Mutational Analysis of EGFR, KRAS, BRAF, PIK3CA, and ERBB2 in Non-Small-Cell Lung Carcinomas (NSCLC)
L Cheng, PA Janne, DM Jackman, BE Johnson, VA Joshi, NI Lindeman. Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Laboratory for Molecular Medicine, Harvard Medical School, Cambridge, MA
Background: Despite advances in the management of EGFR-mutant NSCLC with targeted therapy, prognosis for the majority of patients, whose tumors lack EGFR mutations, remains poor. Nevertheless, the success of EGFR therapy suggests that targeted therapy directed against other molecular alterations, where appropriate, may lead to similarly successful outcomes. Analysis of multiple oncogenes, rather than EGFR alone, was performed on a set of lung cancers to classify and quantitate a variety of molecular abnormalities therein.
Design: Paraffin-embedded, formalin-fixed tumor samples from 54 consecutive nonsmoking patients with advanced-stage non-squamous NSCLC were dissected and analyzed by PCR-Sanger sequencing for mutations in selected exons and splice sites of EGFR, KRAS, BRAF, PIK3CA, and ERBB2.
Results: Mutations were found in 24 (44%) of samples; none of the samples had more than one mutation. Mutations in KRAS were most common, seen in eight patients (14.8%), followed by EGFR in seven (13%), BRAF in five (9.3%), ERBB2 in three (5.6%), and PIK3CA in one (1.9%). Two novel mutations were identified: a 7-bp deletion (2284_90del7) affecting the EGFR exon 20 splice site, and an in-frame deletion of BRAF codon 469.
Conclusions: Mutually-exclusive oncogene mutations were seen in 44% of these NSCLCs. Many of these oncogenes are suitable candidates for directed therapies. Further studies, including prospective clinical trials, are warranted to determine if molecular classification of NSCLC beyond EGFR sequencing can stratify patients into treatment cohorts with improved outcomes.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 259, Tuesday Morning