Approximately 5% to 10% of breast cancers have a familial or genetic link. Mutations in the BRCA family of genes confer a lifetime risk of breast cancer that approaches 85%. BRCA1 and BRCA2 are the main genes involved. These genes also increase the risk of ovarian cancer. The breast cancer that occurs in women >50 years of age or in postmenopausal women is often hormone receptive. Tamoxifen has been found to delay cancer return for more than a decade, and women taking the drug had one third lower risk of dying.

Pathophysiology

Two main categories of breast cancer have been identified. The first is ductal carcinoma in situ (DCIS), which starts in the ductal epithelium. It is considered in situ when it has not penetrated the base membrane and is usually found in older women. Most of these cancers have infiltrated and spread by the time of discovery. This is the most common type of cancer, although the histology of these cancers is varied. The second type of cancer is lobular cancer, which consists of uniform small, round neoplastic cells that are slower to infiltrate. Among these two major categories of cancer are a variety of histologic types. For example, inflammatory cancer is rare but highly malignant. It is rapid growing and characterized by inflammation of the skin. Breast cancer is divided into four classes for optimal selection of treatment: (1) DCIS, (2) primary operable breast cancer, (3) locally advanced breast cancer, and (4) breast cancer with metastasis.

Much research has been related to risk factors, and new ones have been discovered. Box 56-1 lists the well-established risk factors. A breast cancer risk calculator can be found at http://www.cancer.gov/bcrisktool. It also can be obtained by calling 800-4-CANCER, or through AstraZeneca Pharmaceuticals, which manufactures tamoxifen.

Self-breast examination and mammography are effective in screening for early breast cancer. Screening mammography reduces breast cancer mortality by about 33% in women 50 to 70 years old. However, effectiveness is less well established for women younger than 50 years of age. The American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists have agreed that all women should undergo annual screening mammography beginning at age 40.

Aromatase Inhibitors

Anastrozole blocks the aromatase enzyme from converting androstenedione to estrone and testosterone to estradiol. Many breast cancers also contain aromatase. Anastrozole is a potent and selective nonsteroidal aromatase inhibitor; it lowers serum estradiol concentrations.

Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the aromatase enzyme, resulting in reduction of estrogen biosynthesis in all tissues. It is a more potent inhibitor of the aromatase enzyme than is anastrozole.

Exemestane is a steroidal aromatase inactivator. It acts as a false substrate for the aromatase enzyme that binds irreversibly to the active site of the enzyme, causing its inactivation. This results in decreased circulating estrogen concentrations.

(Recommendations may vary depending on whether the patient is premenopausal or postmenopausal.)

Cardinal Points of Treatment

Pharmacotherapeutic Treatment

All these medications have the primary effect of reducing estrogen in the body. Thus, they have many characteristics in common and are effective primarily for estrogen-sensitive cancers.

Tamoxifen was approved in 1994. The other drugs in this chapter are relatively newer. Tamoxifen is used for the prevention of breast cancer in women who are at increased risk (Box 56-1). The benefits are weighed against the risks of drug use (see breast cancer risk calculator at http://www.cancer.gov/bcrisktool). It has a “black box” warning because of the risk of increased endometrial cancer, stroke, pulmonary embolism, and deep venous thrombosis. As with all drugs, the benefits should be weighed against the risks of drug use.

Tamoxifen is used for the treatment of patients with breast cancer in the following situations: when the axillary node is negative after total or partial mastectomy or radiation in tumors >1 cm, for the treatment of node-positive breast cancer in postmenopausal women after total mastectomy or after radiation, and in advanced estrogen receptor–positive metastatic disease in men or women. Women who took tamoxifen for 5 years after a breast cancer diagnosis were nearly 40% less likely to have the cancer return, protection that lasted for more than a decade after they stopped taking the drug. Current tamoxifen therapy is associated with a significantly increased incidence of diabetes in older breast cancer survivors, but aromatase inhibitor use has no known association with diabetes.

Soltamox is a liquid formulation of tamoxifen that has been developed to help improve compliance with medications when the effects of radiation, surgery, or chemotherapy has made it difficult for the patient to swallow the pill form of tamoxifen. Additionally, this formulation is helpful for some people who prefer liquid medications rather than pills or just want to reduce the number of pills they have to take daily. Clinicians may have patients fill out a simple 10-question survey to help assess if they have difficulty swallowing. The EAT-10 is a clinically validated tool available at www.swallowingdifficulties.org and provides results helpful in stimulating discussions about a swallowing problem.

The newer antiestrogen drugs have been associated with fewer adverse reactions. Currently, these are used only for the treatment of patients with breast cancer.

Aromatase inhibitors convey many of the same risks as the antiestrogens. Currently, they are used only for the treatment of breast cancer. Recent studies have shown they are effective in reducing the rate of invasive breast cancer in postmenopausal women at moderately increased risk, although this is not yet a FDA-approved indication.