scholarly journals Circulating Cell-Free DNA-Based Comprehensive Molecular Analysis of Biliary Tract Cancers Using Next-Generation Sequencing

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 233
Author(s):  
Szilvia Lilla Csoma ◽  
Judit Bedekovics ◽  
Gergő Veres ◽  
Anita Árokszállási ◽  
Csilla András ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Molecular Analysis ◽  
Molecular Genetic ◽  
Genetic Alterations ◽  
Anatomical Location ◽  
Precision Oncology ◽  
Cell Free Dna ◽  
Tract Cancer ◽  
Free Dna ◽  
Rare Malignancy

Biliary tract cancer (BTC) is a rare malignancy with a long disease course and an overall poor prognosis. Despite multiple chemotherapy agents, there is no defined second-line treatment opportunity for advanced BTCs. In the era of precision oncology, NGS plays an important role in identifying mutations that may predict the molecular pathomechanism and manage the BTC therapy. The peripheral blood liquid biopsy (LB) of cancer patients represents variable amounts of cell-free DNA (cfDNA) released from tumor foci of any anatomical location. Our study aimed to identify somatic mutations and tumor variant burden (TVB) in cell-free and matched tumor DNA. We found a positive correlation between the estimated tumor volume and cfDNA yield (r = 0.9326, p < 0.0001). Comparing tissue and LB results, similar TVB was observed. SNVs were proven in 84% of the cases, while in two cases, only the LB sample was informative for molecular analysis. The most important aberrations in BTCs, such as FGFR2, IDH1, IDH2, KRAS, and TP53, could be detected in matched LB samples. Our prospective study demonstrates a minimally invasive testing approach to identify molecular genetic alterations in cholangiocarcinoma and gallbladder cancers. Clinical applications of cfDNA reflect by capturing the outstanding spatial tumor heterogeneity and guarantee novel aspects for the precision oncology treatment.

Abstract 2292: Bile cell-free DNA as a powerful liquid biopsy of the somatic variants in biliary tract cancer

2019 ◽  
Author(s):  
Ningjia Shen ◽  
Dadong Zhang ◽  
Lei Yin ◽  
Yinghe Qiu ◽  
Jian Liu ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Liquid Biopsy ◽  
Cell Free Dna ◽  
Tract Cancer ◽  
Free Dna

scholarly journals Cell-free DNA from bile outperformed plasma as a potential alternative to tissue biopsy in biliary tract cancer

ESMO Open ◽  
2021 ◽  
Vol 6 (6) ◽  
pp. 100275
Author(s):  
Q. Gou ◽  
C.Z. Zhang ◽  
Z.H. Sun ◽  
L.G. Wu ◽  
Y. Chen ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Cell Free Dna ◽  
Tract Cancer ◽  
Tissue Biopsy ◽  
Free Dna ◽  
Potential Alternative

Abstract 2292: Bile cell-free DNA as a powerful liquid biopsy of the somatic variants in biliary tract cancer

2019 ◽  
Author(s):  
Ningjia Shen ◽  
Dadong Zhang ◽  
Lei Yin ◽  
Yinghe Qiu ◽  
Jian Liu ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Liquid Biopsy ◽  
Cell Free Dna ◽  
Tract Cancer ◽  
Free Dna

scholarly journals The Evolving Role of Radiation Therapy in the Treatment of Biliary Tract Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Eleni Gkika ◽  
Maria A. Hawkins ◽  
Anca-Ligia Grosu ◽  
Thomas B. Brunner
Keyword(s):  
Biliary Tract ◽  
Survival Rates ◽  
Disease Free Survival ◽  
R0 Resection ◽  
Anatomical Location ◽  
Free Survival ◽  
Tract Cancer ◽  
Complete Surgical Resection ◽  
One Year

Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48–65% after one year and 23–35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting.

scholarly journals Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3370
Author(s):  
Nicola Personeni ◽  
Ana Lleo ◽  
Tiziana Pressiani ◽  
Francesca Colapietro ◽  
Mark Robert Openshaw ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Advanced Disease ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
Anatomical Location ◽  
Molecular Heterogeneity ◽  
Isocitrate Dehydrogenase 1 ◽  
Tract Cancer

Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.

Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 103-103
Author(s):  
Nicolas Guibert ◽  
Greg Jones ◽  
John F. Beeler ◽  
Clive D. Morris ◽  
Vincent Plagnol ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Cell ◽  
Progressive Disease ◽  
Genetic Alterations ◽  
Targeted Sequencing ◽  
Cell Free Dna ◽  
Invasive Approach ◽  
Free Dna ◽  
Poor Outcomes ◽  
Immune Score

103 Background: Tumor mutational burden is an emerging biomarker of response to immune checkpoint inhibitors (ICI), whose clinical adoption is challenging, especially in liquid biopsies. We hypothesized that targeting limited but relevant genetic alterations in plasma cell-free DNA with next generation sequencing (NGS) along with early monitoring may represent a non-invasive approach to predict response to ICI. Methods: Plasma samples from responders (PFS > 6 months) and non-responders (progressive disease at first evaluation) patients collected before nivolumab (second line) initiation and at 1 month were tested using tagged amplicon sequencing of hotspots and coding regions from 36 genes, blinded to clinical outcomes and tumor genotype. Molecular profile of ctDNA, and its early kinetics (1 month) were analyzed as potential early indicators of response. Results: 98 patients were analyzed, of which 86 (39 responders, 47 non-responders) were evaluable for response. Alterations in ctDNA were detectable in 67/86 baseline samples (78%). The detection of a targetable oncogenic driver (5 EGFR, 1 ALK) was associated with progressive disease on the first CT-scan The presence of a PTEN and/or STK11 mutations (b-PS(+)) was correlated with poor outcomes (median PFS 1.5 months vs. 8 months in b-PS(-)) patients, p = 0.0007), while the presence of transversion mutations in KRAS and/or TP53 (b-KP-Tv(+)) predicted good outcomes (median PFS 11 months vs. 2 months in b-KP-Tv(-) patients, p = 0.0088). Combining these results, patients with a low “immune score” (driver and/or b-PS(+) and/or b-KP-Tv(-)) derived poor outcomes (PFS 2 months), compared with patients with a high immune score (no driver, b-PS(-) and b-KP-Tv(+), PFS 14 months, p = 0.0001, HR 2.96). Studying early changes in 65 specimens, molecular response was correlated with clinical outcomes (14 months PFS in patients with early ctDNA decrease compared to 2 months in patients with increase, p < 0.0001; HR 2.7). Using cut-off of 30% and 50% of plasma response increased the ability of ctDNA to predict response (HR 4 and 4.17, respectively). Conclusions: Targeted sequencing of plasma ctDNA and its early variations can predict response to anti-PD-1. Clinical trial information: NCT02827344.

Genomics and translational precision oncology for 803 patients with biliary tract cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4589-4589
Author(s):  
Jianzhen Lin ◽  
Xu Yang ◽  
Yinghao Cao ◽  
Guangyu Li ◽  
Songhui Zhao ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Targeted Therapies ◽  
Objective Response ◽  
Disease Free Survival ◽  
Tumor Board ◽  
Precision Oncology ◽  
Free Survival ◽  
Tract Cancer ◽  
Incidence And Mortality

4589 Background: Both incidence and mortality of biliary tract cancer (BTC) are increasing, and BTCs are characterized by poor prognosis and limited antitumoral treatments. There is no well-received regimen as the non-first-line treatment in patients with advanced BTCs, leading to the urgency of umbrella-setting personalized therapies according to genomic alterations. Methods: We performed genomic sequencing in a total of 803 BTCs, including 160 patients with whole-exome sequencing and 643 patients with hybrid capture–based comprehensive genomic profiling. Our molecular tumor board developed precise targeted therapies for patients with actionable targets. Results: Overall, the median tumor mutation burden was 3.0 (IQR: 0.8-6.1) Mut/Mb, with 10.5% patients of hypermutated BTCs. The most frequently mutated genes included TP53 (51%), KRAS (23%), ARID1A (16%) and SMAD4 (11%). The most common genes with significantly amplified oncogenes were CCND1 (6.97%), MET (6.72%) and MDM2 (6.6%), while the frequently deleted tumor-suppressor genes are CDKN2A (5.73%) and CDKN2B (5.35%). The mutational map of BTCs highlighted pathways of receptor-tyrosine kinase (RTK)/RAS and p53 signaling were frequently altered. Somatic truncating mutations of mismatch repair genes were identified in 6.1% (49/803) of patients, and germline pathogenic mutations in DNA damage response genes occurred in 8% (64/803) of BTCs. In addition, we demonstrate the amplified chromosomal focal at 7q31.2 was an oncogenic factor and it independently predicts both disease-free survival and overall survival of BTC patients. When molecular screening was linked to targeted therapies, 25.4% (204/803) of patients could match biomarker-assigned drug treatment (BADT). The frequent actionable biomarkers included amplifications of ERBB2 and MET, FGFR2/3 fusions and IDH1 mutations. For 46 patients with refractory BTCs received BADT, the objective response rate was 26.1%, with a median progression-free survival (mPFS) of 5.0 (95%CI: 3.5-6.5) months, and 56.8% patients achieved a ≥1.3 ratio of PFS2/PFS1. 4 of 6 (67%) patients with high microsatellite instability (MSI-H) BTCs had a responsive status after immunotherapy of PD1 inhibitor, confirming that MSI-H status was a robust biomarker of anti-PD1 treatments. Conclusions: Our study established the largest cohort in Chinese BTC patients to investigate the tumor mutational profiling and its translational clinical applications. Clinical trial information: NCT02715089 .

scholarly journals Intrahepatic Cholangiocarcinoma: Evolving Concepts and Medical Treatment

2021 ◽  
Vol 26 (1) ◽  
pp. 33-42
Author(s):  
Hong Ja Kim
Keyword(s):  
Biliary Tract ◽  
Intrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancer ◽  
Chemotherapeutic Agents ◽  
Growth Patterns ◽  
Classification Systems ◽  
Anatomical Location ◽  
Extrahepatic Cholangiocarcinoma ◽  
Distal Cholangiocarcinoma ◽  
Tract Cancer

Cholangiocarcinoma (bile duct cancer) is classified into intrahepatic and extrahepatic cholangiocarcinoma (perihilar and distal cholangiocarcinoma) according to the anatomical location of the lesion. The incidence of extrahepatic cholangiocarcinoma has been relatively stagnant in recent decades, but intrahepatic cholangiocarcinoma is steadily increasing worldwide, requiring attention. Various classification systems based on gross growth patterns, histological findings, and tumor-derived cells, as well as classification based on existing anatomical location, have been proposed, however, the consensus has not been established yet. Intrahepatic cholangiocarcinoma is a carcinoma with an extremely poor prognosis. Complete tumor resection is the only curative treatment. The overall survival rate for 5 years after surgery is 15% to 40%, but recurrence after surgery is observed in 2/3 patients. Therefore, determining the right stage before surgery and selecting an appropriate treatment method through a multidisciplinary approach is a very important process in determining proper treatment. Systemic therapy may be used for locally advanced biliary tract cancer or metastatic biliary tract cancer where surgery is not possible. However, the effectiveness of traditional anticancer chemotherapeutic agents is rather pessimistic, therefore treatments using molecular biological properties have recently been attempted. Finding a way to increase the number of resectable cases through early diagnosis is one of the main challenges. In addition, it is also hoped that the selection of new therapeutic targets and therapeutics will be possible as a result of advanced research on gene expression profiles and mutations in cholangiocarcinoma.

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