Chemoprevention of breast cancer in the older patient.

Breast cancer is the most common cancer in women and is the second leading cause of death from cancer in women. It is estimated that in 1999, 176,300 new cases of breast cancer will develop, and one in eight women will develop breast cancer over her lifetime. 52 Age is an important risk factor for breast cancer: 1 in 15 American women between the ages of 60 and 79 years will develop breast cancer. Most known risk factors for breast cancer are factors that affect endogenous estrogen levels. 42,50 A strong family history of breast cancer, however, may be the most important factor for identifying those women at highest risk of developing breast cancer. 15 About 5% of breast cancers are related to genetic predisposition. 58 Mutations in the BRCA1 and BRCA2 genes are implicated in 80% of high-risk families in which three or more members have a history of breast or ovarian cancer. 31,32,97 These genes are located on chromosomes 17 and 13, respectively, and help encode a protein that is important in the suppression of proliferation of breast cells. 41,64,97 Carriers of the BRCA1 or BRCA2 gene mutations have as much as an 85% chance of developing breast cancer 31 and a 50% chance of developing ovarian cancer over their lifetime. 33 Most women with a family history of breast cancer, however, do not have a significant genetic predisposition for breast cancer, because breast cancer is so common that it is not unusual to find for a woman to have a relative with a history of breast cancer. Most breast cancers occur because of chance and are related to multiple risk factors. Factors that increase the likelihood of genetic predisposition include early age of onset in family members (a history of cancer under the age of 50), bilateral breast cancer, and family members with a history of multiple cancers, such as breast and ovarian cancer. 44 The challenge lies in developing a model that adequately estimates the risk of developing breast cancer in women who are not thought to be genetic carriers, because these women represent the largest at-risk population. Dr. Gail from the National Cancer Institute has devised a model to evaluate risk of developing breast cancer. 5 The Gail model, which initially was introduced as a tool for health care professionals to use in counseling women about their risk of breast cancer, combines known risk factors for breast cancer and allows variance in determining risk of developing breast cancer based on years of risk. This model has been incorporated into a computer program to enhance the ease of counseling women regarding their risk. Risk factors in this model include family history of breast cancer among primary family members, age, age at menarche, nulliparity or age at first live birth, history of previous breast biopsies, and the number of years of risk that one is interested in calculating. For example, lifetime risk of developing breast cancer is calculated by starting with the age of 80 and subtracting the woman's current age. Previous breast biopsies that carry the most significant risk are those with evidence of atypical hyperplasia. Atypical hyperplasia is thought to be a precursor to invasive cancer and has been associated with a fourfold increased risk of developing breast cancer. 29,54 The Gail model for evaluating risk has been verified in several other screening populations. It was assessed in the Texas Breast Screening Project and the Nurses' Health Study, and in both populations the model estimated the risk of breast cancer acceptably. 11,85 The Gail model was tested primarily in a white upper-middle-class population of women having annual mammographic screening. Therefore, this model has been criticized because it may not adequately evaluate risk of breast cancer in a minority population of women who are not undergoing regular mammographic screening. This model may not apply to women who are at increased risk of developing breast cancer because of genetic predisposition, and it does not take into account affected secondary family members, age of affected family members, bilaterality, or multiplicity of cancers in family members. The Gail model was used to calculate the risk of developing breast cancer in the first large-scale breast cancer prevention trial, the Tamoxifen Breast Cancer Prevention Trial, and helped determine a population of women at increased risk of developing breast cancer. Recently, the results of this first large-scale breast cancer prevention trial were reported. 37 Tamoxifen, which has been studied in two other prevention trials in Italy and the United Kingdom, was the preventive agent studied in this trial. Tamoxifen, the first antiestrogen available for the treatment of breast cancer, has been in clinical use for the last 30 years as a hormonal treatment for breast cancer 47 and has long been the established hormonal treatment in the management of breast cancer in the metastatic and adjuvant settings. 35,38,43,46,53,60,69,72,73,82 In addition to its antiestrogen benefits seen in the treatment of breast cancer, tamoxifen has been shown to have favorable estrogen agonist effects on serum lipids and bone mineral density. Specifically, tamoxifen has been demonstrated to decrease total serum cholesterol, primarily by decreasing low-density lipoprotein cholesterol. 4,6,12,57 In studies involving postmenopausal women, tamoxifen has been shown to increase bone mineral density. 39,56,70,98 Tamoxifen has estrogen agonist properties on the endometrium, and studies have shown that women receiving tamoxifen therapy have an associated increased risk of developing endometrial cancer. Several breast cancer treatment trials have documented the risk of endometrial cancer as 1 in 1000/year of tamoxifen use. 1,36 The success of tamoxifen encouraged the development of selective estrogen receptor modulators (SERMs). These SERMs mediate estrogen agonist and estrogen antagonist effects in particular tissues and have been developed to target specific tissues at specific sites. 13 Another large-scale breast cancer prevention trial, focusing on the new SERM raloxifene, is on the horizon for women at high risk of developing breast cancer. The ideal SERM for preventing breast cancer in postmenopausal women would maintain favorable estrogen agonist effects that alleviate menopausal symptoms, decrease cardiac mortality, and decrease osteoporotic fractures while displaying antiestrogen effects in the breast and endometrium.