Next-generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA).

Abstract

209 Background: The incidence of CCA is rising and the clinical efficacy of systemic therapy is suboptimal. Next generation sequencing (NGS) technology offers potential for targeted therapeutics against genetically heterogenous solid tumors including cholangiocarcinoma (CCA). Methods: DNA was extracted from biopsy specimens of 61 patients (pts) with CCA seen at MD Anderson Cancer Center Houston, TX. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (performed by Foundation Medicine, Cambridge, MA). Results: 174genomic alterations (GA) were identified from 61 pt samples with an average of 2.85 GAs/pt (range 0-10). GAs identified were mutations (75%), amplifications (16%), loss/deletions (7%) and others (2%). 6 (10%) tumors showed no GAs. Most frequent GAs were TP53 (34%), KRAS (30%), ARID1A (15%), PBRM1 (11%), BAP1 (8%), ERBB2 (8%), FBXW7 (8%), SMAD4 (8%) and IDH1 (8%). ERBB2 GAs included 4 mutations and 1 amplification. KRAS mutation was associated with a statistically significant reduction in overall survival (OS). Mean OS in pts with KRAS mutation was 32 weeks vs. 63 weeks in KRAS wt (t = -2.126, p = 0.039). Ingenuity Pathway Analysis indicated disruption in cell cycle, proliferation, development, death and DNA repair pathways. Targetable signaling pathways from this study are described in the Table. Targetable GAs were noted in 62% of pts. These are potentially targetable by inhibitors to ERBB2, FGF, mTOR, MEK, BRAF and PARP-1. Conclusions: These data are the single largest compilation of NGS analysis on CCA pts and demonstrate the range of GAs that are eligible for investigational targeted therapies. These results can be used as a basis to develop personalized treatments for CCA pts based on individual genetic profiles. [Table: see text]