Breast cancer is a heterogeneous disease, and within the HER-2 positive subtype this is highly exemplified by the presence of substantial phenotypical and clinical heterogeneity, mostly related to hormonal receptor (HR) expression. It is well known how HER-2 positivity is commonly associated with a more aggressive
tumor phenotype and decreased overall survival and, moreover, with a reduced benefit from endocrine treatment. Preclinical studies corroborate the role played by functional crosstalks between HER-2 and
estrogen receptor (ER) signaling in endocrine resistance and, more recently, the activation of ER signaling is emerging as a possible mechanism of resistance to HER-2 blocking agents. Indeed, HER-2 positive
breast cancer heterogeneity has been suggested to underlie the variability of response not only to endocrine treatments, but also to HER-2 blocking agents. Among HER-2 positive
tumors, HR status probably defines two distinct subtypes, with dissimilar clinical behavior and different sensitivity to
anticancer agents. The triple positive subtype, namely, ER/PgR/Her-2 positive
tumors, could be considered the subset which most closely resembles the HER-2 negative/HR positive
tumors, with substantial differences in biology and clinical outcome. We argue on whether in this subgroup the "standard" treatment may be considered, in selected cases, i.e., small
tumors, low
tumor burden, high expression of both hormonal receptors, an overtreatment. This article review the existing literature on
biologic and clinical data concerning the HER-2/ER/PgR positive
tumors, in an attempt to better define the HER-2 subtypes and to optimize the use of HER-2 targeted agents,
chemotherapy and endocrine treatments in the various subsets.