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

Cappuzzo, Federico; Varella-Garcia, Marileila; Shigematsu, Hisayuki; Domenichini, Irene; Bartolini, Stefania; Ceresoli, Giovanni L.; Rossi, Elisa; Ludovini, Vienna; Gregorc, Vanesa; Toschi, Luca; Franklin, Wilbur A.; Crino, Lucio; Gazdar, Adi F.; Bunn, Paul A.; Hirsch, Fred R.

doi:10.1200/jco.2005.09.111

Cited by 369Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

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

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Cappuzzo, Federico, Varella-Garcia, Marileila, Shigematsu, Hisayuki, Domenichini, Irene, Bartolini, Stefania, Ceresoli, Giovanni L., Rossi, Elisa, Ludovini, Vienna +7 more·2005·Journal of Clinical Oncology

DOI 10.1200/jco.2005.09.111

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Abstract

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.

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Cancers with EGFR mutations often have amplification of the mutant EGFR allele.
“Of note, cancers with EGFR mutations often have amplification of the mutant EGFR allele as well (Cappuzzo et al., 2005).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Cappuzzo et al., 2005

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Copy-Number Variation: The Balance between Gene Dosage and Expression in Drosophila melanogaster
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Dosage Sensitivity Shapes the Evolution of Copy-Number Varied Regions
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A versatile method for gene dosage quantification: multiplex PCR and single base extension for copy number and gene-conversion identification of SMN genes.
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Authors: Cappuzzo, F., Varella-Garcia, M., Shigematsu, H., Domenichini, I., Bartolini, S., Ceresoli, G. L., Rossi, E., Ludovini, V., Gregorc, V., Toschi, L., Franklin, W. A., Crino, L., Gazdar, A. F., Bunn, P. A., & Hirsch, F. R.
Affiliations: IRCCS Ospedale San Raffaele (IT)
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,...
ORCID: Cappuzzo, Federico
Bartolini, Stefania
Ceresoli, Giovanni L.
Rossi, Elisa
Ludovini, Vienna
Gregorc, Vanesa
Toschi, Luca
Gazdar, Adi F.
Bunn, Paul A.
Hirsch, Fred R.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2005-08-01
Volume: 23
Issue: 22
Pages: 5007-5018
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2005.09.111
OpenAlex: W2165119042
Cited by: 369
References: 52
Citations by year: 2026: 4 · 2025: 5 · 2024: 2 · 2023: 4 · 2021: 5 · 2020: 10 · 2019: 3 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 15 · 2014: 20 · 2013: 20 · 2012: 19
FWCI: 42.51
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Funders: AstraZeneca
Associazione Italiana per la Ricerca sul Cancro
Cancer Center, University of Colorado
National Cancer Institute (P01-CA 58187, CA58187, P30 CA46934, P30CA046934)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: HER2 gene copy number, gefitinib, non-small cell lung cancer, EGFR-positive tumors, tyrosine kinase inhibitors, HER2 amplification, EGFR mutation, EGFR expression, treatment response, predictive biomarkers
MeSH terms: Gefitinib, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, Humans, Lung Neoplasms, Quinazolines, Cohort Studies, Survival Analysis, Treatment Outcome, In Situ Hybridization, Fluorescence, Gene Dosage, Genes, erbB-2, Gene Expression Profiling, ErbB Receptors

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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

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