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In all likelihood this is the result of better awareness amongst the general public regarding the importance of mammographic screening. Almost 40,000 new cases of DCIS are detected annually. The diagnosis of breast cancer carries with it an ominous prognosis, since there are nearly 40,000 cancer-related deaths each year in the US, making it the second most common cause of cancer death in women (exceeded only by lung cancers). On a happier note, there has been a significant decrease in breast cancer mortality during the last 10 years, primarily as a result of earlier detection and improved therapies.
There is no doubt that breast cancer is a hormone dependent disease. The longer the exposure of the cycling breast epithelium to the ravages of estrogenic hormones, the more the lifetime risk for developing breast cancer. Early menarche, late menopause, and nulliparity are all associated with an increased risk for breast cancer. Notably, oral contraceptive pills are associated with little, if any, increased risk, and the effects of hormone replacement therapy in promoting breast cancer is minimal, far outweighed by the potential benefits.
The cell(s) of origin in the vast majority of breast cancers lies within the terminal ducto-lobular units (TDLU), which comprise the glandular component of normal breast parenchyma. Hence, by extension, virtually all breast cancers are adenocarcinomas. The two main types of adenocarcinomas are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). IDCs, which comprise approximately 80% of invasive breast cancers, recapitulate ductal elements, especially at the well-differentiated end of their histologic spectrum. On the contrary ILCs, which comprise approximately 15% of invasive cancers, recapitulate lobular elements. It is not uncommon to have combined histologic features, given that the TDLU epithelium is considered the common progenitor for both types of cancers. Currently, there are no clinical and prognostic differences between IDC and ILC that would merit different treatment approaches. In addition to these histologic categories, there are several minor subtypes of breast cancers such as medullary cancer (characterized by large, pleomorphic cells, a brisk intratumoral lymphoplasmacytic infiltrate, and a better prognosis than IDC/ILCs); mucinous carcinoma (also known as colloid carcinoma, consists of mucin-producing neoplastic cells floating in pools of extravasated mucin, and associated with a better prognosis than IDC/ILCs); and metaplastic carcinoma (characterized by heterologous sarcomatoid differentiation by the epithelial cells, and associated with an extremely poor prognosis). The single most important factor influencing prognosis in breast cancer is stage, determined by tumor size and axillary node status. The 5-year survival drops from nearly 90% in Stage I localized cancers, to a dismal 15% in Stage IV metastatic cancers.
The genetics of breast cancers is complex and heterogeneous. Family history had long been recognized as a risk factor for cancer, and studies with familial kindreds have led to the isolation of two high-penetrance breast cancer susceptibility genes: BReast CAncer 1 (BRCA1) and BRCA2, on chromosomes 17q21 and 13q12 respectively. Approximately 10% of breast cancers show a strong familial tendency, and women with germline BRCA1 mutations have a 85-90% risk of developing breast cancers (also see OVARIAN CANCERS). Sporadic breast cancers also demonstrate inactivation of BRCA1 by a combination of allelic loss and promoter hypermethylation. Mutations of BRCA1 have so far not been detected outside the familial tumors. Patients with germline BRCA1 mutations develop tumors at a younger age, with an increased frequency of bilaterality and high-grade tumors. Other, much rarer, causes of inherited breast cancers include germline p53 mutations (Li-Fraumeni syndrome), ATM mutations (ataxia telangiectasia) and PTEN mutations (Cowden syndrome). Expectedly, all of these chromosomal loci have also been found to be genetic "hot spots" in sporadic breast cancers. For example, inactivation of p53 is present in up to 50% of breast cancers, irrespective of histology. In most of these studies, p53 mutations have been shown to have an adverse influence on survival.
There are several "conventional" prognostic factors that are assessable by immunohistochemistry, including estrogen and progesterone receptor status, downregulation of which is associated with a poor outcome. Similarly, aneuploidy and a high MIB-1 labeling index are associated with more aggressive tumors. In addition, recent years have seen the emergence of "novel" adjunct prognostic markers, most of which can be assayed on archival material. For example, growth factors and their receptors, including epidermal growth factor (EGF), the EGF receptor and Her-2/neu (c-erbB-2), are overexpressed in 20-40% of breast cancers. Amplification of either EGFR or Her-2/neu has been shown in numerous studies to be adverse prognostic factors in breast cancers, associated with advanced disease, poor treatment response and shorter survival. In this context, the use of FISH technology to identify cases with Her-2/neu amplification and their treatment with the monoclonal antibody to Her-2/neu protein (Herceptin™) has been a major advance in translational cancer research. Similarly, overexpression of the protease cathepsin D has been associated with nodal metastases and shorter event free and overall survival. On the contrary, loss of expression of the adhesion molecule E-cadherin is associated with reduced disease free survival in some series. As newer markers are developed, ongoing studies will be required to validate their importance in risk stratification.
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