QUANTIFICATION OF ERBB2 PROTEIN EXPRESSION IN BREAST-CANCER - 3 LEVELS OF EXPRESSION DEFINED BY THEIR CLINICOPATHOLOGICAL CORRELATIONS

Activation of the ERBB2 oncogene seems to be an early event in breast cancer progression and prevalent in in situ carcinomas. However, its p rognosis value, albeit recognized for node-positive patients, remains controversial for those without apparent nodal involvement. One possib le reason for this problem is likely to be the difficulty of defining threshold levels for ERBB2 protein overexpression. ERBB2 protein expre ssion was therefore analyzed in primary invasive breast tumors. Quanti fication of the gene product by a commercial ELISA test was compared t o results obtained by immunohistochemistry and western blotting, as we ll as to gene amplification status determined by Southern blotting. Co rrelations between results obtained by the different techniques were h ighly significant (P value < 10(-6)). Nevertheless, ELISA permitted us to determine three levels of protein expression corresponding to dist inct tumor subsets. 1) Tumors with p185/ERBB2 expression levels exceed ing 10 U/mu g exhibited in most cases amplification of the gene (83% o f cases), DNA aneuploidy (81%) and absence of estrogen receptor (ER) ( 44%). Such high levels of protein expression were exclusively observed in invasive ductal carcinomas and were prevalent in those showing a s ignificant in situ component. 2) ''Intermediate'' levels of expression (3-10 U/mu g) were rarely observed in tumors exhibiting gene amplific ation (9%), but were preferentially found in cancers of more favorable prognosis (only 49% were aneuploid and 9% estrogen receptor negative) . 3) Levels of p185/ERBB2 below 3 U/mu g were detected in benign masto pathies and, thus, carcinomas presenting such levels were scored ERBB2 negative. Interestingly, invasive lobular carcinomas were rarely ERBB 2 positive, and if so, only at intermediate levels. Moreover, our data show a complex interrelationship between p185/ERBB2 expression and ER levels. Indeed, tumors with more than 10 U/mu g of p185 were prevalen tly ER, whereas those with p185 ranging from 3 to 10 U presented eleva ted levels of ER.