Next Generation Sequencing (NGS) Reveals Pathway Activations and New Routes to Targeted Therapies in Metastatic Cutaneous Melanoma (MM)
Ashley Tarasen, J Andrew Carlson, Christine E Sheehan, Geoff Otto, Gary Palmer, Roman Yelensky, Doron Lipson, Amy Donahue, Kiel Iwanik, Jamie Buell, Sean Downing, John Curran, Vincent Miller, Philip Stephens, Jeffrey S Ross. Albany Medical College, Albany, NY; Foundation Medicine Inc., Cambridge, MA
Background: Comprehensive genomic profiling of clinical samples by NGS has the potential to identify new genomic-derived drug targets of therapy for patients with MM 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 10 MM cases. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 1098X 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 commercially available targeted therapeutics or in registered clinical trials (CT).
Results: The 10 cutaneous melanomas included 6 (60%) male and 4 (40%) female patients with a mean age of 57 years (range 42-83 years). All 10 (100%) of tumors were Stage IV at the time of NGS. The MM samples tested by NGS were obtained from the liver (25%), lung (8%), other visceral sites (17%), lymph nodes (33%), and intra-cutaneous metastatic sites (17%). NGS found a total of 24 GA with at least 2 GA in all 10 (100%) cases with an average of 2.4 (range 2-4) per tumor impacting multiple genomic pathways including MAPK, PI3K/mTOR, cell cycle regulation and regulators of oxidative stress and apoptosis. NGS of 9 (90%) MM had actionable GA and 5 (50%) of MM had GA associated with FDA approved therapies for MM including vemurafenib targeting BRAF V600E (30% of tumors) V600K (10% of tumors) T599_V600insT (10% of tumors). Four MM (40%) had GA associated with FDA approved therapies in other tumor types including everolimus targeting NF1 (20% of tumors) and PTEN (20% of tumors).
Conclusions: Deep NGS of MM uncovers an unexpectedly high frequency of actionable GA that have the potential to influence therapy selection and can direct patients to enter clinical trials to study the benefit of anti-MM targeted therapies in a single comprehensive diagnostic test.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 71, Monday Morning