Color multiplex polymerase chain reaction for quantitative analysis of epidermal growth factor receptor genes in colorectal adenocarcinoma

Layfield, Lester J.; Bernard, Philip S.; Goldstein, Neil S.

doi:10.1002/jso.10272

Cited by 32 publications

(15 citation statements)

References 18 publications

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“…22). EGFR amplification, however, is a rare event in colon cancer, occurring at a frequency of <1% of cases (37)(38)(39). Consistent with this finding, examination of EGFR amplification status in cetuximab-sensitive and cetuximab-resistant cell lines in the present study failed to identify any lines with EGFR amplification.…”

Section: Discussionsupporting

confidence: 84%

PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab

et al. 2008

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Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G 0 -G 1 arrest without inducing apoptosis. Notably, cetuximabsensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTENexpressing cell lines (14 F 5.0% versus 38.5 F 6.4% growth inhibition, mean F SE; P = 0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10.8 F 4.3% versus 38.8 F 5.9% growth inhibition, respectively; P = 0.002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy.

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Section: Discussionsupporting

confidence: 84%

PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab

et al. 2008

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“…The presence of a small but defined proportion of colorectal cancers that show EGFR gene amplification is in agreement with a recent report that used fluorescent in situ hybridization and IHC, 32 but differ from earlier studies that used Southern blot-or polymerase chain reaction (PCR)-based methods. In studies that used Southern blotting 33 or PCR, 34 no gene amplification was demonstrated in colorectal carcinoma cell lines or tissues microdissected from paraffin blocks, despite the presence of protein expression. Such discrepant results may be explained by dilution of tumor lysates by non-neoplastic tissues or sampling limitations since only a small fraction of EGFR IHCpositive primary colorectal carcinomas showed gene amplification as demonstrated by this study and by the study by Ooi et al 32 Using fluorescent in situ hybridization and IHC, Ooi et al 32 showed that only 21% (11/53) of EGFR IHC-positive (1 þ , 2 þ or 3 þ ) colorectal carcinomas showed gene amplification.…”

Section: Resultsmentioning

confidence: 99%

Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study

et al. 2005

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Recent data suggest that detection of epidermal growth factor receptor protein by immunohistochemistry (IHC) does not predict response to the antiepidermal growth factor receptor drug, cetuximab, in patients with colorectal carcinoma. In searching for foundation for further investigation to optimize patient selection for cetuximab therapy, this study sought to exploit the tissue microarray and chromogenic in situ hybridization techniques to evaluate the status of epidermal growth factor receptor gene amplification in colorectal cancer and its relationship with protein expression by IHC. The study included 158 primary or metastatic colorectal adenocarcinomas. Immunohistochemical results were scored as 0-3 þ based on the intensity of membrane staining. The in situ hybridization signals were counted in 30 nuclei per tissue core. Overall, the rate of tissue loss was 7%, yielding 147 analyzable cases: 123 primary, 24 metastatic. Positive immunohistochemical staining of any intensity was detected in 85% (105/123) of primary and 79% (19/24) of metastatic tumors, whereas gene amplification (45 gene copies/nucleus) was only seen in 12% (15/123) of primary and 8% (2/24) of metastatic tumors. Only 2/15 primary and 1/2 metastatic tumors that showed gene amplification were amplified at a high level (410 gene copies/nucleus). Although a positive correlation was detected between the intensity of protein expression and the likelihood of gene amplification in both the primary (P ¼ 0.01) and the metastatic (P ¼ 0.05) tumors, IHC had a low specificity (17% in primary, 23% in metastatic) in predicting gene amplification. Conversely, all tumors that did not express the protein by IHC lacked gene amplification. Thus, this study shows that only a small fraction of epidermal growth factor receptor-positive colorectal carcinomas detected by IHC are associated with gene amplification. Additional studies are needed to determine whether epidermal growth factor receptor gene amplification bears any informative value in predicting response to cetuximabbased therapy. The epidermal growth factor receptor (EGFR) is a member of the HER tyrosine kinase growth factor receptor family, and is involved in signaling pathways affecting cell growth. [1][2][3][4] Recent studies have shown that EGFR expression is present in approximately 60-80% of colorectal carcinomas 5,6 and the receptor has emerged as a rational target for anticancer therapy in these tumors. 2,7 Cetuximab is a human-murine chimeric monoclonal antibody that specifically blocks the EGFR. Several clinical trials have demonstrated activity of cetuximab in patients with advanced colorectal carcinoma 3,4 and the drug is currently licensed in the US and Switzerland for use in such patients.

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“…The expression of EGF or PDGF and their receptors has been shown to correlate with progressive growth of human carcinomas of the prostate (43,44), ovary (45,46), lung (47,48), colon (49,50), stomach (51,52), and esophagus (53,54), breast (55,56) as well as gliomas (57,58) and melanomas (59,60); therefore, blockade of their signaling pathways has been developed as a new therapeutic strategy (61)(62)(63)(64)(65). Specifically, blockade of EGF-R signaling has been shown to produce arrest at the G 1 restriction point (66,67) and to increase apoptosis (68,69).…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Blockade of Platelet-Derived Growth Factor-Receptor and Epidermal Growth Factor-Receptor Signaling and Systemic Administration of Paclitaxel as Therapy for Human Prostate Cancer Metastasis in Bone of Nude Mice

et al. 2004

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Once prostate cancer metastasizes to bone, conventional chemotherapy is largely ineffective. We hypothesized that inhibition of phosphorylation of the epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) expressed on tumor cells and tumorassociated endothelial cells, which is associated with tumor progression, in combination with paclitaxel would inhibit experimental prostate cancer bone metastasis and preserve bone structure. We tested this hypothesis in nude mice, using human PC-

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Color multiplex polymerase chain reaction for quantitative analysis of epidermal growth factor receptor genes in colorectal adenocarcinoma

Cited by 32 publications

References 18 publications

PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab

PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab

Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study

Simultaneous Blockade of Platelet-Derived Growth Factor-Receptor and Epidermal Growth Factor-Receptor Signaling and Systemic Administration of Paclitaxel as Therapy for Human Prostate Cancer Metastasis in Bone of Nude Mice

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