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from Part 3.1 - Molecular pathology: carcinomas
Published online by Cambridge University Press: 05 February 2015
Introduction
Our molecular understanding of breast cancer has increased significantly over the past 20 years. This has resulted in a system of breast cancer classification that is dependent upon their expression of specific proteins, thus breast cancers are often described as estrogen-receptor (ER) positive, ERBB2 over-expressing, or triple negative for ER, progesterone receptor (PR), and ERBB2 expression. In addition, molecular profiling has further refined the classification of breast cancers into five main subgroups, based on distinct gene-expression patterns: luminal A, luminal B, ERBB2 positive, basal, and normal breast-like (1). These groups correlate with many clinical parameters, including patient survival. This has encouraged the rational development of targeted cancer therapies, some of which are in clinical use. The classic example of a treatment that was developed based on our understanding of the biology of the tumor is tamoxifen, a selective ER modulator that interferes with the ligand-stimulated functions of the receptor. For the past 35 years tamoxifen has been the gold standard adjuvant or first-line therapy for patients with ERα- positive tumors and new ER-targeted therapies such as selective receptor down-regulators and aromatase inhibitors are now being used in clinics. The role of ER in breast cancer, the treatments that have been developed to target it and their clinical efficacy are discussed elsewhere (2).
In this review we will discuss the ERBB2 receptor tyrosine kinase (RTK), which has been successfully targeted by antibody-based approaches and by tyrosine kinase inhibitors (TKIs). We will also discuss an emerging target whose inhibition leads to blockade of DNA single-strand break repair in breast tumors with BRCA mutations. Finally, combination treatments targeting different pathways are generally more successful than single treatments in cancer therapy. We will discuss approaches being investigated to combine targeting of ERBB2, ERα, and PI3K.
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