Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)5007-5018
Number of pages12
JournalJournal of Clinical Oncology
Volume23
Issue number22
DOIs
Publication statusPublished - 2005

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erbB-2 Genes
Gene Dosage
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
erbB-1 Genes
Fluorescence In Situ Hybridization
Protein-Tyrosine Kinases
Therapeutics
Mutation
Immunohistochemistry
gefitinib
Gene Amplification
DNA Sequence Analysis
Patient Selection
Exons
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / 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.

In: Journal of Clinical Oncology, Vol. 23, No. 22, 2005, p. 5007-5018.

Research output: Contribution to journalArticle

Cappuzzo, F, Varella-Garcia, M, Shigematsu, H, Domenichini, I, Bartolini, S, Ceresoli, GL, Rossi, E, Ludovini, V, Gregorc, V, Toschi, L, Franklin, WA, Crino, L, Gazdar, AF, Bunn, PA & Hirsch, FR 2005, 'Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients', Journal of Clinical Oncology, vol. 23, no. 22, pp. 5007-5018. https://doi.org/10.1200/JCO.2005.09.111
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. / Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 22. pp. 5007-5018.
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title = "Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients",
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.",
author = "Federico Cappuzzo and Marileila Varella-Garcia and Hisayuki Shigematsu and Irene Domenichini and Stefania Bartolini and Ceresoli, {Giovanni L.} and Elisa Rossi and Vienna Ludovini and Vanesa Gregorc and Luca Toschi and Franklin, {Wilbur A.} and Lucio Crino and Gazdar, {Adi F.} and Bunn, {Paul A.} and Hirsch, {Fred R.}",
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T1 - Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients

AU - Cappuzzo, Federico

AU - Varella-Garcia, Marileila

AU - Shigematsu, Hisayuki

AU - Domenichini, Irene

AU - Bartolini, Stefania

AU - Ceresoli, Giovanni L.

AU - Rossi, Elisa

AU - Ludovini, Vienna

AU - Gregorc, Vanesa

AU - Toschi, Luca

AU - Franklin, Wilbur A.

AU - Crino, Lucio

AU - Gazdar, Adi F.

AU - Bunn, Paul A.

AU - Hirsch, Fred R.

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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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