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%,...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.展开更多
文摘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.
