Evaluation of Cholangiocarcinomas (CCA) by Next Generation Sequencing (NGS) Reveals Frequent Actionable Genomic Abnormalities and New Routes to Targeted Therapies
Rami Al-Rohil, Janne V Rand, David M Jones, Hwa Jeong Lee, Christine E Sheehan, Geoff Otto, Gary Palmer, Roman Yelensky, Doron Lipson, Emily White, Sohail Balasubramanian, Lazaro Garcia, Kristin Mahoney, Tina Richards, Selmira Terzic, Vera Banning, John Curran, Sean Downing, Vincent Miller, Philip Stephens, Jeffrey S Ross. Albany Medical College, Albany, NY; Foundation Medicine Inc., Cambridge, MA
Background: Metastatic CCA has a poor prognosis and systemic therapies are commonly extrapolated from those used in other GI malignancies. We hypothesized that comprehensive genomic profiling of clinical CCA samples by NGS could identify genomic-derived drug targets of therapy for patients with this lethal cancer in a single diagnostic test.
Design: NGS was performed on hybridization-captured, adaptor ligation based libraries using DNA extracted from 4 formalin-fixed paraffin embedded sections cut at 10 microns from 13 CCA. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 to at an average sequencing depth of 936X and evaluated for genomic alterations (GA) including point mutations (mut), insertions, deletions, copy number alterations (amp), and select gene fusions/rearrangements. Actionable GA were defined as those identifying anti-cancer drugs on the market or in registered clinical trials (CT).
Results: There were 8 (61.5%) female and 5 (38.5%) male CCA patients with a median age 55.2 years (range 46-69years). There were 7 (54%) grade II and 6 (46%) grade III tumors. Nine (69%) CCA were Stage I and 4(31%) were Stage III at time of NGS. Thirteen (100%) of CCA has NGS performed on a needle biopsy of the primary tumor in the liver. All 13(100%) had GA on NGS with a total of 31 GA and an average of 2.4 GA per tumor. The most common GA were ARID1A (39%), IDH1/2 (39%), TP53 mut (39%) and MCL1 amp (30%) which are currently not actionable. Seven/thirteen (54%) CCA had at least 1 actionable GA with an average of 0.85 actionable GA per patient including: MET amplification (15%), CDK6 amplification 15%), CDKN2A splice (15%), FGFR2 amp (8%), PTEN splice (8%), NF1 truncation (8%), KRAS mut (8%), NRAS mut (8%), and ERBB3 mut (8%).
Conclusions: When CCA is evaluated by deep NGS, over half the patients in this study harbored GA which have the potential to influence and personalize therapy selection and guide patients to CT using novel agents. Given the limited treatment options and poor prognosis of patients with metastatic disease, comprehensive NGS genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 256, Monday Morning