The characterization of ERBB family mutations in Chinese biliary tract cancers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15595-e15595
Author(s):  
Tianqiang Song ◽  
Wei Zhang ◽  
Huikai Li ◽  
Ping Chen ◽  
Xiaoqian Chen ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Biliary Tract ◽  
Copy Number Variations ◽  
High Rate ◽  
Chinese Patients ◽  
Common Mutation ◽  
Biliary Tract Cancers ◽  
Erbb Family ◽  
Erbb2 Gene ◽  
Major Mutation

e15595 Background: Next generation sequencing has been applied to identify actionable mutations in biliary tract cancers (BTCs). ERBB family genes, especially ERBB2 and ERBB3, serve as effective biomarkers for BTCs targeted therapy as shown in MyPathway and SUMMIT clinical trials. However, the distribution and major mutation types of ERBB family genes were not clear in Chinese BTC patients. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples collected from a cohort of 716 Chinese BTC patients. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, gene rearrangements and fusions were analyzed. Results: A total of 14% (101/716) of patients with a median age of 62 years old, including 45 males and 56 females, were identified harboring ERBB family mutations. Somatic ERBB family mutations occurred with a rate of 29% in gallbladder carcinoma (GBCA), 13% in extrahepatic cholangiocarcinoma (EHCCA), 12% in hilar cholangiocarcinoma (HCCA) and 8% in intrahepatic cholangiocarcinoma (IHCCA). No germline mutation was detected. A high rate of ERBB2 gene amplification was observed in GBCA (17%). In IHCCA and EHCCA, SNV/Indel accounted for 3% and 5%, respectively, and was the major variation in ERBB2. In HCCA, SNV/Indel was the most common mutation in ERBB3 (8%). In BTC patients, TP53 (81%) and CDK12 (36%) were the top-ranked co-mutant genes with ERBB2. The mutant frequency of CDK12 was significantly different between patients with or without an ERBB2 mutation ( p< 0.001). ERBB2 S310F/Y, ERBB3 V104L/M were hotspot mutations within the ERBB family in BTCs. Conclusions: ERBB family mutations were detected in 14% of Chinese BTC patients. Similar to Western populations (PMID: 27622582), ERBB2 gene amplification was the most common mutation in GBCA in Chinese patients. Unlike ERBB2/ ERBB3 amplification which has been reported as the major mutation in previous studies, our study of other BTC types revealed ERBB2/ ERBB3 SNV/Indel as the major mutation. BTC patients harboring ERBB family mutations have the potential to benefit from pan-HER inhibitors.

The landscape of MET mutations in Chinese biliary tract cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16652-e16652
Author(s):  
Shifeng Xu ◽  
Wei Rao ◽  
Yuanwen Zheng ◽  
Jianping Wang ◽  
Weiyu Hu ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Biliary Tract ◽  
Clinical Laboratory ◽  
Performance Status ◽  
Treatment Options ◽  
Copy Number Variations ◽  
Chinese Patients ◽  
Gene Rearrangements ◽  
Extrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancers

e16652 Background: Biliary tract cancers (BTCs) are malignancies with poor prognosis and limited treatment options. MET is recurrently altered in various cancers that confer susceptibility to targeted MET inhibitors. It has been reported that the MET mutation frequency is 2-7% in intrahepatic cholangiocarcinoma (ICC) and 3.7% in extrahepatic cholangiocarcinoma (ECC) in Western countries. However, the characterization of MET in Chinese BTCs are not clear. Methods: Next-generation sequencing (NGS) targeting 450 cancer genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples that collected from a cohort of 926 Chinese BTC patients. Genomic alterations, including single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, and gene rearrangements/fusions, were analyzed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: MET mutations were detected in 4.1% of patients with BTCs, including 5.3% in ICC, 3.4% in hilar cholangiocarcinoma (HCCA), 3.0% in ECC, and 2.6% in gallbladder cancer (GBCA). Gene amplification was the most common type of MET mutation in BTC (2.6%) compared with gene rearrangements/fusions (1.1%) and SNV (0.9%). Novel MET fusion partners, including TNS3 and TRIM4, and MET exon 14 skipping mutation, were also detected. There was no difference in tumor mutational burden (TMB) between patients with and without MET mutation (average TMB: 6.5 vs. 5.6 muts/Mb, P= 0.213). Among these BTC patients, an advanced ICC patient (performance status [PS] 3) who harbored MET gene amplification, received crizotinib as the first-line treatment. Four months later, the patient had a complete response without obvious side effects. Conclusions: To our knowledge, this is the largest BTCs cohort and the first report of MET mutation profiling in the Chinese patients. MET mutations were detected in 4.5% BTCs, and MET inhibitors may be potential treatment options for BTC patients. All types of MET mutations, including gene amplification, SNVs, and gene fusions, were detected in BTCs, which demonstrated that NGS might be a powerful tool to detect MET mutations. Altogether, MET is a promising target in BTCs, and detection of MET mutations is important and essential for predicting the sensitivity of targeted therapy. Clinical trial information: NCT03892577 .

BRAF mutation in Chinese biliary tract cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16678-e16678
Author(s):  
Wendong Li ◽  
Yanzhi Cui ◽  
Fei Yin ◽  
Li Peng ◽  
Xiaogang Liu ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Clinical Laboratory ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Copy Number Variations ◽  
Braf V600e ◽  
Chinese Patients ◽  
Cancer Genes ◽  
Single Nucleotide Variants ◽  
Braf Mutations

e16678 Background: Biliary tract cancers (BTCs) are a group of relatively rare invasive carcinomas including gallbladder carcinoma (GBC), intrahepatic (ICC), hilar (HCCA), and extrahepatic (ECC) cholangiocarcinoma. In the ROAR basket trial, dabrafenib, a BRAF inhibitor, combined with trametinib, a MEK inhibitor, demonstrated promising efficacy in patients with BTCs with an overall response rate (ORR) of 41% and a favorable safety profile. The frequency of BRAF mutations reported in BTC varies widely, and BRAF V600E mutations have been reported in 0% to 20% of BTCs. However, the frequencies of BRAF mutations in Chinese BTCs are not clear. Methods: A total of 926 BTC patients (203 ECC, 195 GBC, 59 HCCA, and 469 ICC) were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from these patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations including single nucleotide variants, insertions and deletions, copy number variations, and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: BRAF activating mutations were detected in 5.5% of Chinese BTC patients. There were 5.1% in ICC cases, 8.9% in ECC cases, 5.1% in HCCA cases, and 3.1% in GBC cases. BRAF V600E, the most common hotspot mutation, was detected in ICC and GBC with frequencies of 1.5% and 0.5%, respectively. No BRAF V600E was detected in ECC or HCCA. The top-ranked co-mutation genes with BRAF were TP53 (54%), ARID1A (40%), and SMAD4 (32%). Compared with BRAF wild-type cohort, the frequencies of ARID1A and SMAD4 mutations were significantly higher in patients with BRAF mutations cohort (40% vs 17%, P< 0.001; 32% vs 14%, P< 0.001), while KRAS mutations were mutually exclusive with BRAF mutations. Conclusions: To our knowledge, this is the largest BTCs cohort used to study the characterization of BRAF mutations in the Chinese patients. BRAF mutations occurred in 5.5% of patients, and BRAF V600E in 0.9%. These patients could benefit from treatment with a BRAF inhibitor combined with a MEK inhibitor. Analysis of BRAF V600E should be considered in patients with BTCs, especially in ICC and GBC. Clinical trial information: NCT03892577 .

The characterization of IDH1 mutations in Chinese biliary tract cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16674-e16674
Author(s):  
Kui Wang ◽  
Feng Xie ◽  
Mingtai Hu ◽  
Yuting Zheng ◽  
Zhengang Yuan ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Biliary Tract ◽  
Tricarboxylic Acid Cycle ◽  
Copy Number Variations ◽  
Idh1 Mutation ◽  
Common Type ◽  
Wild Type ◽  
Biliary Tract Cancers ◽  
Idh1 Mutations

e16674 Background: Next-generation sequencing (NGS) has been used to identify actionable mutations in biliary tract cancers (BTCs). IDH1 is an enzyme that catalyzes the conversion of isocitrate to alpha-ketoglutarate, and is involved in the tricarboxylic acid cycle. Mutations in IDH1 are associated with aberrant conversion of alpha- ketoglutarate to 2-hydroxyglutarate, which is an oncogenic metabolite. In addition, IDH1 showed an effective biomarker for cholangiocarcinoma targeted therapy in the ClarIDHy study. Therefore, the detection of IDH1 mutations is essential for predicting sensitivity to targeted therapy. Methods: Deep sequencing targeting 450 cancer genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples that collected from a cohort of 926 Chinese BTC patients, including 469 intrahepatic (ICC), 203 extrahepatic (ECC), 195 gallbladder cancers (GC), and 59 hilar (HCCA) cholangiocarcinoma. Single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, gene rearrangements, and fusions, were analyzed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: IDH1 mutations were detected in 3.9% patients, with a median age of 59 years old. The rate of IDH1 mutations was 7% in ICC, 1% in ECC, 0.5% in GC, and 0% in HCCA. IDH1 R132C (75.8%) substitution was the most common type of IDH1 mutation in ICC. In BTC patients, ARID1A (25%), TP53 (22%), and PBRM1 (22%) were the top-ranked co-mutation genes with IDH1. Compared with the IDH1 wild-type cohort, the frequencies of KRAS and TP53 mutations were significantly lower in the IDH1 mutated cohort (29.3% vs. 2.8%, p = 0.001; 56.6% vs. 22.2%, p < 0.001). In addition, IDH1 mutations were associated with a significantly lower TMB value compared to the wild-type cases (average TMB: 3.2 vs. 5.8 muts/Mb, p < 0.001). Conclusions: To date, this was the largest cohort used to study the characterization of IDH1 mutations in Chinese BTCs. The mutation frequency of IDH1 was lower in Chinese ICCs compared with non-Asian populations (7.0% vs. 16.5%). Consistent with the results from previous reports, IDH1 R132C substitution was the most common type of IDH1 mutation in ICCs (PMID: 31392056). TMB value and the frequency of TP53 and KRAS mutations were lower in patients with IDH1 mutation, which may provide clues for sensitivity to targeted therapy and prognosis.

Clinical utility of comprehensive genomic profiling and targeted therapy in biliary tract cancers: A real-world experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16671-e16671
Author(s):  
Mahum Shahid ◽  
Mohamed A. Abdallah ◽  
Moataz Ellithi ◽  
Hafez Mohammad Abdullah ◽  
Morgan Nelson ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Biliary Tract ◽  
Medical Center ◽  
Genetic Alterations ◽  
Molecular Therapy ◽  
Common Mutation ◽  
Genomic Profiling ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling

e16671 Background: Biliary tract cancers (BTC) are a highly aggressive group of malignancies with high mortality and poor prognosis. Chemotherapy is the mainstay of treatment for advanced disease. The role of molecular targeted therapy and immunotherapy using comprehensive genomic profiling (CGP) is evolving. We investigated the role of CGP directed therapy in patients with BTC. Methods: A multi-center retrospective study of CGP done on 35 patients with BTC at Sanford USD Medical Center and Avera McKennan Hospital, Sioux Falls, SD, between 2014 and 2019. 27 patients had cholangiocarcinoma (fifteen intrahepatic, two extrahepatic and ten unclassified), two had gallbladder carcinoma and six had ampullary carcinoma. Results: 22 of 35 BTC (63%) had potentially actionable genetic alterations(GA). Nine of these 22 (41%) received molecular therapy based on CGP. Four patients had microsatellite instability (MSI-H) and two of them received immunotherapy (Table). CDKN2A/B was the most common mutation (23%) followed by PIK3CA (13%), ARID1A (13%) and Tp53(13%). By the end of the follow up period, median overall survival (OS) was 569 days(19 months) for those who received targeted therapy compared to 315 days(10.5 months) for those who did not. (P = 0.051). Conclusions: In this multi-center cohort, 63% of patients had at least one targetable GA. Furthermore, CGP guided treatment decisions in 41% of patients. CGP has the potential to provide clinically meaningful treatment options for patients with BTC. New studies are warranted to further investigate this promising prospect for BTC management. [Table: see text]

scholarly journals A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada

2021 ◽  
Vol 28 (1) ◽  
pp. 417-427
Author(s):  
Carissa Beaulieu ◽  
Arthur Lui ◽  
Dimas Yusuf ◽  
Zainab Abdelaziz ◽  
Brock Randolph ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Demographic Data ◽  
Performance Status ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Intrahepatic Bile Duct ◽  
Population Based ◽  
Phase Iii ◽  
First Line ◽  
Biliary Tract Cancers

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19–99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.

scholarly journals Synergistic Combination of Cytotoxic Chemotherapy and Cyclin Dependent Kinase 4/6 Inhibitors in Biliary Tract Cancers

Hepatology ◽  
2021 ◽  
Author(s):  
Mansi Arora ◽  
James M. Bogenberger ◽  
Amro M. Abdelrahman ◽  
Jennifer Yonkus ◽  
Roberto Alva‐Ruiz ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Cytotoxic Chemotherapy ◽  
Cyclin Dependent Kinase ◽  
Biliary Tract Cancers ◽  
Synergistic Combination

scholarly journals Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers

JAMA Oncology ◽  
2019 ◽  
Vol 5 (6) ◽  
pp. 824 ◽  
Author(s):  
Rachna T. Shroff ◽  
Milind M. Javle ◽  
Lianchun Xiao ◽  
Ahmed O. Kaseb ◽  
Gauri R. Varadhachary ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancers

Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers

2017 ◽  
Vol 36 (1) ◽  
pp. 156-162 ◽  
Author(s):  
Marie Bréchon ◽  
Marie Dior ◽  
Johann Dréanic ◽  
Bertrand Brieau ◽  
Marie-Anne Guillaumot ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Antiangiogenic Therapy ◽  
Biliary Tract Cancers

scholarly journals Adjuvant chemotherapy for resected biliary tract cancers: a systematic review and meta-analysis

HPB ◽  
2017 ◽  
Vol 19 (9) ◽  
pp. 741-748 ◽  
Author(s):  
Michele Ghidini ◽  
Gianluca Tomasello ◽  
Andrea Botticelli ◽  
Sandro Barni ◽  
Giampietro Zabbialini ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adjuvant Chemotherapy ◽  
Biliary Tract ◽  
Meta Analysis ◽  
Biliary Tract Cancers
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