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Research Articles: Therapeutics, Targets, and Development

Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy

Departments of ¹ Molecular Pharmacology and Experimental Therapeutics, ² Oncology, ³ Laboratory Medicine and Pathology, and ⁴ Health Sciences Research, and the ⁵ Cytogenetics Shared Resource, Mayo Clinic College of Medicine, Rochester, Minnesota; ⁶ Eastern Maine Medical Center, Bangor, Maine; and ⁷ Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Matthew P. Goetz, Department of Oncology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-4849; Fax: 507-284-1803. E-mail: goetz.matthew{at}mayo.edu

Abstract

Metaplastic breast carcinoma, a rare tumor composed of adenocarcinomatous and nonglandular growth patterns, is characterized by a propensity for distant metastases and resistance to standard anticancer therapies. We sought confirmation that this tumor is a basal-like breast cancer, expressing epidermal growth factor receptor (EGFR) and stem cell factor receptor (KIT). EGFR activating mutations and high copy number (associated with response to tyrosine kinase inhibitor gefitinib) and KIT activating mutations (associated with imatinib sensitivity) were then investigated. Seventy-seven metaplastic cases were identified (1976-2006); 38 with tumor blocks available underwent pathologic confirmation before EGFR and KIT immunohistochemical analyses. A tissue microarray of malignant glandular and metaplastic elements was constructed and analyzed immunohistochemically for cytokeratin 5/6, estrogen receptor, progesterone receptor, and p63, and by fluorescence in situ hybridization for EGFR and HER-2/neu. DNA isolated from individual elements was assessed for EGFR and KIT activating mutations. All assessable cases were negative for estrogen receptor, progesterone receptor, and (except one) HER2. The majority were positive for cytokeratin 5/6 (58%), p63 (59%), and EGFR overexpression (66%); 24% were KIT positive. No EGFR or KIT activating mutations were present; 26% of the primary metaplastic breast carcinomas were fluorescence in situ hybridization-positive, displaying high EGFR copy number secondary to aneusomy (22%) and amplification (4%). We report here that metaplastic breast carcinoma is a basal-like breast cancer lacking EGFR and KIT activating mutations but exhibiting high EGFR copy number (primarily via aneusomy), suggesting that EGFR tyrosine kinase inhibitors should be evaluated in this molecular subset of breast carcinomas. [Mol Cancer Ther 2008;7(4):944–51]

Grant support: Paul Calabresi Program in Clinical-Translational Research at Mayo Clinic grant CA 90628 (M.P. Goetz), Career Development Award from Mayo Cancer Center Breast Cancer SPORE grant CA 116201 (M.P. Goetz), and Mayo Comprehensive Cancer Center grant CA 15083 (M.M. Ames).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J.A. Gilbert and M.P. Goetz contributed equally to this work.

This work was presented in preliminary form at the 29th Annual San Antonio Breast Cancer Symposium in December 2006.

⁸ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/17/07; revised 1/14/08; accepted 2/21/08.