Active signaling by HER-2/neu in a subpopulation of HER-2/neu-overexpressing ductal carcinoma in situ: clinicopathological correlates.

HER-2/neu overexpression occurs in a proportion of invasive breast carcinomasand is an adverse prognostic indicator, although its apparent strength as a prognostic indicator varies in different studies. Paradoxically, HER-2/neu is overexpressed with particularly high frequency in ductal carcinoma in situ (DCIS). We have hypothesized and presented supporting data that HER-2/neu is actively signaling in a subset of the tumors in which it is overexpressed. We use an activation state-dependent anti-HER-2/neu monoclonal antibody (PN2A) produced in our laboratory to study this paradigm immunohistochemically. In this report, we analyze the characteristics of 219 cases of DCIS with respect to HER-2/neu expression and activation state. We find that 58% of cases of DCIS with overexpression have the receptor in the activated state, a substantially greater proportion than we have previously noted for invasive carcinomas. Although HER-2/neu overexpression in general was inversely correlated with hormone receptor expression, cases with activated HER-2/neu had the lowest hormone receptor positivity rate. Statistically significant correlations with activated HER-2/neu were not noted for tumor size, presence of calcifications, necrosis or fibrosis, or indicators of angiogenesis. These results suggest that examination of activated HER-2/neu status may better reflect the biology of a tumor than overall determination of HER-2/neu levels. Our finding that active signaling by HER-2/neu, as detected by this assay, is more frequent in DCIS than previously noted for invasive carcinoma implicates signaling by HER-2/neu as having a critical role in the early stages of breast tumorigenesis.