EPIDERMAL GROWTH-FACTOR RECEPTOR EXPRESSION IN CERVICAL INTRAEPITHELIAL NEOPLASIA AND ITS MODULATION DURING AN ALPHA-DIFLUOROMETHYLORNITHINE CHEMOPREVENTION TRIAL
Iv. Boiko et al., EPIDERMAL GROWTH-FACTOR RECEPTOR EXPRESSION IN CERVICAL INTRAEPITHELIAL NEOPLASIA AND ITS MODULATION DURING AN ALPHA-DIFLUOROMETHYLORNITHINE CHEMOPREVENTION TRIAL, Clinical cancer research, 4(6), 1998, pp. 1383-1391
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
.