Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

Abstract

BackgroundCholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.MethodsWe describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.ResultsThere were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.ConclusionThere are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma—2 case reports and a brief review

“…Our results are in line with 3 additional case reports of dabrafenib and tramatenib in BRAF mutant ICC. These include 2 cases with a clinical benefit from MDACC (not detailed) and one case with a PR lasting more than 8.5 months from Penn University (11,12). While ideal, the conduct of future conclusive first-line phase III randomized clinical trials of dual BRAF/MEK inhibitors against gemcitabine plus cisplatin will be challenging.…”

Genetic alterations in Japanese extrahepatic biliary tract cancer

“…Numerous previous studies have performed genetic analyses of BTC (15,16), and identified TP53 mutations in 8.2-35.7% of GBC cases (17,18), and KRAS mutations in 2-20% of GBC cases (18). KRAS mutations were identified in 20-67% of EBDC cases (19,20), and in 28.6-37.0% of AVC cases (21)(22)(23).…”

Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States

“…The results of these studies should be interpreted with caution as patients with metastatic disease have a worse survival compared to regional disease (2) as metastatic diseases may have a more aggressive biology (2,3,12). This is suggested by a genomic analysis study of cholangiocarcinoma in which it was shown EHC with mutations in BAP1 and PBRM1 are more likely to be associated with bone metastases and worse survival (13). This was also suggested in the ABC-02 trial where the benefit seen in metastatic disease (HR =0.74) was not as remarkable as in the unresectable locally advanced (HR =0.47) (4,14).…”