TY - JOUR
T1 - Practical considerations in screening for genetic alterations in cholangiocarcinoma
AU - Bekaii-Saab, T. S.
AU - Bridgewater, J.
AU - Normanno, N.
N1 - Funding Information:
Editorial assistance was provided by Roland Tacke, PhD, CMPP, and Simon J. Slater, PhD, CMPP of Envision Pharma Group, Inc. (Philadelphia, PA), which was funded by Incyte Corporation. Editorial assistance for this review was funded by Incyte Corporation (no grant number). TSB-S received research funding (to institution) from Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Abgenomics, Incyte, and BMS; consulting fees (to institution) from Ipsen, Array Biopharma, Bayer, Genentech, Incyte, and Merck; and fees (to self) as member of independent data monitoring committee (IDMC) or data and safety monitoring board (DSMB) for AstraZeneca, Exelixis, Lilly, PanCan, and 1Globe. JB received research support from UCLH/UCL Biomedical Research Centre; served as a consultant or advisor for AstraZeneca, Merck Serono, and Roche; and received travel/accommodation/other expenses from the European Society for Medical Oncology and Merck Serono. NN received speaker's fee from and/or served on advisory boards for MSD, QIAGEN, Bayer, Biocartis, Incyte, Roche, BMS, Merck, Thermofisher, Boehringer Ingelheim, AstraZeneca, Sanofi, Eli Lilly, and Illumina; received research support (to institution) from Merck, Sysmex, Thermofisher, QIAGEN, Roche, AstraZeneca, Biocartis, and Illumina; and has been (nonfinancial interests) president of the International Quality Network for Pathology (IQN Path) and the Italian Cancer Society (SIC).
Funding Information:
Editorial assistance was provided by Roland Tacke, PhD, CMPP, and Simon J. Slater, PhD, CMPP of Envision Pharma Group, Inc. (Philadelphia, PA), which was funded by Incyte Corporation.
Publisher Copyright:
© 2021 The Authors
PY - 2021/9
Y1 - 2021/9
N2 - Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and ∼10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the United States. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient's genetic signature.
AB - Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and ∼10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the United States. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient's genetic signature.
KW - actionable genetic alterations
KW - cholangiocarcinoma
KW - genomic profiling
KW - next-generation sequencing
KW - targeted therapy
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U2 - 10.1016/j.annonc.2021.04.012
DO - 10.1016/j.annonc.2021.04.012
M3 - Review article
C2 - 33932504
AN - SCOPUS:85107454601
SN - 0923-7534
VL - 32
SP - 1111
EP - 1126
JO - Annals of Oncology
JF - Annals of Oncology
IS - 9
ER -