@article{6a5a8f1ac0104b328af8d2df41f63c74,
title = "Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial",
abstract = "Objective To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2x2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. Design The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. Results From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). Conclusion Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.",
keywords = "gastric cancer, chemotherapy, adjuvant treatment, COMPREHENSIVE MOLECULAR CHARACTERIZATION, CISPLATIN, CHEMOTHERAPY, 5-FLUOROURACIL, SENSITIVITY, DOCETAXEL, THERAPY, FAMILY, TUMORS, UFT",
author = "R. Sundar and N.B. Kumarakulasinghe and Y.H. Chan and K. Yoshida and T. Yoshikawa and Y. Miyagi and Y. Rino and M. Masuda and J. Guan and J. Sakamoto and S. Tanaka and A.L.K. Tan and M.M. Hoppe and A.D. Jeyasekharan and C.C.Y. Ng and {De Simone}, M. and H.I. Grabsch and J. Lee and T. Oshima and A. Tsuburaya and P. Tan",
note = "Funding Information: Competing interests RS: Advisory board: BMS, Merck, Eisai, Bayer, Taiho; honoraria for talks: MSD, Eli Lilly, BMS, Roche, Taiho; Travel funding: Roche, Astra Zeneca, Taiho, Eisai; Research funding: Paxman Coolers, MSD. These are outside the submitted work.TO: Research Funding: Taiho pharmaceutical, Chugai pharmaceutical, Ono pharmaceutical, Daiitisankyo pharmaceutical, Nippon Kayaku and Eli Lilly Japan K. K. Lecture fees: Nippon Kayaku, Ono pharmaceutical and Bristol-Myers Squibb K. K. Speaker Bureau: Taiho pharmaceutical, Chugai pharmaceutical, Ono pharmaceutical, Bristol-Myers Squibb K. K and Eli Lilly Japan K. K. These are outside the submitted work. TY: Lecture fees from: MSD, ONO, BMS, Taiho, Chugai, Daiichi-Sankyo, Lilly, Johnson & Johnson, Covidien and Olympus. Personal grant from Lilly. These are outside the submitted work. KY: Personal fees from Taiho Pharm and Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from Asahi Kasei Pharma, Chugai Pharm., Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, Johnson & Johnson, MerkSerono, MSD, Nippon Kayaku, Novartis, Ono Pharm., Otsuka Pharm., Sanofi, Tsumura, Yakult Honsha, Takeda Pharm., grants from Abbott, Abbvie, Astellas, Biogen Japan, Celgene, GlaxoSmithKline, KCI, Kyowa Kirin, Meiji Seika Pharma, Toray Medical, Koninklijke Philips, personal fees from AstraZeneka, Denka, EA Pharma, Olympus, Pfizer, Sanwa Kagaku Kenkyusho, SBI Pharma, Teijin Phamra, TERUMO. These are outside the submitted work. YR: Speaker Bureau from; Daiichi-Sankyo, Johnson & Johnson, Otsuka, Lilly, Taiho pharmaceutical, Bristol-Myers Squibb. Research Funding: Taiho pharmaceutical, Abbott, Asahi Kasei, Daiichi-Sankyo, Tsumura & Co., Covidien, Zeria pharmaceutical, Otsuka, EA Pharma, Johnson & Johnson. These are outside the submitted work. YM: Lecture fees from AstraZeneca, Taiho, Chugai, and Daiichi-Sankyo. Consigned research fund from Toso company, Japan. These are outside the submitted work. MM: Research Funding from Chugai pharmaceutical, Teijin pharmaceutical, Daiitisankyo pharmaceutical, Takeda pharmaceutical, Terumo, Japan Lifelin, Senkod. These are outside the submitted work. ST: Lecture fee: Bayer Yakuhin, Amgen Astellas BioPharma K.K. Consultation fee: Boehringer Ingelheim. These are outside the submitted work. ADJ: honoraria from AstraZeneca, Janssen and MSD, travel funding from Perkin Elmer, and research funding from Janssen. These are outside the submitted work. HG: honoraria for participation in an expert meeting from MSD. These are outside the submitted work. AL-KT: Lecture fees Chugai Pharmaceutical. These are outside the submitted work. PT: Travel: Illumina, Research funding: Thermo Fisher, Kyowa Hakko Kirin. These are outside the submitted work. Funding Information: Funding This work was supported by the Epidemiological & Clinical Research Information Network (ECRIN) and Kanagawa Standard Anti-Cancer Therapy Support System (KSATSS), which are non-profit organizations, JSPS KAKENHI Grant Numbers 842038 and 26461984, the Project Promoting Clinical Trials for Development of New Drugs (18lk0201061t0003 and 20lk0201061t0005) from the Japan Agency for Medical Research and Development (AMED), and a Grant-in-Aid for Scientific Research in Singapore. RS is supported by a National Medical Research Council (NMRC) Fellowship (NMRC/Fellowship/0059/2018), Singapore. PT is supported by Duke-NUS Medical School and the Genome Institute of Singapore, Agency for Science, Technology and Research. PT was also supported by the Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. This research was supported by the Singapore Ministry of Health{\textquoteright}s National Medical Research Council under its Open Fund-Large Collaborative Grant (“OF-LCG”) (MOH-OFLCG18May-0003). This work was also supported by National Medical Research Council grants NR13NMR111OM, and NMRC/STaR/0026/2015. Publisher Copyright: {\textcopyright} 2022 Authors",
year = "2022",
month = apr,
doi = "10.1136/gutjnl-2021-324060",
language = "English",
volume = "71",
pages = "676--685",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "4",
}