Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas Journal Article


Authors: Arcila, M. E.; Chaft, J. E.; Nafa, K.; Roy Chowdhuri, S.; Lau, C.; Zaidinski, M.; Paik, P. K.; Zakowski, M. F.; Kris, M. G.; Ladanyi, M.
Article Title: Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas
Abstract: Purpose: Activating mutations in the tyrosine kinase domain of HER2 (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 (N = 1,478) were first screened for mutations 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 and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA,MEK1, and AKT was conducted by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH. Results: We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for96%(24/25) of the cases. Compared with 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. HER2 mutations were more frequent among never-smokers (P < 0.0001) but there were no associations with sex, race, or stage. Conclusions: HER2 mutations 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. ©2012 AACR.
Journal Title: Clinical Cancer Research
Volume: 18
Issue: 18
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2012-09-15
Start Page: 4910
End Page: 4918
Language: English
DOI: 10.1158/1078-0432.ccr-12-0912
PROVIDER: scopus
PUBMED: 22761469
PMCID: PMC3865806
DOI/URL:
Notes: --- - "Export Date: 1 October 2012" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Khedoudja Nafa
    181 Nafa
  2. Marc Ladanyi
    861 Ladanyi
  3. Jamie Erin Chaft
    125 Chaft
  4. Chyau-Yueh Christopher Lau
    20 Lau
  5. Maureen F Zakowski
    275 Zakowski
  6. Paul K Paik
    88 Paik
  7. Maria Eugenia Arcila
    336 Arcila
  8. Mark Kris
    597 Kris