Authors: Raghav Sundar, Nesaretnam Barr Kumarakulasinghe, Yiong Huak Chan, Kazuhiro Yoshida, Takaki Yoshikawa, Yohei Miyagi, Yasushi Rino, Munetaka Masuda, Jia Guan, Junichi Sakamoto, Shiro Tanaka, Angie Lay-Keng Tan, Michal Marek Hoppe, Anand D. Jeyasekharan, Cedric Chuan Young Ng, Mark De Simone, Heike I. Grabsch, Jeeyun Lee, Takashi Oshima, Akira Tsuburaya, Patrick Tan
Published: 2021-05-12
DOI: 10.1136/gutjnl-2021-324060
Source: Full article
ObjectiveTo 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 2×2 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.DesignThe 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.ResultsFrom 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).ConclusionUsing machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.Trial registration numberUMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial)