Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention Journal Article

Authors: Lowery, M. A.; Ptashkin, R.; Jordan, E.; Berger, M. F.; Zehir, A.; Capanu, M.; Kemeny, N. E.; O'Reilly, E. M.; El-Dika, I.; Jarnagin, W. R.; Harding, J. J.; D'Angelica, M. I.; Cercek, A.; Hechtman, J. F.; Solit, D. B.; Schultz, N.; Hyman, D. M.; Klimstra, D. S.; Saltz, L. B.; Abou-Alfa, G. K.
Article Title: Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention
Abstract: Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations. Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients. Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 17
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-09-01
Start Page: 4154
End Page: 4161
Language: English
DOI: 10.1158/1078-0432.ccr-18-0078
PROVIDER: scopus
PUBMED: 29848569
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Leonard B Saltz
    580 Saltz
  2. David Solit
    431 Solit
  3. James Joseph Harding
    66 Harding
  4. Ghassan Abou-Alfa
    219 Abou-Alfa
  5. Marinela Capanu
    206 Capanu
  6. David S Klimstra
    843 Klimstra
  7. William R Jarnagin
    583 Jarnagin
  8. David Hyman
    181 Hyman
  9. Ahmet Zehir
    149 Zehir
  10. Eileen O'Reilly
    316 O'Reilly
  11. Michael Forman Berger
    380 Berger
  12. Nancy Kemeny
    347 Kemeny
  13. Nikolaus D Schultz
    196 Schultz
  14. Emmet John Jordan
    29 Jordan
  15. Imane El Dika
    10 El Dika