scholarly journals Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

2021 ◽  
Vol 9 (11) ◽  
pp. e003214
Author(s):  
Xiaofeng Chen ◽  
Deqiang Wang ◽  
Jing Liu ◽  
Jingrong Qiu ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Poor Prognosis ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Chinese Patients ◽  
Genomic Alterations ◽  
Early Stage Disease ◽  
Tract Cancer

BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

scholarly journals Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Advanced Biliary Tract Cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Chen Chen ◽  
Tao Wang ◽  
Mengmei Yang ◽  
Jia Song ◽  
Mengli Huang ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Circulating Tumor Dna ◽  
Chinese Patients ◽  
Ras Signaling ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Genomic Changes ◽  
Tract Cancer ◽  
Tumor Dna

Background: Biliary tract cancer is a highly lethal malignancy with poor clinical outcome. Accumulating evidence indicates targeted therapeutics may provide new hope for improving treatment response in BTC, hence better understanding the genomic profile is particularly important. Since tumor tissue may not be available for some patients, a complementary method is urgently needed. Circulating tumor DNA (ctDNA) provides a noninvasive means for detecting genomic alterations, and has been regarded as a promising tool to guide clinical therapies.Methods: Next-generation sequencing of 150 cancer-related genes was used to detect gene alterations in blood-derived ctDNA from 154 Chinese patients with BTC. Genomic alterations were analyzed and compared with an internal tissue genomic database and TCGA database.Results: 94.8% patients had at least one change detected in their ctDNA. The median maximum somatic allele frequency was 6.47% (ranging 0.1–34.8%). TP53 and KRAS were the most often mutated genes. The frequencies of single nucleotide variation in commonly mutated genes in ctDNA were similar to those detected in tissue samples, TP53 (35.1 vs. 40.4%) and KRAS (20.1 vs. 22.6%). Pathway analysis revealed that mutated genes were mapped to several key pathways including PI3K-Akt, p53, ErbB and Ras signaling pathway. In addition, patients harboring LRP1B, TP53, and ErbB family mutations presented significantly higher tumor mutation burden.Conclusions: These findings demonstrated that ctDNA testing by NGS was feasible in revealing genomic changes and could be a viable alternative to tissue biopsy in patients with metastatic BTC.

The identification of the age effects in 1,287 patients with biliary tract cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 244-244
Author(s):  
Kumiko Umemoto ◽  
Shuichi Mitsunaga ◽  
Kazuo Watanabe ◽  
Hiroyuki Okuyama ◽  
Yusuke Hashimoto ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Poor Prognosis ◽  
Peritoneal Dissemination ◽  
Age Groups ◽  
Age Effects ◽  
Tract Cancer ◽  
Elder Patients ◽  
Ecog Ps

244 Background: Age is a mirror for pathogenesis in some of biliary tract cancer (BTC) as liver fluke- or pancreaticobiliary maljunction-associated BTCs. However, the age effects including prognosis in BTC were not fully understood. The identification of the age effects might be helpful for the management of BTC. Methods: For the years 1992-2014, 1287 patients receiving initial treatment for BTC in our institution were reviewed. According to age at diagnosis of BTC, patients were divided into the five age groups as <50, 50-59, 60-69, 70-79, and ≥80. The relationships between overall survival time (OS) and the five age groups were analyzed using wilcoxon test to choose a prognostic cut-off of age. On the basis of a prognostic cut-off of age, the prognostic age classification was constructed. The multivariate analysis with logistic regression modeling was performed to determine the influence of gender, Eastern Cooperative Oncology Group performance status scale [ECOG-PS], primary site, and metastatic site on the prognostic age classification. Results: Median age was 67 years with male 59%. ECOG PS of 0 was 63.7%.The sites of primary tumor included intrahepatic (25.2%) and extrahepatic bile duct (34.0%), gallbladder (31.9%) and ampulla of Vater (8.9%). The prognostic cut-off of age was age less than 60 (21.8% of all). Median OS in younger patients (age<60, median OS: 7.9mo) was shorter than that in elder patients (age≥60, median OS 12.4mo, P<0.01). In univariate analysis, the prevalence of bone metastasis, distal lymph node metastasis and peritoneal dissemination was higher in younger BTC than elder patients. Multivariate analysis revealed that peritoneal dissemination was an independent younger BTC related-factor (OR=1.9, P<0.01). Conclusions: Younger BTC patients (age<60) showed poor prognosis and the high frequency of peritoneal dissemination, compared to elder BTC patients. The relationship between age and peritoneal dissemination of BTC might be a key to elucidate the age effect concomitant with poor prognosis.

PD-L1 expression as a prognostic marker in patients with advanced biliary tract cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16679-e16679
Author(s):  
Hyera Kim ◽  
Jung Yong Hong ◽  
Jeeyun Lee ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Group Analysis ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Tract Cancer ◽  
Positive Score ◽  
Combined Positive Score

e16679 Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered as a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score (CPS) positivity. Results: In all 186 patients, the median age was 62 years (range 38-82), and the primary tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 72 patients (38.7%), extrahepatic (EH)-CCC in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). There were 158 (84.9%) patients with recurrent disease and 28 (15.1%) with metastatic disease. Among the 186 patients, 53 (28.5%) had PD-L1 CPS positivity, and 133 were CPS negative. The median overall survival (OS) of patients with PD-L1 CPS positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. The OS and PFS were not statistically different between groups. In sub-group analysis, EH-CCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p= 0.002) and PFS (7.8 vs. 5.4 months, p= 0.005) than those that were PD-L1 negative. However, this finding was not reproduced in patients with IH-CCC or GB cancer. Univariate analysis of the association between PD-L1 expression and OS in patients with advanced BTC indicated that PD-L1 CPS positivity has a prognostic role in sub-populations older than 60 years (HR 1.743, CI 1.001-3.034, p = 0.050), those with EH-CCC (HR 2.449, CI 1.355-4.426, p = 0.003), and those with liver metastasis (HR 2.511, CI 1.362-4.626, p = 0.003). Conclusions: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EH-CCC but not for patients with IH-CCC or GB cancer.

scholarly journals Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer

2021 ◽  
Vol Volume 14 ◽  
pp. 1873-1882
Author(s):  
Poshita-Kumari Seesaha ◽  
Kang-Xin Wang ◽  
Guo-Qun Wang ◽  
Ting-Yun Cui ◽  
Feng-Jiao Zhao ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Future Perspectives ◽  
Tract Cancer

Hyperfibrinogenemia predicts poor prognosis in patients with advanced biliary tract cancer

Tumor Biology ◽  
2015 ◽  
Vol 37 (3) ◽  
pp. 3535-3542 ◽  
Author(s):  
Heming Li ◽  
Tong Zhao ◽  
Xuening Ji ◽  
Shanshan Liang ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Poor Prognosis ◽  
Tract Cancer

scholarly journals Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing

2016 ◽  
Vol 9 (3) ◽  
pp. 173-178 ◽  
Author(s):  
Kwai Han Yoo ◽  
Nayoung K.D. Kim ◽  
Woo Il Kwon ◽  
Chung Lee ◽  
Sun Young Kim ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Targeted Sequencing ◽  
Genomic Alterations ◽  
Tract Cancer

Blood-based genomic profiling of circulating tumor DNA from patients with advanced biliary tract cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1576-1576
Author(s):  
Junying Wang ◽  
Jia Song ◽  
Jing Zhao ◽  
Yuzi Zhang ◽  
Shangli Cai ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Tumor Heterogeneity ◽  
Circulating Tumor Dna ◽  
Pi3k Pathway ◽  
Chinese Patients ◽  
Tissue Samples ◽  
Tract Cancer ◽  
Tumor Dna

1576 Background: Biliary tract cancer (BTC) is a highly lethal malignancy as diagnosis occurring at late stages and marginally sensitive to chemotherapy. Increasing evidence indicates targeted therapeutics may provide new hope for improving clinical response in BTC, hence better comprehending the genomic profile is particularly important. However, tissue of BTC is highly wide tumor heterogeneity and often inadequate for molecular characterization, a proper method is urgently needed. Circulating tumor DNA (ctDNA) is an emerging technology for detecting actionable alterations, and may be regarded as a reliable tool to reveal genomic signature. Methods: Next-generation sequencing (NGS) targeted 150 cancer-related genes was used to detect blood-based ctDNA from 154 Chinese patients with BTC. The mean sequencing depth was more than 3000×. Somatic genomic alternations (GA) including single nucleotide variation (SNV), copy number variation (CNV) and fusion were analyzed and compared with an internal tissue genomic database (545 Chinese patients with BTC) tested by NGS and TCGA database (n = 227) tested by the whole exome sequencing (WES). Allele frequency (AF) represented the percentage of mutant allele reads relative to total allele reads (mutant plus wild type). Maximum somatic allele frequency (MSAF) was defined as the maximum AF (0.1% < AF < 35%) of all the somatic alterations identified per sample. Results: Among ctDNA database, at least one GA was found in 95% (147/154) of samples (a median of 4 GA per patient). The median MSAF across all cases was 6.47% (range, 0%-34.8%). Pathologic type (P < 0.001) and sex (P < 0.001) were significantly related with MSAF, respectively. Frequencies of SNV in commonly mutated genes from ctDNA were similar to those observed among tissue samples, like TP53 (35.1% vs 40.4%) and KRAS (20.1% vs 22.6%), however, a little lower in TCGA database (TP53 24.2%; KRAS 10.1%). Besides, the consistency of CNV detected from ctDNA and tissue was relatively poor, and tumor heterogeneity might be in charge of this phenomenon. Among the highly frequent mutations (AF > 5%) in ctDNA, 45% of genes was considered as druggable targets, such as EGFR/RAS/RAF pathway and AKT/mTOR/PI3K pathway. Conclusions: These findings demonstrated that ctDNA tested by NGS was feasible in revealing genomic profiles and identifying potential therapeutic targets. Noninvasive ctDNA could be used as a complementary approach to tissue testing in patients with metastatic BTC.

scholarly journals Immunotherapy in Biliary Tract Cancer: Worthy of a Second Look

2020 ◽  
Vol 27 (3) ◽  
pp. 107327482094804 ◽  
Author(s):  
Angela Dalia Ricci ◽  
Alessandro Rizzo ◽  
Giovanni Brandi
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Published Data ◽  
Tract Cancer ◽  
Selection Of Patients ◽  
Selection Of

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several malignancies, the role of immunotherapy in biliary tract cancer (BTC) is currently under investigation and ICIs are still looking for their niche in this setting. In this Editorial, we discuss recently published data regarding ICIs in BTC, with a particular focus in terms of selection of patients and biomarker-driven trials.

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