Breast Cancer Genetics

tality associated with the disease. This can be achieved either by cure of existing cancer or prevention of new cases. Cure rates are enhanced when breast cancer is diagnosed at an early stage and when therapies are applied according to clearly defined indicators. The problem being confronted is enormous. In the United States, an estimated 203,500 women will have been diagnosed with breast cancer in 2002, and 40,000 will die from the disease (Tables 5.1 and 5.2).1 Breast cancer progression is the result of a multistep process in which the cumulative effect of successive discrete genetic alterations leads to a gradual transition from normal through premalignant to frankly malignant tissue and ultimately to metastasis.2 Our understanding of breast cancer biology continues to increase through the characterization of the genes involved in this progressive transformation.3–7 Much of this knowledge is derived from studies of the alterations that occur in breast tumor cells and from studies of families with inherited susceptibility to breast cancer.3–12 Our increasing knowledge provides many opportunities for intervention, including increased surveillance of populations at risk, institution of chemoprevention therapy (tamoxifen) for patients at high risk of disease (genetic predisposition, prior breast cancer) as well as for patients with preinvasive lesions (carcinoma in situ), and specific therapy for early stage invasive cancer based on specific prognostic and predictive indicators. Even for advanced breast cancer, knowledge of the genetic abnormalities underlying a cancer’s progression can impact patient well being and survival (e.g., HER2/neu overexpression). Because breast cancer has been termed a genetic disease, it is easy to assume that any woman with a positive family history who develops breast cancer has done so because of an inherited predisposition. In fact, only 20% to 30% of all women who develop breast cancer report a positive family history, and not all of these women have hereditary susceptibility to the disease.13–15 Several nongenetic factors can lead to familial clustering of breast cancer, including: (1) a large family in which many women reach old age, and chance alone causes multiple women to develop this common cancer; (2) an extended family 5