scholarly journals Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology

2021 ◽  
Vol 11 ◽  
Author(s):  
Ashish Manne ◽  
Edward Woods ◽  
Allan Tsung ◽  
Arjun Mittra
Keyword(s):  
Molecular Markers ◽  
Growth Factor ◽  
Precision Medicine ◽  
Biliary Tract ◽  
Targeted Therapies ◽  
Messenger Rna ◽  
Genetic Alterations ◽  
New Drugs ◽  
Fibroblast Growth Factor Receptors ◽  
Biliary Tract Cancers

The effective management of biliary tract cancers (BTCs) has been hampered by limited options for systemic therapy. In recent years, the focus on precision medicine has made technologies such as next-generation sequencing (NGS) accessible to clinicians to identify targetable mutations in BTCs in tumor tissue (primarily) as well as blood, and to treat them with targeted therapies when possible. It has also expanded our understanding of functional pathways associated with genetic alterations and opened doors for identifying novel targets for treatment. Recent advances in the precision medicine approach allowed us to identify new molecular markers in BTCs, such as epigenetic changes (methylation and histone modification) and non-DNA markers such as messenger RNA, microRNA, and long non-coding RNA. It also made detecting these markers from non-traditional sources such as blood, urine, bile, and cytology (from fine-needle aspiration and biliary brushings) possible. As these tests become more accessible, we can see the integration of different molecular markers from all available sources to aid physicians in diagnosing, assessing prognosis, predicting tumor response, and screening BTCs. Currently, there are a handful of approved targeted therapies and only one class of immunotherapy agents (immune checkpoint inhibitors or ICIs) to treat BTCs. Early success with new targets, vascular endothelial growth factor receptor (VEGFR), HER2, protein kinase receptor, and Dickkopf-1 (DKK1); new drugs for known targets, fibroblast growth factor receptors (FGFRs) such as futabatinib, derazantinib, and erdafitinib; and ICIs such as durvalumab and tremelimumab is encouraging. Novel immunotherapy agents such as bispecific antibodies (bintrafusp alfa), arginase inhibitors, vaccines, and cellular therapy (chimeric antigen receptor—T cell or CAR-T, natural killer cells, tumor-infiltrating lymphocytes) have the potential to improve outcomes of BTCs in the coming years.

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9094-9094
Author(s):  
Shingo Matsumoto ◽  
Takaya Ikeda ◽  
Kiyotaka Yoh ◽  
Akira Sugimoto ◽  
Terufumi Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Targeted Therapies ◽  
Advanced Nsclc ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Gene Testing ◽  
Genomic Screening ◽  
Nsclc Patients

9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phase and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%], p < 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%], p < 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p < 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.

scholarly journals Precision medicine for patients with advanced biliary tract cancers: Updated results from the prospective MOSCATO trial

2017 ◽  
Vol 28 ◽  
pp. v247
Author(s):  
L. Verlingue ◽  
D. Malka ◽  
A. Allorant ◽  
C. Massard ◽  
C. Ferté ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Biliary Tract ◽  
Biliary Tract Cancers

scholarly journals Emerging role of precision medicine in biliary tract cancers

2018 ◽  
Vol 2 (1) ◽  
Author(s):  
James M. Bogenberger ◽  
Thomas T. DeLeon ◽  
Mansi Arora ◽  
Daniel H. Ahn ◽  
Mitesh J. Borad
Keyword(s):  
Precision Medicine ◽  
Biliary Tract ◽  
Biliary Tract Cancers

Prognostic molecular markers in resected extrahepatic biliary tract cancers; a systematic review and meta-analysis of immunohistochemically detected biomarkers

2015 ◽  
Vol 9 (8) ◽  
pp. 763-775 ◽  
Author(s):  
Robert P Jones ◽  
Nicholas TE Bird ◽  
Richard A Smith ◽  
Daniel H Palmer ◽  
Steven W Fenwick ◽  
...  
Keyword(s):  
Systematic Review ◽  
Molecular Markers ◽  
Biliary Tract ◽  
Meta Analysis ◽  
Biliary Tract Cancers

Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers

2011 ◽  
Vol 103 (2) ◽  
pp. 252-261 ◽  
Author(s):  
Hirokazu Ohashi ◽  
Yasushi Adachi ◽  
Hiroyuki Yamamoto ◽  
Hiroaki Taniguchi ◽  
Katsuhiko Nosho ◽  
...  
Keyword(s):  
Growth Factor ◽  
Biliary Tract ◽  
Growth Factor Receptor ◽  
Receptor Expression ◽  
Insulin Like Growth Factor ◽  
Therapeutic Activity ◽  
Biliary Tract Cancers

scholarly journals Genetics of Biliary Tract Cancers and Emerging Targeted Therapies

2010 ◽  
Vol 28 (21) ◽  
pp. 3531-3540 ◽  
Author(s):  
Aram F. Hezel ◽  
Vikram Deshpande ◽  
Andrew X. Zhu
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Targeted Therapies ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Individual Treatment ◽  
Biliary Tract Cancers ◽  
Animal Modeling ◽  
Treatment Regimens ◽  
Tumor Genetics

Biliary tract cancers (BTC), which encompass intra- and extrahepatic cholangiocarcinomas and gallbladder carcinomas, are a genetically diverse collection of cancers. Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in BTC. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here, we summarize the molecular pathogenesis and genetics of BTCs and animal modeling and relate these to recent and ongoing clinical trials with targeted agents.

Precision medicine for patients with advanced biliary tract cancers: An effective strategy within the prospective MOSCATO-01 trial

2017 ◽  
Vol 87 ◽  
pp. 122-130 ◽  
Author(s):  
Loic Verlingue ◽  
David Malka ◽  
Adrien Allorant ◽  
Christophe Massard ◽  
Charles Ferté ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Biliary Tract ◽  
Effective Strategy ◽  
Biliary Tract Cancers

Drug discovery in rare indications: opportunities and challenges

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 19-23 ◽  
Author(s):  
Victoria M. Richon
Keyword(s):  
Drug Discovery ◽  
Rare Diseases ◽  
Targeted Therapies ◽  
Rapid Growth ◽  
Genetic Alterations ◽  
New Drugs ◽  
New Therapies ◽  
The Past ◽  
Select Patient ◽  
Patient Subgroups

Abstract Over the past decade, the number of new therapies developed for the treatment of rare diseases continues to increase. The most rapid growth has been in the development of new drugs for oncology indications. One focus in drug discovery for oncology indications is the development of targeted therapies for select patient subgroups characterized by genetic alterations. The identification of these patient subgroups has increased in the past decade and has resulted in a corresponding increase in the development of new drugs for genetically defined patient subgroups. As an example of the development of new therapeutics for rare indications, I describe here the drug discovery efforts leading to the development of DOT1L inhibitors for the treatment of MLL-rearranged leukemia.

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