Human Cancer Biology Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas

Purpose: Activatingmutations in the tyrosine kinase domain ofHER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in U.S. patients. Experimental Design: Lung ADC samples (N1⁄4 1,478) were first screened formutations in EGFR (exons 19 and 21) and KRAS (exon 2), and negative cases were then assessed for HER2 mutations (exons 19–20) using a sizing assay andmass spectrometry. Testing for additional recurrent pointmutations in EGFR, KRAS, BRAF,NRAS, PIK3CA,MEK1, andAKTwas conducted bymass spectrometry.ALK rearrangements andHER2 amplification were assessed by FISH. Results: We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon20accounted for 96%(24/25)of the cases. Comparedwith insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12 bp insertion causing duplication of amino acids YVMA at codon 775. Morphologically, 92% (23/25) were moderately or poorly differentiated ADC. HER2 mutation was not associated with concurrent HER2 amplification in 11 cases tested for both. HER2mutationsweremore frequent amongnever-smokers (P<0.0001) but therewere no associationswith sex, race, or stage. Conclusions:HER2mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, routine clinical genotyping of lung ADC should include HER2. Clin Cancer Res; 18(18); 4910–8. 2012 AACR.