Prognostic Applications of the Epidermal Growth Factor Receptor and Its Ligand, Transforming Growth Factor-α

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Abstract
Because growth factors and their receptors have a central role in regulating developmental and neoplastic processes, the expression and action of various growth factor receptors and their ligands in human neoplasia have been extensively investigated. During the past two decades, several investigators have described the amplification of the epidermal growth factor receptor (EGFR) at the genotypic level and overexpression of the EGFR protein at the phenotypic level in many tumors (1–16). However, great heterogeneity in the incidence of overexpression, in the intensity and localization of receptor deposition, and of prognostic significance has been observed both within and between various tumor types. EGFR protein overexpression has been reported to occur and to be of prognostic value for predicting either shorter disease-free survival or shorter overall survival in endometrial carcinoma [49% incidence (1) ], esophageal carcinoma [43% incidence (2) ], bladder carcinoma [35% incidence (3) ], and prostatic carcinoma (4). In several other tumor types where multiple studies have been reported, the results have been mixed. Overexpression of EGFR has been frequently reported in non-small-cell lung carcinoma (5–8); however, the incidence of EGFR overexpression ranges from 12% (21 of 169 cases) to 37.5% (12 of 32 cases), with no demonstrated association between disease-free or overall survival. Similar heterogeneity has been reported in ovarian cancer with observed incidences of 19% (9) to 50% (10); both studies claimed an association of EGFR with either advanced stage (10) or poorer prognosis (9). Verbeek et al. (11) reported overexpression of EGFR in 20%- 30% of breast cancer cases investigated by immunostaining and claimed an association with poorer prognosis; however, by use of either conventional (12) or quantitative (13) radioimmunohistochemistry, two studies have suggested that the expression level of EGFR is significantly lower in malignant breast tissue than in benign and normal breast epithelium. Although Iwase et al. (14) reported a 38.8% incidence of EGFR positivity among tumor tissue samples in 80 breast carcinoma cases, EGFR expression was inferior to lymph node involvement or tumor size as a prognostic indicator. Similarly, conflicting reports of quantitative analysis of lower than normal tissue levels of EGFR in cervical carcinoma (15) versus increased levels in patients with invasive cervical carcinoma (16) without prognostic significance have been reported. As summarized by Robertson et al. (13), a great deal of this heterogeneity may be attributable to a general lack of standardization between laboratories for EGFR assay procedures. Quantitative methodologies, whether by labeled ligand or by messenger RNA (mRNA) or DNA analyses, are performed on preparations derived from tumor biopsy specimens containing malignant cells and non-tumor-cell populations and thus do not necessarily represent the neoplastic cell population; immunohistochemical analysis, while subjectively capable of discriminating between normal and neoplastic elements, is not readily quantifiable. Conflicting series observations will need to be clarified by carefully controlled studies comparing quantitative and qualitative determinations of frequency and identity of EGFR-expressing cells and examination of sufficiently large patient cohorts to determine potential prognostic significance.

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