Comprehensive Genomic Profiling of Epithelial Ovarian Cancer (OC) by Next Generation Sequencing (NGS) Reveals New Routes to Targeted Therapies
Jeffrey S Ross, Christine E Sheehan, Gary Palmer, Siraj Ali, Geoff Otto, Sean Downing, John Curran, Roman Yelensky, Doron Lipson, Kiel Iwanik, Jamie Buell, Emily White, Philip Stephens, Vincent Miller. Albany Medical College, Albany, NY; Foundation Medicine Inc., Cambridge, MA
Background: The recent introduction of NGS to clinical samples has enabled the discovery of novel and unanticipated genomic-derived drug targets of therapy for patients with relapsed OC.
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 31 pre-treatment OC that had relapsed after primary surgery and platinin-based chemotherapy. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 (Illumina Inc. San Diego, CA) to at an average sequencing depth of 943X and evaluated for genomic alterations (GA) including point mutations (mut), insertions, deletions, copy number alterations (amp), and gene fusions/translocations. Actionable GA were defined as impacting anti-cancer drugs on the market or in registered clinical trials (CT).
Results: The study included 22 (71%) papillary serous (PS), 5 (16%) endometrioid (EC), 3 (10%) clear cell (CC), and 1 (3%) undifferentiated carcinomas. One (3%) tumor was FIGO grade 1, 5 (16%) grade II and 25 (81%) grade III. Twenty-two (71%) OC were Stage III and 9 (29%) Stage IV at diagnosis. NGS found a total of 89 GA in the OC series with an average of 2.9 GA per tumor. 25 GA (0.8 per tumor) were potentially associated with clinical benefit of targeted therapies and 0 GA associated with targeted therapy resistance. The GA generated potential entry into a total of 150 CT (average 4.8 per tumor). The most common GA were TP53 mut (65%); myc amp (19%), KRAS mut/amp (19%) and BRCA1 mut (13%) There were no HER2 amp, but one tumor featured a HER2 mut. 4/5 (80%) of ARID1A mut occurred in non-PS tumors. 2/3 (67%) of CC featured cMET amp validated by both FISH and IHC.
Conclusions: NGS of conventional therapy resistant OC uncovers an unexpectedly high frequency of GA that could influence therapy selection for the disease. Deep sequencing of genomic DNA can provide a broad cancer-related gene survey at a depth of coverage that provides sensitive detection for all classes of GA, and when applied to OC patients can reveal actionable GA that inform treatment decisions.
Category: Gynecologic & Obstetrics
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 186, Wednesday Morning