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 .

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.

FOLFIRI in advanced biliary tract cancers.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 451-451 ◽  
Author(s):  
Jonathan Mizrahi ◽  
Valerie Gunchick ◽  
Kabir Mody ◽  
Lianchun Xiao ◽  
Phani Keerthi Surapaneni ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Group Performance ◽  
Performance Status ◽  
Treatment Options ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Second Line ◽  
Extrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancers

451 Background: Gemcitabine plus platinum (GP) is the standard of care first-line treatment for advanced biliary tract cancers (BTC). There is no established second-line therapy, and retrospective reviews report progression-free survival (PFS) for second-line treatment to be < 3 months. 5-Fluorouracil plus irinotecan (FOLFIRI) is a commonly used regimen in patients (pts) with BTC who have progressed on GP, though there is a paucity of data regarding its efficacy in this population. Methods: We retrospectively evaluated pts with advanced BTC who were treated with FOLFIRI at MD Anderson, University of Michigan and Mayo Clinic in Jacksonville. Data were obtained on pt demographics, type of BTC, PFS, and overall survival (OS). Results: Ninety-eight pts were included of which 74 (76%) had metastatic disease at the time of treatment with FOLFIRI. The median age was 59 (range, 22 to 86) years. The number of pts with extrahepatic cholangiocarcinoma (CCA)/gall bladder (GB)/intrahepatic CCA were 10, 17, and 71. FOLFIRI was used as 1st, 2nd, 3rd or 4th – Nth lines in 8, 50, 36, and 4 pts, respectively. Of the 65 pts whose best responses were documented, 23 (35%) had stable disease and 7 (11%) had a partial response per RECIST v1.1. Median duration on FOLFIRI was 2.2 months. The median PFS and OS were 2.4 (95% CI 1.7 to 3.1) and 6.6 (95% CI 4.7 to 8.4) months, respectively. Median PFS for pts treated with FOLFIRI in 1st, 2nd, 3rd or 4th – Nth lines were 3.1, 2.5, 2.3 and 1.5 months, respectively. Eighteen pts received concurrent bevacizumab (13) or EGFR-targeted therapy (5) with FOLFIRI, and both of groups exhibited a median PFS of 2.7 months. Eastern Cooperative Oncology Group performance status (PS) of 0-1 was associated with improved OS (P = 0.006) compared to PS of 2-3. Conclusions: In this multi-institution retrospective review of 98 pts with BTC treated with FOLFIRI, efficacy of this regimen appears to be modest. While PFS and OS outcomes were similar to what has been previously reported, the 46% disease control rate in this group of predominantly pretreated pts is encouraging. Given the lack of other standard therapies, FOLFIRI may still have a role in this pt population, but these results emphasize the need for more effective treatment options for pts with advanced, pretreated BTC.

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 .

Immune related biomarkers in biliary tract cancers (BTC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16191-e16191
Author(s):  
Zoya Sandhu ◽  
Jorge Sanchez-Garcia ◽  
Tyler Barker ◽  
Sharanya Raghunath ◽  
Katherine Shortt ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Immune Therapy ◽  
Treatment Options ◽  
Extrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancers ◽  
Immune Mediated ◽  
Programmed Death ◽  
Tumor Mutational Burden ◽  
The Mean

e16191 Background: Biliary tract cancers are aggressive tumors with limited treatment options. Several ongoing clinical trials are currently exploring role of immune therapy in advanced BTC. Programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability (MSI) are commonly used immune related-biomarkers. Herein, we analyzed the TMB, MSI and PD-L1 expression in advanced BTC. Methods: We retrospectively evaluated the association of TMB, MSI and PD-L1 expression with survival and related treatment outcomes. Results: The immune mediated biomarkers were reported in a total of 62 BTC patients (pts). The mean age of the pts is 73 (range 32-83) years, with predominant females (59%) and Caucasians (82%). The most common histology noted was intrahepatic cholangiocarcinoma (67%) followed by extrahepatic cholangiocarcinoma (18%) and gallbladder carcinoma (15%). Approximately, 40% received 2 or more lines of therapy while 20% of patients didn’t receive any treatment and over. The treatment regimen included gemcitabine-based regimen (35%), 5FU based regimen (18%), immune therapy (15%) and targeted therapy (6%). The TMB was low in 52 pts (83%), intermediate 7 pts (11%) and high in 2 pts (3%). MSI is stable in 55 pts (89%) and PD-L1 expression is negative in 29 pts (47%) and positive in 23 pts (37%). Conclusions: Our data suggests the BTC’s have in general low TMB, are microsatellite stable and have low PD-L1 expression. The potential prognostic and predictive value of these immune related- biomarkers need to be validated in larger studies.

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 Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2190 ◽  
Author(s):  
Ines Malenica ◽  
Matteo Donadon ◽  
Ana Lleo
Keyword(s):  
Biliary Tract ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Ampulla Of Vater ◽  
Current Treatment ◽  
Medical Community ◽  
Small Subset ◽  
Molecular Heterogeneity ◽  
Biliary Tract Cancers

Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community.

scholarly journals Contemporary Tailored Oncology Treatment of Biliary Tract Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Fiona Turkes ◽  
Juliet Carmichael ◽  
David Cunningham ◽  
Naureen Starling
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Genomic Profiling ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling ◽  
Genomic Aberrations ◽  
Oncology Treatment

Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.

ABC-08: A phase Ib, multi-centre, open-label study of a first-in-class nucleotide analogue NUC-1031 in combination with cisplatin in patients with locally advanced/metastatic biliary tract cancers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS544-TPS544 ◽  
Author(s):  
Mairead Geraldine McNamara ◽  
John A. Bridgewater ◽  
Daniel H. Palmer ◽  
Harpreet Singh Wasan ◽  
David Ryder ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Standard Dose ◽  
Performance Status ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Cancer Resistance ◽  
Open Label ◽  
Ecog Performance Status ◽  
Biliary Tract Cancers ◽  
Phase Ib

TPS544 Background: The UK ABC-02 study established cisplatin and gemcitabine as the reference regimen for first-line treatment of patients (pts) with advanced biliary tract cancers (BTCs) (median overall survival (OS): 11.7 months). No clinical studies since ABC-02 have reported an extension in OS, and therefore effective new agents/combinations are required. NUC-1031 was designed to improve on gemcitabine’s relatively poor efficacy by overcoming its associated key cancer resistance mechanisms, through cellular uptake independent of nucleoside transporters, activation independent of deoxycytidine kinase and protection from cytidine deaminase inactivation, resulting in over 200x the intracellular levels of the anti-cancer metabolite, dFdCTP, greater stability and reduction in the generation of toxic metabolites. NUC-1031 showed activity as monotherapy in a phase I/II study in 7 pts with BTC, refractory to all standard treatments (Blagden et al ASCO 2015; abstract 2514). Methods: ABC-08 is a multi-centre phase Ib study of NUC-1031 combined with cisplatin in pts with non-resectable or recurrent/metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma, aged ≥18 years with an ECOG performance status of 0-1, who have received no prior systemic therapy. The starting dose for NUC-1031 is 625 mg/m2 administered IV on days 1 and 8 in combination with cisplatin (standard dose of 25 mg/m2) (21 day schedule). The dose will be escalated sequentially in cohorts of 3-6 pts using an accelerated titration procedure (725mg/m2, 825mg/m2, 925mg/m2). Treatment will continue until intolerable toxicity/progressive disease. The primary endpoints are safety and RP2D. Secondary endpoints are progression-free survival, OS, response rate and pharmacokinetic endpoints, including assessments of multiple plasma and intracellular analytes: NUC-1031, cisplatin, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU, and will be correlated with safety profile and clinical activity. Planned accrual is 15-24 pts over 2 years. Cohort 1 has been completed without dose-limiting toxicities. Enrolment to cohort 2 is on-going. Clinical trial information: NCT02351765.

Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4085-4085 ◽  
Author(s):  
Gilbert Spizzo ◽  
Alberto Puccini ◽  
Joanne Xiu ◽  
Richard M. Goldberg ◽  
Axel Grothey ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Brca Mutation ◽  
Treatment Strategies ◽  
Missense Mutations ◽  
Brca Mutations ◽  
Extrahepatic Cholangiocarcinoma ◽  
Similar Frequency ◽  
Biliary Tract Cancers ◽  
Tract Cancer

4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p < 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p<0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p < 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.

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