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14.1 Breast Cancer

Breast cancer (malignant breast neoplasm) is cancer that initiates from breast tissue, usually from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are identified as ductal carcinomas; those originating from lobules are identified as lobular carcinomas. There are several diverse types of breast cancer, with different aggressiveness, stages (spread), and genetic makeup; survival differs significantly based on these factors. Depending on staging and superlative treatment, 10-year disease-free survival varies from 98 to 100%. Treatment consists of surgery, drugs (hormonal therapy and chemotherapy), and radiation.

Several breast cancers require hormones (estrogen and progesterone) to grow, and have receptors for those hormones. After surgery, these types of cancers are treated with drugs that interfere with these hormones, usually tamoxifen, and with drugs that shut off the production of estrogen in the ovaries or elsewhere; this can harm the ovaries and end fertility. Low-risk, hormone-sensitive breast cancers can be treated with hormone therapy and radiation alone after surgery. Breast cancers without hormone receptors that have extended to lymph nodes in the armpits, or that express certain genetic characteristics present a higher risk and are treated more aggressively.

One usual regimen, established in the United States, is cyclophosphamide plus doxorubicin (Adriamycin), identified as CA. These drugs damage DNA in the cancer, but also in fast-growing normal cells where they cause serious side effects. Occasionally a taxane drug, such as docetaxel, is added, and the regime is then identified as CAT. Taxane attacks the microtubules in cancer cells. An analogous treatment, established in Europe, is cyclophosphamide, methotrexate, and fluorouracil (CMF). Monoclonal antibodies such as trastuzumab (Herceptin) are used for cancer cells that have the HER2 mutation. Radiation is typically added to the surgical bed to kill cancer cells left after surgery. Although radiation usually extends survival, its exposure to the heart can be harmful and cause heart failure in succeeding years.

Breast tumors are categorized into four different stages based on their size, location, and evidence of metastasis. Mode of treatment depends on stage and expression of multidrug-resistant (MDR) transporters that actively pump chemotherapeutic drugs out of the cell and reduce intracellular drug doses below lethal threshold levels. Treatment of primary breast cancer has mainly consisted of initial surgery followed by radiation and various forms of systemic adjuvant therapy. Conventional drug delivery approaches suffer from several limitations such as lack of selectivity and cytotoxicity by nontargeted cells. Therefore, successful targeting strategies must be determined to overcome nonspecific uptake by nontargeted cells. The new signaling networks that regulate cellular activities (such as proliferation and survival) include membrane growth factor receptors, cytoplasmic signaling molecules, nuclear cell cycle proteins, modulators of apoptosis, and molecules that promote angiogenesis. These networks were identified by molecular and genetic approaches in the late 1980's, after which many drugs targeted at key proteins resulted in the beginning of a new targeted-therapy era of cancer drug development.

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