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Initial observational studies of the natural history of breast cancer (untreated) viewed all breast cancers as the same, causing death a median of 2.7 years after presentation.1 Similarly, initial treatment trials2-4 viewed breast cancer as a homogeneous disease with no consideration of possible biological differences. Fortunately, in the 1960s, breast cancer heterogeneity was beginning to be recognized and included such factors as tumor size, the number of tumor-involved lymph nodes,5-7 and later the influence of estrogen receptor (ER) and progesterone receptor (PR).8-10

This progress in understanding the heterogeneity of breast cancer has accelerated in the past 2 decades. Another example of this heterogeneity is the human epidermal growth receptor 2 (HER-2) and its correlation with relapse and survival.11,12 Approximately 20% of tumors have high levels of HER-2 expression (3+ by immunohistochemical staining or an amplified HER-2 gene number copy by fluorescence in situ hybridization). HER-2 represents an important prognostic factor because it identifies patients who may benefit from HER-2-directed therapy.13-15 Most recently, gene expression studies have identified several major subtypes of breast cancer16: the luminal subtypes, which typically express hormone receptor (HR)-related genes, and 2 HR-negative subtypes, the HER-2+/ER− subtype and the basal-like subtype. Prognosis varies by subtype, with worse outcomes traditionally seen with the 2 HR-negative subgroups compared to the luminal subgroups.17-19 "Triple-negative" breast cancer (phenotypically ER, PR, and HER-2 negative) have an early aggressive clinical course when compared with other forms of breast cancer, but the effect appears transient.

This chapter reviews selection of therapy (especially preoperative therapy) in regard to molecular and genetic profiling and the use of genomic testing and Internet mathematical tools (Adjuvant!) for risk stratification.

Gene Expression Arrays

Initially, the heterogeneity of breast cancer was defined by light microscopy histologic differences with hematoxylin and eosin (H&E) stains and then specific immunostains. Moving beyond conventional light microscopy and basic histology, gene expression microarrays attempt to identify which genes are overexpressed or underexpressed in a given breast cancer specimen as compared with normal controls.

From breast cancer specimens, sets of DNA sequences are immobilized on solid substrates. Genes of interest are labeled and hybridization to the array occurs. After a period of time, an image of the array is obtained showing the individual nucleic acid species based on the amount of hybridization to complementary DNAs in known positions on the array. Different fluorescent dyes are used to quantify the relative abundance of a particular gene; the ratio of the intensities of 2 fluorescent dyes provides this answer. This allows researchers to examine and compare genes under varying conditions, that is, to know when and where a gene is expressed.20,21

Clustering of breast cancers according to their intrinsic gene expression patterns by gene expression array profiling studies on breast tumors reveal at least 5 intrinsic subtypes: 16-19 luminal A and B, ...

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