Progress in breast cancer research

Abstract

Breast cancer is a heterogeneous disease composed of multiple different subtypes with distinct molecular features and clinical behavior (1). Gene expression profiling studies have identified at least four major subtypes classified as luminal A, luminal B, HER2+, and basal-like (2). Genome-wide expression profiling of breast tumors has not entered routine clinical practice, but molecular classification according to immunohistochemical assessment of estrogen and progesterone receptors and of HER2 is the basis of individualized therapy that has been guiding the clinical management of patients with breast cancer for the past two decades. Indeed, the first molecular target for cancer therapy was the estrogen receptor (ER) in breast cancer; inhibitors of estrogen signaling display profound antitumor effects in ER+ tumors that show dependency for this pathway (3). Similarly, breast tumors with amplification and overexpression of HER2 (the ERBB2 oncogene) respond well to anti-HER2 targeted therapy (4). ER and HER2 are two of the best examples for molecules that are therapeutic targets and also identify patients who are likely to show a response to treatment, satisfying two important goals of clinical oncology. As a result, the application of antihormonal and anti-HER2 targeted therapies led to dramatic improvements in the outcomes of patients with ER+ and HER2+ disease. However, one of the inevitable consequences of targeted therapy is the selection for tumor cells with inherent or acquired resistance to treatment. Unfortunately, a significant fraction of patients with ER+ or HER2+ tumors do not show a response to treatment or experience relapse and disease progression. Thus, in addition to continuous improvements in the efficacy of antihormonal and anti-HER2 targeted therapies, investigating and overcoming resistance mechanisms and identifying new therapeutic targets have been one of the most intense areas of breast cancer research. The large number of articles focusing on these topics included in this special feature issue of PNAS is a good reflection of the importance of these efforts.