Pingzhou Yang1, Milind Javle2, Fei Pang3, Wei Zhao4, Reham Abdel-Wahab2,5, Xiaofeng Chen6, Funda Meric-Bernstam7, Huanwei Chen8, Mitesh J Borad9, Yu Liu10, Chuntao Zou3, Shuo Mu3, Yutong Xing3, Kai Wang3, Chuang Peng1, Xu Che11. 1. Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China. 2. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. OrigiMed Inc., Shanghai 201114, China. 4. Department of Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266024, China. 5. Department of Clinical Oncology, Assiut University Hospitals, Assiut, Egypt. 6. Department of Oncology, The Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China. 7. Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 8. Department of Liver surgery, First People's Hospital of Foshan, Foshan 528314, China. 9. Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA. 10. Department of Pathology, People's Hospital of Hunan Province, Changsha 410005, China. 11. National Cancer Center/National Clinical Research Center for Cancer/Department of Pancreatic and Gastric Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College/National Cancer Center/National Clinical Research Center for Cancer/Department of Hepatobiliary and Pancreatic Surgery, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
Abstract
BACKGROUND: Gallbladder cancer (GBC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%, and the median survival time is less than a year with standard gemcitabine-based chemotherapy. Survival benefit with second-line treatment is unknown. Thus, there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing (NGS) may be of value. METHODS: Comprehensive genomic profiling (CGP) was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients. Clinical data were collected using an IRB approved protocol from a single-center in US and from China. RESULTS: In Chinese and US GBC cohorts, an average of 6.4 vs. 3.8 genomic alterations (GAs) were identified per patient. The most frequent alterations were TP53 (69.4%), CDKN2A/B (26%), ERBB2 (18.5%), PIK3CA (17%) and CCNE1 (13%) in Chinese cohort, TP53 (57.9%), CDKN2A/B (25%), SMAD4 (17%), ARID1A (14%), PIK3CA (14%) and ERBB2 (13.1%) in US patients. NFE2L2 mutations were present in 6.5% of Chinese patients and not observed in the US cohort. Interestingly, ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases. Out of the top 9 dysregulated genetic pathways in cancer, Chinese patients harbored more frequent mutations in ERBB genes (30.6% vs. 19.0%, P=0.04). High frequency of PI3K/mTOR pathway variations was observed in both Chinese (37%) and US cohort (33%) (P=0.5). Additionally, both Chinese and US GBC patients exhibited a relatively high tumor mutational burden (TMB) (17.6% and 17.0%, respectively). In the Chinese cohort, a significant association was seen between direct repair gene alterations and TMB ≥10 muts/Mb (P=0.004). CONCLUSIONS: In our study, over 83% Chinese and 68% US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options. The identification of high TMB, ERBB2, CDKN2A/B, PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors. 2019 Hepatobiliary Surgery and Nutrition. All rights reserved.
BACKGROUND: Gallbladder cancer (GBC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%, and the median survival time is less than a year with standard gemcitabine-based chemotherapy. Survival benefit with second-line treatment is unknown. Thus, there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing (NGS) may be of value. METHODS: Comprehensive genomic profiling (CGP) was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients. Clinical data were collected using an IRB approved protocol from a single-center in US and from China. RESULTS: In Chinese and US GBC cohorts, an average of 6.4 vs. 3.8 genomic alterations (GAs) were identified per patient. The most frequent alterations were TP53 (69.4%), CDKN2A/B (26%), ERBB2 (18.5%), PIK3CA (17%) and CCNE1 (13%) in Chinese cohort, TP53 (57.9%), CDKN2A/B (25%), SMAD4 (17%), ARID1A (14%), PIK3CA (14%) and ERBB2 (13.1%) in US patients. NFE2L2 mutations were present in 6.5% of Chinese patients and not observed in the US cohort. Interestingly, ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases. Out of the top 9 dysregulated genetic pathways in cancer, Chinese patients harbored more frequent mutations in ERBB genes (30.6% vs. 19.0%, P=0.04). High frequency of PI3K/mTOR pathway variations was observed in both Chinese (37%) and US cohort (33%) (P=0.5). Additionally, both Chinese and US GBC patients exhibited a relatively high tumor mutational burden (TMB) (17.6% and 17.0%, respectively). In the Chinese cohort, a significant association was seen between direct repair gene alterations and TMB ≥10 muts/Mb (P=0.004). CONCLUSIONS: In our study, over 83% Chinese and 68% US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options. The identification of high TMB, ERBB2, CDKN2A/B, PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors. 2019 Hepatobiliary Surgery and Nutrition. All rights reserved.
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