-102 efficacy in metastatic colorectal cancer (mCRC) patients (pts). Methods: As a first preclinical process, we selected candidate cytokines according to our transcriptomic and cell biological analysis. We then validated predictive value of the cytokines in mCRC pts receiving TAS-102 (discovery) and regorafenib (control). Blood samples were obtained at baseline (BL), before second cycle (2nd) and progressive disease (PD), and cytokine levels were measured using ELISA. The change patterns were defined as ‘increased’ or ‘decreased’ from BL. Results: 93 pts were included in this study: 67 received TAS-102 and 26 received regorafenib. Preclinical cDNA microarray analysis with colon cancer cell lines demonstrated marked changes in the RNA expression of interleukin-8, VEGF-A and epiregulin (EREG) after FTD treatment. Particularly, in preclinical model, EREG secretion was highly measured after FTD treatment in FTD-sensitive cells, while not in FTD-resistant cells. In the discovery cohort, increased EREG levels at 2nd showed trend toward longer PFS and OS than decreased changes (2.6 vs 2.3 mos, P= 0.096; 10.8 vs 6.2 mos, P= 0.091). Meanwhile, decreased EREG levels at PD were marginally associated with longer PFS and significantly with longer OS than increased (4.0 vs 2.3 mos, P= 0.130; 9.8 vs. 6.2 mos, P= 0.016). Combined analysis of EREG changes showed that pts with either increased at 2nd or decreased at PD had significantly longer PFS and OS compared to those with both decreased at 2nd and increased at PD (3.0 vs 2.0 mos, HR: 0.47, 95%CI: 0.24-0.93, P= 0.031; 10.8 vs 5.3 mos, HR: 0.30, 95%CI: 0.14-0.61, P= 0.001). The findings were confirmed in the multivariate analysis for OS (HR: 0.311, 95%CI: 0.15-0.66, P= 0.002), and no significant differences were observed in the control cohort. Conclusions: Our preclinical data-based translational validation study suggests that serum EREG levels may predict clinical outcome in mCRC pts receiving TAS-102.
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Disclosures
2024 ASCO Gastrointestinal Cancers Symposium
First Author: Mitsukuni Suenaga
2023 ASCO Annual Meeting
First Author: Timothy Jay Price
2022 ASCO Gastrointestinal Cancers Symposium
First Author: Christopher Duane Nevala-Plagemann
2023 ASCO Gastrointestinal Cancers Symposium
First Author: Kynan Feeney