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Molecular subtypes of breast cancer
MOLECULAR PROFILING — Molecular profiling, based upon variations in gene expression, has been used to characterize breast cancers beyond the conventional use of grade, histology, and immunohistochemical analysis of hormone receptors and human epidermal growth factor receptor-2 (HER2) overexpression. The resulting taxonomy defines the breast cancer intrinsic subtypes. Molecular profiling of a different kind has also enhanced our ability to predict clinical outcome and response to therapy. The cellular and molecular heterogeneity of breast cancer and the large number of genes involved in controlling cell growth, death, and differentiation emphasize the importance of studying multiple genetic alterations in concert. Gene expression profiling, using microarrays to which cDNA or oligonucleotide probes have been affixed, allows the simultaneous measurement of the activity (expression) of thousands of genes in a breast cancer cell. BREAST CANCER INTRINSIC SUBTYPES — Gene expression studies have identified several distinct breast cancer subtypes. These include two main subtypes of estrogen receptor (ER)-negative tumors, basal-like and human epidermal growth factor receptor-2 (HER2)-enriched, and two subtypes of ER-positive tumors, luminal A and luminal B. These subtypes differ markedly in prognosis and in the therapeutic targets they express. Using the semisupervised approach described above and using multiple different platforms and populations, several naturally occurring breast cancer subtypes have been reproducibly identified. The list of genes that differentiates these subtypes is called the intrinsic list and is made up of several clusters of genes relating to ER expression (the luminal cluster), HER2 expression, proliferation, and a unique cluster of genes called the basal cluster. The intrinsic subtypes segregate into two groups that correspond to expression of hormone receptor-related genes. This separation is supported by the literature and clinical experience that suggest that ER-positive and ER-negative status define breast cancers that are biologically different and may derive from different progenitor cells. The luminal cancers, luminal A and luminal B, so called because they are characterized by expression of genes also expressed by normal breast luminal epithelial cells, have overlap with ER-positive breast cancers. There are also several subtypes characterized by low expression of hormone receptor-related genes (ER-negative), one of which is called the "HER2-enriched" subtype (previously called HER2+/ER-) and another called the "basal-like" subtype. The basal-like subtype is named because it expresses many genes characteristic of normal breast basal epithelial cells. Luminal subtypes — The name "luminal" derives from similarity in expression between these tumors and the luminal epithelium of the breast; they typically express luminal cytokeratins 8 and 18. These are the most common subtypes, make up the majority of ER-positive breast cancer, and are characterized by expression of ER, PR, and other genes associated with ER activation. Luminal A and luminal B have some important molecular and prognostic distinctions.
HER2-enriched — The HER2-enriched subtype (previously the HER2+/ER- subtype) makes up about 10 to 15 percent of breast cancers and is characterized by high expression of the HER2 and proliferation gene clusters, and low expression of the luminal cluster. For this reason, these tumors are typically negative for ER and PR, and positive for HER2. It is important to note that this subtype comprises only about half of clinically HER2-positive breast cancer. The other half have high expression of both the HER2 and luminal gene clusters and fall in a luminal subtype. In the era before HER2-targeted therapy, this subtype carried a poor prognosis. This adverse natural history has been markedly affected by therapeutic advances in HER2-directed therapy. Basal-like — The basal-like subtype, so called because of some similarity in expression to that of the basal epithelial cells, makes up about 15 to 20 percent of breast cancers. It is characterized by low expression of the luminal and HER2 gene clusters. For this reason, these tumors are typically ER-, PR-, and HER2-negative on clinical assays, which has prompted the nickname "triple negative" to describe them. However, while most triple negative tumors are basal-like, and most basal-like tumors are triple negative, there is significant discordance (up to 30 percent) between these two classification methods that must be kept in mind when evaluating studies focused upon basal-like breast cancer. These tumors have high expression of the proliferation cluster of genes, are virtually always high grade, and evidence widespread genomic instability even early in the disease. They also have high expression of the epidermal growth factor receptor (EGFR), as well as a unique cluster of genes called the basal cluster, which includes basal epithelial cytokeratins 5, 14, and 17. Basal-like breast cancer has unique risk factors. Among the most intriguing is the strong association with cancers arising in women born with a mutation in the breast cancer gene 1, early onset (BRCA1) gene, in whom over 80 percent are basal-like.Even so, most basal-like breast cancers are sporadic, and the BRCA1 gene and protein appear intact in these tumors. A commonly held, but unproven, assumption is that the BRCA1 pathway is abnormal in sporadic basal-like breast cancer, which may have therapeutic implications since this pathway is important in DNA repair. Another notable association is between the basal-like subtype and race and age. Population-based studies suggest that the basal-like subtype is overrepresented in breast cancer developing during the premenopausal years and in African-American women. For this reason, it is particularly prevalent among young African-American women. Basal-like breast cancer carries a poor prognosis; it is possible that this prevalence may contribute in part to the worse outcomes experienced by African-American women with breast cancer. Fortunately, studies suggest that basal-like breast cancers are sensitive to modern chemotherapy However, the absence of targeted therapy of known effectiveness in this subtype remains a real obstacle to improving outcomes. Prognosis — The intrinsic subtypes were developed to identify relevant biology, not for prognostication; however, in multiple independent datasets, these subtypes correlate with prognosis. In general, patients with the luminal A subtype have the best prognosis; patients with the other major hormone receptor-positive subtype, luminal B, suffer a significantly worse outcome. Both the basal-like and HER2-enriched subtypes have the worst survival, at least until recently; the era of HER2-targeting has altered the outcome for the HER2-enriched subtype and HER2-positive luminal cancers. Studies in population-based samples mimic these results. In a population-based study of nearly 500 tumors using immunohistochemical proxies for the subtypes, the best outcome was observed among patients with luminal A tumors compared with the other subtypes, and the worst outcome was seen among basal-like breast cancers SUMMARY — Molecular profiling, based upon variations in gene expression, has identified several distinct breast cancer subtypes, named the breast cancer intrinsic subtypes.
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