Milind Javle1, Tanios Bekaii-Saab2, Apurva Jain1, Ying Wang3, Robin Katie Kelley4, Kai Wang5, Hyunseon C Kang6, Daniel Catenacci7, Siraj Ali5, Sunil Krishnan8, Daniel Ahn2, Andrea Grace Bocobo4, Mingxin Zuo1, Ahmed Kaseb1, Vincent Miller5, Philip J Stephens5, Funda Meric-Bernstam9, Rachna Shroff1, Jeffrey Ross10. 1. Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas. 2. Division of Medical Oncology, Ohio State University Medical Center, Columbus, Ohio. 3. Department of Bioinformatics & Computational Biology, UT-MD Anderson Cancer Center, Houston, Texas. 4. Department of Medicine (Hematology/Oncology), UCSF, San Francisco, California. 5. Foundation Medicine, Inc., Cambridge, Massachusetts. 6. Department of Diagnostic Radiology, UT-MD Anderson Cancer Center, Houston, Texas. 7. Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois. 8. Department of Radiation Oncology, UT-MD Anderson Cancer Center, Houston, Texas. 9. Department of Investigational Cancer Therapeutics, UT-MD Anderson Cancer Center, Houston, Texas. 10. Department of Pathology, Albany Medical College Albany, New York.
Abstract
BACKGROUND: Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit. METHODS: Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 412 intrahepatic cholangiocarcinomas (IHCCAs), 57 extrahepatic cholangiocarcinomas (EHCCAs), and 85 gallbladder carcinomas (GBCAs). The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients. Clinical variables, detected mutations, and administered therapies were correlated with overall survival (OS) in a Cox regression model. RESULTS: The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA. Fibroblast growth factor receptor (FGFR; 11%) and IDH mutations (20%) were mostly limited to IHCCA but appeared to be mutually exclusive. In the IHCCA group, TP53 and KRAS mutations were associated significantly with poor OS, whereas FGFR2 mutations were associated with improved OS (P = .001), a younger age at onset, and female sex. IDH1/2 mutations were not prognostic. In a multivariate model, the effects of TP53 and FGFR GAs remained significant (P < .05). Patients with FGFR GAs had superior OS with FGFR-targeted therapy versus standard regimens (P = .006). Targeted therapy in IHCCA was associated with a numerical OS improvement (P = .07). CONCLUSIONS: This is the largest clinically annotated data set of BTC cases with CGP and indicates the potential of CGP for improving outcomes. CGP should be strongly considered in the management of BTC patients. Cancer 2016;122:3838-3847.
BACKGROUND:Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit. METHODS: Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 412 intrahepatic cholangiocarcinomas (IHCCAs), 57 extrahepatic cholangiocarcinomas (EHCCAs), and 85 gallbladder carcinomas (GBCAs). The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients. Clinical variables, detected mutations, and administered therapies were correlated with overall survival (OS) in a Cox regression model. RESULTS: The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA. Fibroblast growth factor receptor (FGFR; 11%) and IDH mutations (20%) were mostly limited to IHCCA but appeared to be mutually exclusive. In the IHCCA group, TP53 and KRAS mutations were associated significantly with poor OS, whereas FGFR2 mutations were associated with improved OS (P = .001), a younger age at onset, and female sex. IDH1/2 mutations were not prognostic. In a multivariate model, the effects of TP53 and FGFR GAs remained significant (P < .05). Patients with FGFR GAs had superior OS with FGFR-targeted therapy versus standard regimens (P = .006). Targeted therapy in IHCCA was associated with a numerical OS improvement (P = .07). CONCLUSIONS: This is the largest clinically annotated data set of BTC cases with CGP and indicates the potential of CGP for improving outcomes. CGP should be strongly considered in the management of BTC patients. Cancer 2016;122:3838-3847.
Authors: Huat C Lim; Meagan Montesion; Thomas Botton; Eric A Collisson; Sarah E Umetsu; Spencer C Behr; John D Gordan; Phil J Stephens; Robin K Kelley Journal: Oncologist Date: 2018-04-05
Authors: Maeve A Lowery; Ryan Ptashkin; Emmet Jordan; Michael F Berger; Ahmet Zehir; Marinela Capanu; Nancy E Kemeny; Eileen M O'Reilly; Imane El-Dika; William R Jarnagin; James J Harding; Michael I D'Angelica; Andrea Cercek; Jaclyn F Hechtman; David B Solit; Nikolaus Schultz; David M Hyman; David S Klimstra; Leonard B Saltz; Ghassan K Abou-Alfa Journal: Clin Cancer Res Date: 2018-05-30 Impact factor: 12.531
Authors: Lipika Goyal; Lei Shi; Leah Y Liu; Ferran Fece de la Cruz; Jochen K Lennerz; Srivatsan Raghavan; Ignaty Leschiner; Liudmila Elagina; Giulia Siravegna; Raymond W S Ng; Phuong Vu; Krushna C Patra; Supriya K Saha; Raul N Uppot; Ron Arellano; Stephanie Reyes; Takeshi Sagara; Sachie Otsuki; Brandon Nadres; Heather A Shahzade; Ipsita Dey-Guha; Isobel J Fetter; Islam Baiev; Emily E Van Seventer; Janet E Murphy; Cristina R Ferrone; Kenneth K Tanabe; Vikram Deshpande; James J Harding; Rona Yaeger; Robin K Kelley; Alberto Bardelli; A John Iafrate; William C Hahn; Cyril H Benes; David T Ting; Hiroshi Hirai; Gad Getz; Dejan Juric; Andrew X Zhu; Ryan B Corcoran; Nabeel Bardeesy Journal: Cancer Discov Date: 2019-05-20 Impact factor: 39.397
Authors: Megan R D'Andrea; Corey M Gill; Melissa Umphlett; Nadejda M Tsankova; Mary Fowkes; Joshua B Bederson; Priscilla K Brastianos; Raj K Shrivastava Journal: Oncologist Date: 2019-11-06