QUANTITATIVE ESTIMATION OF EPIDERMAL GROWTH-FACTOR RECEPTOR AND C-ERBB-2 IN HUMAN BREAST-CANCER

Epidermal growth factor receptor (EGFR) expression by human breast can cer has been shown to predict poor patient outcome, as has amplificati on of the c-erbB-2 proto-oncogene. We have developed a quantitative im munohistochemical method for measuring protein levels of both receptor s and have applied this to a series of 123 breast primaries. We find E GFR expression is substantially lower than normal in nearly all breast cancers (97%). Quantification of p185(erbB-2) indicates overexpressio n in 91% of the tumors. Two separate tumor populations are apparent wi th levels of c-erbB-2 expression ranging from 0.33 to 19 and 45 to 480 times normal, respectively. Within the lower population, p185(erbB-2) expression is inversely related to EGFR expression (rank correlation, P < 0.0005), Using fluorescent in situ hybridization we show that tum ors in the latter population have c-erbB-2 amplification and that ampl ification is restricted to this group. Our findings indicate that sign ificant overexpression of p185(erbB-2) occurs in the absence of amplif ication; these lower levels of expression may have functional signific ance. Fifty-three patients underwent in vivo bromodeoxyuridine labelin g, allowing flow cytometric analysis of tumor cell cycle kinetics. EGF R expression correlates directly to the labeling index (P = 0.011) and indirectly to potential doubling time (P = 0.010), but not to the dur ation of the S-phase (P = 0.502). Conversely, p185(erbB-2) expression does not relate to indices of proliferation, Our results have importan t implications for the use of both receptor types as therapeutic targe ts.