Abstract
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 56 patients of 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.Results: 162 genomic variations (GV) were identified from 56 patient samples with an average of 2.89 GVs/patient (range 0-10). GVs identified were mutations (72%), amplifications (17%), loss/deletions (7%) and others (4%). 6 (11%) tumors showed no GVs. Most frequent GVs were TP53 (35%), KRAS (31%), ARID1A (16%), PBRM1 (11%), BAP1 (9%), ERBB2 (9%), FBXW7 (9%), SMAD4 (9%) and IDH1 (7%). ERBB2 GVs included 4 mutations and 1 amplification. KRAS mutation was associated with a statistically significant reduction in overall survival (OS). Mean OS in patients 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 Table 1. Targetable GVs were noted in 59% of patients. These are potentially targetable by inhibitors to ERBB2, FGF, mTOR, MEK, BRAF and PARP-1.
Conclusion: These data are the single largest compilation of NGS analysis on CCA patients and demonstrate the range of GVs that are eligible for investigational targeted therapies. These results can be used as a basis to develop personalized treatments for CCA patients based on individual genetic profiles.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B132.
Citation Format: Chaitanya R. Churi, Asif Rashid, Rachna Shroff, Lopa Mishra, Mingxin Zuo, Ahmed Kaseb, Filip Janku, Thomas A. Aloia, Jean-Nicholas Vauthey, Steven Curley, Siraj Ali, Gary Palmer, Milind Javle. Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B132.