Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

Chung, Ki Young; Shia, Jinru; Kemeny, Nancy E.; Shah, Manish A.; Schwartz, Gary K.; Tse, Archie; Hamilton, Audrey; Pan, Dorothy; Schrag, Deborah; Schwartz, Lawrence B.; Klimstra, David S.; Fridman, Daniel; Kelsen, David P.; Saltz, Leonard B.

doi:10.1200/jco.2005.08.037

Cited by 1,019 publications

(624 citation statements)

References 22 publications

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“…Among patients with colon cancer, for example, cetuximab-a chimeric monoclonal antibody that targets the extracellular domain of EGFRappears to show activity in patients whose tumors are negative for EGFR by immunohistochemistry. 42 Accordingly, whether anti-EGFR therapies might benefit more patients with rhabdomyosarcoma than is suggested by our immunohistochemistry results remains to be determined in controlled prospective studies. The latter would also overcome another Figure 3 Fluorescence in situ hybridization results demonstrating the presence of (a) two copy numbers of the ErbB-2 gene (red) and (b) two copy numbers of the EGFR gene (green).…”

Section: Discussionmentioning

confidence: 86%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors. Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/ 66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P ¼ 0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, Po0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21. In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.

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Section: Discussionmentioning

confidence: 86%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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“…[106][107][108][109] Many studies suggest that immunohistochemistry-based assays measuring EGFR expression do not serve as a robust predictors of response to TKI therapy. 110 The study from Li et al 111 further emphasized that EGFR overexpression appears to be independent of EGFR mutation.…”

Section: Total Egfrmentioning

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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“…15,17,[21][22][23] In this regard, immunohistochemical detection of EGFR expression may be used to identify eligible patients, although the degree of EGFR expression does not appear to correlate with the likelihood of tumor regression in response to cetuximab treatment. [24][25][26] Squamous cell carcinoma of the anal canal is an uncommon malignancy but its incidence has increased considerably in recent years among women and among men younger than 45 years. 27,28 Population-based case-control studies have linked this increase to changes in sexual behavior, 27 with a strong etiopathogenetic association with human papillomavirus infection.…”

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confidence: 99%

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

et al. 2006

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Immunohistochemical detection of expression of the epidermal growth factor receptor (EGFR) has been utilized to identify eligible patients with solid malignant tumors, including colorectal adenocarcinoma, for monoclonal antibody therapy (eg, cetuximab). The EGFR status in squamous cell carcinoma of the anal canal, an uncommon malignancy traditionally treated with chemoradiation, has not been well investigated. In this study, 38 primary squamous cell carcinomas of the anal canal were immunohistochemically examined for EGFR expression and analyzed by fluorescence in situ hybridization (FISH) for EGFR gene copy numbers. The results showed a variable degree of EGFR expression in 21 (55%) tumors, among which 13 (62%) cases exhibited a 2 þ to 3 þ staining pattern according to the Dako EGFR phamDx interpretation guide. There were no significant differences among tumors stratified by stage, degree of keratinization, or tissue block storage times. FISH analysis showed that none of the 34 cases with interpretable results had EGFR gene amplification. Increased gene copy numbers due to polysomy 7 were seen in seven of 18 (39%) cases that expressed EGFR protein and four of 16 (25%) cases that did not (P ¼ 0.3876). Ten (56%) tumors with positive EGFR staining showed a balanced disomy 7 pattern and one case with monosomy 7 exhibited strong EGFR expression (3 þ ). These results demonstrate that EGFR is overexpressed in more than one-half of the squamous cell carcinomas of the anal canal through mechanisms other than gene amplification. These observations may have important therapeutic implications since EGFR-based targeted therapies have shown promise for other malignant neoplasms.

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Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

Cited by 1,019 publications

References 22 publications

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Molecular pathology of lung cancer: key to personalized medicine

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

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