Molecular Predictors of Outcome With Gefitinib in a Phase III Placebo-Controlled Study in Advanced Non–Small-Cell Lung Cancer

Hirsch, Fred R.; Varella‐Garcia, Marileila; Bunn, Paul A.; Franklin, Wilbur A.; Dziadziuszko, Rafał; Thatcher, Nick; Chang, Alex Y.; Parikh, Purvish M.; Pereira, José Rodrígues; Ciuleanu, Tudor-Eliade; Pawel, Joachim von; Watkins, Claire; Flannery, Angela V.; Ellison, Gillian; Donald, Emma; Knight, Lucy; Parums, Dinah V.; Botwood, N.; Holloway, Brian R.

doi:10.1200/jco.2006.06.3958

Cited by 660 publications

(496 citation statements)

References 30 publications

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“…These findings suggest that, based on current paradigms of assessing responsiveness to EGFRtargeted therapies in carcinomas, it is uncertain whether epithelioid sarcomas would show a meaningful response to EGFR tyrosine kinase inhibitors. Nevertheless, one study in refractory, advanced nonsmall cell lung carcinoma has shown EGFR protein expression as a biomarker predictive of better survival, 33 suggesting that EGFR expression may have at least some clinical implication in sarcomas.…”

Section: Discussionmentioning

confidence: 99%

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

2010

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Epithelioid sarcoma is a rare, malignant, soft tissue neoplasm that can be classified into proximal, distal and fibroma-like subtypes. Regardless of subtype, epithelioid sarcoma often shows morphologic and immunophenotypic evidence of epithelial differentiation. Current therapeutic strategies include surgical resection, amputation, radiation or chemotherapy, although the overall prognosis remains poor. The epidermal growth factor receptor (EGFR) is a novel therapeutic target in carcinomas. In some carcinomas, EGFR kinase domain mutations or gene amplification may correlate with response to specific inhibitors. EGFR expression has been reported in some sarcoma types, but expression, amplification and mutations have not been studied in epithelioid sarcoma. We evaluated 15 cases of epithelioid sarcoma from 14 patients for EGFR expression using immunohistochemistry, EGFR copy number aberration using fluorescence in situ hybridization and screened for mutations in the tyrosine kinase domain of the EGFR gene using direct sequencing. In all, 14 of the 15 epithelioid sarcomas (93%) showed expression of EGFR by immunohistochemistry. A majority of the cases (n ¼ 11, 73%) showed strong (2 þ to 3 þ ) and homogeneous (475% of cells) membrane staining. No amplification or polysomy of the EGFR gene or mutations of the tyrosine kinase domain of EGFR (exons 18-21) were detected. These results imply that although EGFR is expressed in most epithelioid sarcomas regardless of subtype, gene amplification and activating mutations in the tyrosine kinase domain appear to be rare or absent. Thus, the benefit of targeted therapy against EGFR in patients with epithelioid sarcoma remains to be determined.

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Section: Discussionmentioning

confidence: 99%

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

2010

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“…An analysis of biomarkers and clinical response in this trial identified high EGFR gene copy number as a predictor of clinical benefit with gefitinib (Hirsch et al, 2006). High EGFR gene copy numbers were detected in 31% of 370 patients with tissue samples available for FISH analysis, and a high EGFR protein expression was found in 70% of 379 evaluable patients.…”

Section: Predictive Value Of Egfr Amplification and Overexpressionmentioning

confidence: 91%

“…The ISEL trial was a double-blind, randomized, placebo-controlled, multicenter phase III study evaluating the efficacy of gefitinib in 1692 patients with refractory, locally advanced or metastatic NSCLC (Hirsch et al, 2006). An analysis of biomarkers and clinical response in this trial identified high EGFR gene copy number as a predictor of clinical benefit with gefitinib (Hirsch et al, 2006).…”

Section: Predictive Value Of Egfr Amplification and Overexpressionmentioning

confidence: 99%

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

2009

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Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.

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“…Pao et al (2005b) first suggested that patients with NSCLC whose tumors harbor mutations are resistant to EGFR TKI. To date, among 75 NSCLC patients harboring KRAS mutations who were treated with TKIs (Pao et al, 2005b;Hirsch et al, 2006;Massarelli et al, 2007;Miller et al, 2008;Zhu et al, 2008), only one patient has been reported to respond (Zhu et al, 2008). Interestingly, this patient's tumor also had an EGFR gene amplification.…”

Section: Genetic Polymorphisms and Egfr-targeted Drugsmentioning

confidence: 95%

“…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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Molecular Predictors of Outcome With Gefitinib in a Phase III Placebo-Controlled Study in Advanced Non–Small-Cell Lung Cancer

Abstract: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

Cited by 660 publications

References 30 publications

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

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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