Epidermal Growth Factor Receptor in Non–Small-Cell Lung Carcinomas: Correlation Between Gene Copy Number and Protein Expression and Impact on Prognosis

Hirsch, Fred R.; Varella‐Garcia, Marileila; Bunn, Paul A.; Maria, Michael V. Di; Veve, Robert; Bremnes, Roy M.; Barón, Anna E.; Zeng, Chan; Franklin, Wilbur A.

doi:10.1200/jco.2003.11.069

Cited by 1,322 publications

(1,006 citation statements)

References 20 publications

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“…Compared to other lung neoplasms, EGFR expression occurs more frequently in salivary gland-type tumors. Indeed, EGFR is expressed in about 80% of squamous cell carcinomas, 21 50% of lung adenocarcinomas, 21 and in less than 5% of the neuroendocrine carcinomas, 13 whereas it was expressed in more than 90% of the cases in our series. Some studies have suggested that the mechanisms of EGFR protein overexpression vary depending on tumor type.…”

Section: Discussionmentioning

confidence: 46%

Salivary gland-type lung carcinomas: an EGFR immunohistochemical, molecular genetic, and mutational analysis study

Macarenco¹,

Uphoff

Gilmer

et al. 2008

Modern Pathology

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Salivary gland-type lung carcinomas are uncommon neoplasms of the lung, the two most common being adenoid cystic carcinoma and mucoepidermoid carcinoma. Although they usually have an indolent behavior, adenoid cystic carcinomas can be more aggressive, with 5-year survival as low as 55%. Unfortunately, these tumors do not respond well to chemotherapy. In contrast to the most common subtypes of lung carcinomas, epidermal growth factor receptor studies have not been carried out in this group of tumors. Herein we report a series of 24 cases (12 adenoid cystic and 12 mucoepidermoid carcinomas) tested for epidermal growth factor receptor protein expression, epidermal growth factor receptor gene copy gains, and epidermal growth factor receptor gene mutational status, through immunohistochemistry, fluorescence in situ hybridization, and sequencing of the exons 18-21, respectively. Overall, 91 and 92% of the adenoid cystic carcinomas and mucoepidermoid carcinomas expressed epidermal growth factor receptor protein. Chromosome 7 polysomy occurred in 25% of the cases (four adenoid cystic carcinomas and two mucoepidermoid carcinomas). No epidermal growth factor receptor gene amplification was detected and no mutation was found in exons 18-21 of the epidermal growth factor receptor gene. Immunoexpression of epidermal growth factor receptor in salivary gland-type lung carcinomas is not related to epidermal growth factor receptor gene copy number or mutational status. Keywords: salivary gland-type lung carcinoma; adenoid cystic carcinoma; mucoepidermoid carcinoma; epidermal growth factor receptor; immunohistochemistry; FISH Salivary gland-type lung carcinomas are uncommon, representing less than 1% of all lung tumors. Adenoid cystic carcinoma and mucoepidermoid carcinoma are the two most common subtypes. 1,2 Salivary gland-type lung carcinomas are generally reported as having a good prognosis. Indeed, mucoepidermoid carcinoma usually presents as a localized disease that can be completely resected with surgery and the reported 5-and 10-year survivals rates are both 87%. 3 However, patients with mucoepidermoid carcinomas can develop local or distant metastasis, which are typically unresponsive to conventional chemotherapy and radiation. In contrast, adenoid cystic carcinoma tends to present at a higher stage, is often unresectable, or, if resected, often has positive margins and subsequent local recurrences. The prognosis is also poorer with recent reported 5-and 10-year survivals of 55 and 39%, respectively. 3 As with mucoepidermoid carcinoma, the survival does not appear to be affected by traditional chemotherapy and radiation. Therefore, there appears to be a potential use for targeted novel therapies in the care of these patients.

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Section: Discussionmentioning

confidence: 46%

Salivary gland-type lung carcinomas: an EGFR immunohistochemical, molecular genetic, and mutational analysis study

Macarenco¹,

Uphoff

Gilmer

et al. 2008

Modern Pathology

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“…EGFR mutations were detectable in 70% (15/21) of patients who had a gain of EGFR copy number. There are several methods for detecting and determining EGFR gene copy number, or dosage, including FISH, 25,30,102 chromogenic in situ hybridization, 32,103 and realtime quantitative PCR. 10,104,105 When compared with EGFR mutations, EGFR gene copy number gain was a less sensitive and less specific marker, and may therefore not be considered clinically suitable for patient selection.…”

Section: Egfr Copy Number Alterationmentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…EGFR immunohistochemistry as a prognostic and predictive biomarker Studies using different antibody sources have reported a high prevalence of EGFR immunostaining in NSCLCs (Rusch et al, 1997;Fontanini et al, 1998;Hsieh et al, 2000;Hirsch et al, 2003). The rate is consistently higher in squamous-cell carcinomas (55-100%) than in adenocarcinomas (35-60%) or large-cell carcinomas (20-60%).…”

Section: Molecular Predictors Of Response To Egfr Antagonistsmentioning

confidence: 99%

“…In the Italian Expanded Access Study of gefitinib, the BR.21 and the ISEL studies, an association was observed between EGFR FISH positivity and either increased response rates or an improved survival benefit (Hirsch et al, 2003(Hirsch et al, , 2006Tsao et al, 2005;see Hirsch et al, 2009). The high EGFR gene copy number detected by FISH may also be predictive of benefit from chemotherapy combined with cetuximab (Hirsch et al, 2008b).…”

Section: Egfr Fish As a Prognostic And Predictive Biomarkermentioning

confidence: 99%

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

2009

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Epidermal Growth Factor Receptor in Non–Small-Cell Lung Carcinomas: Correlation Between Gene Copy Number and Protein Expression and Impact on Prognosis

Cited by 1,322 publications

References 20 publications

Salivary gland-type lung carcinomas: an EGFR immunohistochemical, molecular genetic, and mutational analysis study

Salivary gland-type lung carcinomas: an EGFR immunohistochemical, molecular genetic, and mutational analysis study

Molecular pathology of lung cancer: key to personalized medicine

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

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