From Goeffrey Oxnard and colleagues: EGFR exon 19 insertions and lung adenocarcinoma

http://www.ncbi.nlm.nih.gov/pubmed/22190593

Clin Cancer Res. 2011 Dec 21. [Epub ahead of print]
EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma.
He M, Capelletti M, Nafa K, Yun CH, Arcila ME, Miller VA, Ginsberg MS, Zhao B, Kris MG, Eck MJ, Janne PA, Ladanyi M, Oxnard GR.
Source
Department of Pathology, Brown University Warren Alpert Medical School.

Abstract
PURPOSE:
EGFR genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with TKI-sensitivity in lung adenocarcinoma is uncertain.

EXPERIMENTAL DESIGN:
Patients from two institutions with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to TKIs. In patients receiving TKI, response magnitude was assessed with serial CT measurement.

RESULTS:
Twelve cases harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all demonstrated an 18 bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to TKI. Six patients with measurable disease received TKI and 5 had a response on serial CT.

CONCLUSIONS:
EGFR exon 19 insertions are a newly appreciated family of TKI-sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of fragment length analysis to multi-gene assays allows sensitive detection of both exon 19 insertion and deletion mutations.