HRT for breast cancer survivors

Commonly accepted dogma says that HRT is not recommended for survivors of breast cancer. This is partly because of the possibility that it will exacerbate the illness and partly because any potential benefits are diminished by the risk of death from breast cancer in these women. These ideas have not withstood the test of time, however, and consideration of HRT seems reasonable in some survivors of breast cancer. This may include women who have severe, debilitating symptoms due to estrogen deprivation; who have menopause-related illnesses such as osteoporosis; who initially had tumors with a favorable prognosis and remained disease-free for extended periods; and those with other indications for HRT. For these women, who should be fully informed about the risk and benefits, low-dose estrogen (0.625 mg/d or less of conjugated estrogens, with or without progestin) may relieve symptoms and is apparently safe.

Hot flashes can be the most bothersome of menopausal symptoms among survivors of breast cancer. A variety of nonestrogenic agents may have mild to moderate effects on hot flashes in some women. Patients with hot flashes or vasomotor symptoms who are taking tamoxifen may also obtain relief with concurrent HRT. Although this combination of therapies is sometimes used, the overall effect is unknown. In some European studies in which concomitant therapy was used, tamoxifen was shown to have no preventive benefit against breast cancer, although patients in a specific study did show a reduced risk of subsequent breast cancer.

Possible chemopreventive agents

The development of SERMS to prevent breast cancer is complex because of the myriad physiologic functions affected by estrogen. The ideal agent for postmenopausal women would take advantage of the short- and long-term beneficial effects of HRT (especially in treating symptoms such as hot flashes while preventing osteoporosis and cardiovascular disease) and minimize adverse effects on the breast and uterus. SERMs offer the possibility of selectively targeting various estrogen responses to prevent the sequelae of estrogen deficiency and menopause. Two major classes of synthetic SERMs are the nonsteroidal triphenylethylenes (tamoxifen and toremifene) and the benzothiophenes (raloxifene). The next generation of SERMs will likely be increasingly tissue- and disease-selective as a much greater understanding is gained of the estrogen response mechanism. Aromatase inhibitors currently being investigated may provide another chemopreventive option in the future.

Who should receive tamoxifen?

For the past 20 years, tamoxifen has been used in the treatment of breast cancer. In 1998, it received FDA approval for reducing the threat of breast cancer in women at high risk for the disease based on the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, which had the largest sample size, greatest statistical power, and greatest number of new breast cancer cases of any similar study conducted to date. But as others had reported, long-term effects of tamoxifen were observed in this study. Endometrial cancers were more common in the tamoxifen group, with a tamoxifen-to-placebo risk ratio of 2.53; risk was greatest in women 50 years of age or older. Moreover, the rates of stroke, Pulmonary embolism, and deep vein thrombosis (DVT) were as great in the tamoxifen group as among HRT users, particularly among those aged 50 or older.

Although tamoxifen has a favorable effect on lipids, evidence for favorable effects on cardiac events has not been consistent. New data were obtained recently on this issue by a large study, the Breast Cancer Prevention Trial (BCPT), conducted by the National Cancer Institute. Researchers found that when used for breast cancer prevention in 13,388 women with and without heart disease, tamoxifen did not reduce the threat of cardiovascular disease, but neither did it increase the risk. Interestingly, tamoxifen is also associated with several beneficial effects, including a reduction in hip, radius, and spine fractures, probably due to maintenance of bone mineral density.

At present, ACOG recommends that the decision to use tamoxifen for reducing the risk of breast cancer be made on an individual basis after taking into consideration the patient’s medical history, risk assessment, and preferences. The American Society of Clinical Oncology defines appropriate risk as comparable to women in the BCPT - at least a 1.67% 5-year risk as calculated by the Gail model.

Although the NCI estimates that 29 million women in the United States are at great enough risk for breast cancer to be candidates for prophylactic therapy with tamoxifen, 20 mg/d, for 5 years, the means of calculating risk are not determined and there are risks of tamoxifen that are not accounted for by the Gail model. But, according to the NCI, those at high risk are women whose risk is equal to or greater than that of the average 60-year-old woman based on the Gail Model, a statistical model of breast cancer risk. The relative benefits of tamoxifen in women taking HRT and in those with specific breast cancer genotypes remains unclear.

We still have no definitive answer about the prophylactic use of tamoxifen for one group of women: cancer-free breast cancer survivors who were diagnosed 5 or more years ago, but who were not then treated with adjuvant tamoxifen. Data from several NSABP protocols examined the subsequent risk of breast cancer in women who survived disease-free for 5 years following an initial diagnosis of invasive breast cancer and who had not received adjuvant tamoxifen. The subsequent 5-year cumulative risk of contralateral invasive breast cancer was 3.4%, which is close to the 3.3% risk for invasive breast cancer in the placebo arm of the P-1 trial; the cumulative risk of all invasive breast cancer in such women was 14.4%. The decision to use tamoxifen for risk reduction in these patients must be based on an assessment of the duration and quality of life remaining, the risks as well as potential benefits of tamoxifen, and the presence of competing morbidity that may weigh against the use of tamoxifen. For example, tamoxifen may be appropriate in a 50-year-old woman who is otherwise healthy, but less suitable for a 68-year-old woman with a history of cataracts and DVT.