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Increased HER2 Gene Copy Number Is Associated With Response to Gefitinib Therapy in Epidermal Growth Factor Receptor–Positive Non–Small-Cell Lung Cancer Patients

From the Department of Medicine/Medical Oncology and Pathology, University of Colorado Cancer Center, Aurora, CO; Department of Medical Oncology, Bellaria Hospital; CINECA-Interuniversity Consortium, Bologna; Department of Medical Oncology, Scientific Institute University Hospital San Raffaele, Milano; Department of Medical Oncology, Policlinico Monteluce, Perugia, Italy; and Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX

Address reprint requests to Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center, Department of Medicine and Pathology, 12801 E. 17th Avenue, PO Box 6511, Mail 8111, Aurora, CO 80010; e-mail: fred.hirsch{at}uchsc.edu

PURPOSE: In non-small-cell lung cancer (NSCLC), response to tyrosine kinase inhibitors (TKIs) is significantly associated with the presence of increased copy number and/or activating mutations of the epidermal growth factor receptor gene (EGFR). Preclinical data indicate that HER2, a member of the EGFR family, could enhance TKI sensitivity.

PATIENTS AND METHODS: HER2 gene copy numbers per cell were evaluated by fluorescent in situ hybridization (FISH) in 102 NSCLC patients treated with gefitinib, and previously evaluated for EGFR status by FISH, immunohistochemistry, and presence of mutations.

RESULTS: Patients with HER2 high copy number (high polysomy and gene amplification [HER2 FISH positive]) represented 22.8% of patients, and compared with patients with no or low gain (HER2 FISH negative), had significantly better objective response (OR, 34.8% v 6.4%; P = .001), disease control rate (DCR, 56.5% v 33.3%; P = .04), time to progression (TTP, 9.05 v 2.7 months; P = .02), and a trend toward longer overall survival (OS, 20.8 v 8.4 months; P = .056). HER2 protein expression investigated by immunohistochemistry was positive in only five of 72 (7%) patients analyzed and all 89 patients tested by DNA sequencing were negative for mutations in HER2 exon 20. Patients with HER2 FISH-positive tumors displaying increased expression of EGFR protein, gene gain, or mutations (EGFR positive) had a significantly better OR, DCR, TTP, and OS than patients negative for both receptors.

CONCLUSION: Increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, supporting use of HER2 FISH analysis for selection of patients for TKI therapy.

Supported by National Cancer Institute grants Cancer Center shared grant P30-CA46934 and Specialized Program of Research Excellence P01-CA58187. F.C. was a Visiting Professor at the University of Colorado Health Sciences Center sponsored by the Department of Medical Oncology of the Bellaria Hospital, Bologna, Italy. Supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro.

Both F.C. and M.V.-G. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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