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The inherent heterogeneity associated with breast cancer makes determination of tumor characteristics that greatly impact patient outcome (such as aggressiveness, ability to metastasize, response to various chemotherapeutic agents) difficult or impossible, especially at the time of initial diagnosis. Given that a number of different genetic, chromosomal, and epigenetic changes contribute to the development of breast cancer, every tumor is intrinsically complex and potentially distinct. Because the aberrant cells that give rise to these tumors accumulate numerous molecular changes during neoplastic transformation and tumorigenesis, the response to treatment and eventual progression for a given tumor is determined by the combined influence of numerous genes (and other factors). Thus, understanding the molecular mechanisms that affect numerous genes concurrently may hold the key for better clinical management of breast cancer.

Recent advances in our understanding of the gene expression patterns that characterize different classes of breast cancer and the links between gene expression, tumor behavior, and patient outcome promise to provide better prognostication for individual patients, as well as guides for clinicians in choosing appropriate treatment strategies (33, 35, 37). The development of targeted therapies for some subsets of breast cancer (such as ER+ and Her2+ breast tumors) has greatly reduced the cancer burden and mortality rates associated with these breast tumors, and extended the life expectancy for many women.

While these advances have improved breast cancer treatment, several classes of tumors remain difficult to treat effectively. Tumors types that lack targeted therapies (such as basal breast cancer) are more difficult to treat and clinicians are left with cytotoxic chemotherapeutics as the only means of treatment. As a result, these tumors account for a disproportionate number of breast cancer deaths each year. Thus, there is an urgent need not only for better targeted treatment strategies, but also for an improved understanding of the molecular basis of these poor-prognosis breast tumors in order to improve the long-term outcome of women with these tumors. Better understanding, rapid identification, and improved treatment of basal-like tumors will result in substantial alleviation of the overall breast cancer burden since the poorest outcome tumors account for a large portion of breast cancer deaths.

Challenges of Basal Breast Cancer

Women with triple negative (ER-/PR-/Her2-) breast cancer, of which basal tumors make up a large subset, are among those with the poorest overall survival rates (35, 40, 50). Breast tumors of the basal subtype make up ~25% of all breast cancers and tend to display more aggressive tumor characteristics, such as increased size, rapid tumor growth, increased rate of metastasis to other organ sites, higher incidence of relapse, and lower overall patient survival (40, 49, 272, 273). The genetic and epigenetic events that lead to development of these cancers is incompletely understood, and, represents the focus of much scientific inquiry in the hopes of uncovering the molecular basis of these neoplasms (46). In addition to possessing a number of aggressive characteristics, basal breast cancers have been reported to exhibit a number of unique features that are not well understood. For example, basal breast cancer appears to occur at a higher incidence in pre-menopausal African-American women

(compared either pre-menopausal Caucasians or post-menopausal women of either ethnicity), complicating the understanding of incidence of this subtype (40). In fact, a recent study of 148 Nigerian women with breast cancer revealed that 59% of these women had basal-like breast cancer, a rate more than double what would be expected (reviewed in 46). Although the true cause remains unclear, the factors that account for this overrepresentation of poor- prognosis basal tumors in women of African ancestry may include genetic predisposition, environmental factors, cultural practices, socioeconomic factors (access to care), or a combination of all of these. Additionally, several studies have reported findings that seem to indicate that basal breast cancers may metastasize in unique ways, being less likely to metastasize to the bone than the viscera, and having higher rates of brain metastases compared to metastatic breast cancers of other subtypes (46, 50, 274). Better understanding of the unusual features of basal-like breast cancer may lead to the development of new therapies and more rapid molecular diagnostics.

Current Treatment Options for Basal Breast Cancer

Basal breast tumors display a general resistance to most currently available targeted treatment options for breast cancer, including hormonal therapies (as they are typically ER- and PR-), as well as trastuzumab (as they are typically Her2-). Whereas numerous studies have shown that basal-like breast cancers generally respond well to preoperative chemotherapy (52, 275), patients who do not achieve pathologic complete response with such treatment face a higher likelihood of relapse than patients with breast cancers representing the other molecular subtypes. Additionally, basal breast cancers tend to be highly proliferative (46), which may partially explain this tendency towards initial response to treatment followed by relapse. The higher proliferation rates of these tumors may result in

more rapid death of a high percentage of tumor cells after drug treatment, but leaving a few resistant tumor cells which could cause to eventual relapse. The genetic instability exhibited by many basal breast cancers may also confer an increased likelihood toward development of resistance to whichever treatment regime is administered (46). For example, many basal breast cancers are p53 mutant. The p53 status of these breast cancers impact significantly on drug treatment, since p53 mutant tumors have been reported to be resistant to certain anthracycline-based chemotherapeutic regimens (276).

Currently a number of signaling molecules are under investigation as potential targets for basal-like breast cancers. For example, EGFR signaling has been inhibited successfully in other cancers and EGFR is frequently overexpressed in basal-like breast cancers (46). However the development of an IHC-based assay that accurately measures EGFR protein levels has proven difficult to achieve (277), slowing the progress on this front. Drugs that target the growth factor receptor c-KIT (such as imatinib) are already used to treat many cancers. However, c-kit is only expressed by ~30% of basal breast cancers, limiting the potential usefulness of imatinib. Furthermore, imatinib was found to have no activity against metastatic breast cancers in a recent phase II clinical trail (278). Many other signaling targets are currently under investigation for development of drugs for use against breast malignancies, including inhibitors of Ras, Raf, MEK, MTOR, and Src (46), but until the unique mechanisms underlying basal breast cancer are better understood, progress in treating these malignancies will be incremental at best.