Comprehensive Analysis for Clinically Relevant Oncogenic Driver Mutations in 1131 Consecutive Lung Adenocarcinomas.
Maria E Arcila, Christopher Lau, Suresh Jhanwar, Maureen F Zakowski, Mark G Kris, Marc Ladanyi. Memorial Sloan Kettering Cancer Center, New York, NY
Background: Somatic mutations within several signaling molecules of the EGFR pathway have been shown to drive lung adenocarcinoma. With the advent of targeted therapies, the prospective assessment of tumors for a growing number of clinically relevant genetic alterations is becoming necessary. In this study, we aimed to determine the proportion of lung adenocarcinomas with known mutations based on a comprehensive panel interrogating 38 mutations in 8 genes.
Design: Consecutive tumors samples accrued between 1/2009 and 2/2010 at MSKCC were analyzed for recurrent mutations in EGFR, KRAS, NRAS, HER2, BRAF, PIK3CA, AKT1 and MAP2K1 using a combination of methods including standard Sanger sequencing, fragment analysis and mass spectrometry genotyping (Sequenom) assays. Cases negative for EGFR, KRAS and BRAF were subsequently tested for EGFR exon 20 insertions and HER2 exon 20 insertions (by fragment analysis) and EML4-ALK fusions by fluorescent in-situ hybridization.
Results: A total of 1131 specimens were analyzed for all mutations. Of these, 845 were from former/current smokers and 286 from non-smokers; 719 females and 411 males. KRAS mutations were found in 358 tumors (32%), 256 (23%) harbored EGFR mutations, 16 (1.4%) BRAF, 3 (0.2%) AKT, 20 (18%) PIK3CA, 5 (0.4%) NRAS and 20 (1.8%) HER2 mutations. Of all cases tested by FISH for evidence of the EML4-ALK fusion, 40 were positive (8%). The estimated overall rate of 4%. With the exception of PIK3CA mutations and the EGFR T790M secondary mutation, all mutations concurrently tested were mutually exclusive. In all, 718/1131 tumors (63%) harbored a mutation.
Conclusions: To our knowledge, this study represents the largest comprehensive analysis of recurrent oncogenic mutations in lung adenocarcinoma. Prospective testing of lung adenocarcinomas can identify targetable oncogenic mutations in over 60% of samples which may help assign specific kinase inhibitors or aid in the further management of these patients.
Monday, February 28, 2011 1:00 PM
Platform Session: Section E, Monday Afternoon