EPIDERMAL GROWTH-FACTOR RECEPTOR EXPRESSION IN CERVICAL INTRAEPITHELIAL NEOPLASIA AND ITS MODULATION DURING AN ALPHA-DIFLUOROMETHYLORNITHINE CHEMOPREVENTION TRIAL

Chemoprevention trials designed to prevent progression to invasive cer vical cancer will benefit from the identification of biomarkers that a ssess the risk of developing tumors, predict likelihood of response to treatment, and measure biological response to intervention. The purpo se of this study was to examine expression of epidermal growth factor receptor (EGFR) as a marker for progression of cervical intraepithelia l neoplasia (CIN) and as a surrogate end point biomarker in a chemopre vention trial with alpha-difluoromethylornithine (DPMO), an inhibitor of ornithine decarboxylase. To evaluate quantitative and spatial chang es in EGFR expression during cervical tumorigenesis, paraffin sections from 42 archival cervical cone biopsies, each containing multiple sta ges of CIN, were immunohistochemically stained for EGFR, and the level and spatial expression of EGFR were quantitated by image analysis. In the progression from normal epithelium to CIN 1 to CIN 2 to CIN 3 to invasive cancer, EGFR expression showed two types of changes. Normal c ontrol epithelium showed EGFR expression predominantly confined to the basal layer, while histologically normal epithelium in specimens cont aining CIN showed relatively increased EGFR expression in the basal la yer and the extension of EGFR expression away from the basal layer. Th e total EGFR relative staining intensity (RSI) of epithelium increased with the degree of CIN, predominantly due to a progressive expansion of EGFR expressing cells away from the basal layer rather than an incr ease in the level of EGFR expression per cell. To determine whether EG FR expression would be modulated by a 1-month chemopreventive interven tion with DFMO, pretreatment and posttreatment cervical biopsy specime ns from 25 patients (22 evaluable) were examined for EGFR expression. Although the overall levels of EGFR expression were not modulated in e ither histological responders or nonresponders, responders showed a pr ominent down-regulation of EGFR expression away from the basal layer a fter DFMO treatment. Interestingly, pretreatment EGFR expression level s predicted for DPMO response [i.e., eight responses (72.7%) for 11 ca ses with RSI levels below 0.35 versus one response (9.1%) for 11 cases ,vith RSI levels above 0.35 (P < 0.01)], These results suggest that CI N progression is associated with a spatial dysregulation of EGFR expre ssion that can be reversed by DFMO treatment, especially in patients w hose pretreatment CIN 3 lesions exhibit relatively low EGFR expression .