Ziyu Li1, Yongning Jia1, Honglin Zhu2, Xiaofang Xing3, Fei Pang1, Fei Shan1, Shuangxi Li1, Danhua Wang2, Fangping Zhao2, Tonghui Ma2, Sizhen Wang2, Jiafu Ji4. 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China. 2. Genetron Health (Beijing) Technology, Co. Ltd, Beijing, 102206, China. 3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Center for Molecular Diagnostics, Peking University Cancer Hospital and Institute, Beijing, 100142, China. 4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China. jijiafu@hsc.pku.edu.cn.
Abstract
BACKGROUND: Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. METHODS: We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. RESULTS: High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). CONCLUSION: The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated with better DFS, and can be evaluated at the time of diagnosis.
BACKGROUND: Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. METHODS: We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. RESULTS: High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). CONCLUSION: The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated with better DFS, and can be evaluated at the time of diagnosis.
Authors: Mi Sun Kim; Joon Seok Lim; Woo Jin Hyung; Yong Chan Lee; Sun Young Rha; Ki Chang Keum; Woong Sub Koom Journal: World J Gastroenterol Date: 2015-03-07 Impact factor: 5.742
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Authors: David Cunningham; William H Allum; Sally P Stenning; Jeremy N Thompson; Cornelis J H Van de Velde; Marianne Nicolson; J Howard Scarffe; Fiona J Lofts; Stephen J Falk; Timothy J Iveson; David B Smith; Ruth E Langley; Monica Verma; Simon Weeden; Yu Jo Chua Journal: N Engl J Med Date: 2006-07-06 Impact factor: 91.245