This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-09-2477v1 69/21/8341    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sholl, L. M. Articles by Chirieac, L. R. PubMed PubMed Citation Articles by Sholl, L. M. Articles by Chirieac, L. R.

Lung Adenocarcinoma with EGFR Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers

¹ Department of Pathology, Brigham and Women's Hospital; Departments of ² Medicine and ³ Pathology, and ⁴ Pulmonary and Critical Care Unit, Massachusetts General Hospital; ⁵ Department of Pathology, Dana-Farber Cancer Institute; ⁶ Harvard School of Public Health, Boston, Massachusetts; ⁷ Department of Chest Surgery, Kaohsiung Veteran General Hospital; ⁸ Department of Family Medicine, Kaohsiung Medical University Hospital and Graduate Institute of Occupational Safety and Health, Kaohsiung, Taiwan; ⁹ National Yang-Ming University, Taipei, Taiwan; and ¹⁰ Cell Signaling Technology, Inc., Danvers, Massachusetts

Requests for reprints: Lucian R. Chirieac, Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-8126; Fax: 617-264-5118; E-mail: lchirieac{at}partners.org.

In a subset of lung adenocarcinomas, the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. For this study, we selected 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion–mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, and low and high polysomy (100% versus 54%, P = 0.009). EGFR amplification occurred invariably on the mutated and not the wild-type allele (median mutated/wild-type ratios 14.0 versus 0.33, P = 0.003), was associated with solid histology (P = 0.008), and advanced clinical stage (P = 0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival, 16 versus 31 months, P = 0.01) and when adjusted for stage (P = 0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and show distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology. [Cancer Res 2009;69(21):8341–8]

Key Words: EGFR • Lung Cancer • Non-smokers