Selective Estrogen-Receptor Modulators in 2001

Breast cancer is the most common cancer seen in women in the United States, and it is estimated than one in eight women will develop the disease. Tamoxifen(Drug information on tamoxifen) (Nolvadex) is a selective estrogen-receptor modulator (SERM) that acts as an antiestrogen in certain tissues, including the breast, while acting like a partial estrogen in other tissues, such as bone and the uterus. Tamoxifen is currently the hormonal treatment of choice for patients with all stages of hormone-responsive breast cancer and has been approved by the US Food and Drug Administration (FDA) for the prevention of breast cancer in high-risk women.[1] Despite the fact that tamoxifen is generally well tolerated, its use is associated with hot flashes and more serious toxicities, including an increased incidence of endometrial cancer and thromboembolic events.[1,2]

Raloxifene (Evista), another SERM, has been approved for the prevention of osteoporosis in postmenopausal women and is being compared with tamoxifen as a preventive agent for breast cancer in high-risk women. There is no indication at present that raloxifene(Drug information on raloxifene) is associated with endometrial cancer,[3] although patients receiving raloxifene have a comparable incidence of hot flashes.[4] A number of new agents, including other SERMs, selective estrogen-receptor downregulators (SERDs), and aromatase inhibitors, are being developed to treat and prevent breast cancer and prevent osteoporosis.

Tamoxifen in Treatment and Prevention

Breast Cancer Treatment

Tamoxifen is FDA-approved for the treatment of all stages of hormone-responsive breast cancer in women of all ages. The overview analysis of adjuvant breast cancer trials demonstrates conclusively that 5 years of tamoxifen prolongs disease-free and overall survival in women of all ages (both pre- and postmenopausal) with node-positive or node-negative, early-stage breast cancer (Figure 1).[2] Tamoxifen improves outcomes only in patients with estrogen-receptor-positive and/or progesterone(Drug information on progesterone)-receptor-positive disease.[2]

The duration of tamoxifen therapy is important, since 5 years of treatment results in better outcomes, compared with shorter durations.[2,5-7] What is not clear is whether tamoxifen should be stopped at 5 years or continued for longer periods. In node-negative patients, tamoxifen results in worse outcomes when it is continued longer than 5 years,[8,9] and the National Cancer Institute (NCI) currently recommends stopping tamoxifen at 5 years.

This issue remains controversial, however, especially in patients with node-positive, early-stage breast cancer. Two large, ongoing trials—the aTTom (Adjuvant Tamoxifen Treatment-Offer More) and the ATLAS (Adjuvant Tamoxifen-Longer Against Shorter)—are randomizing patients to adjuvant tamoxifen for 5 years or longer and hopefully will provide a definitive answer to the question of optimal duration of therapy.

Women with a diagnosis of breast cancer are at increased risk of cancer in the opposite breast. The 1998 overview analysis clearly demonstrates that tamoxifen significantly reduces this risk (Figure 2).[2] As in early-stage breast cancer, longer terms of adjuvant tamoxifen, compared with shorter durations, result in a greater reduction in contralateral breast cancer, with a 50% reduction noted after 5 years. The beneficial effect of tamoxifen persists even after the drug is stopped.[2]

Tamoxifen has a significant antitumor effect in advanced breast cancer. Response rates to endocrine agents, including tamoxifen, are dependent on tumor expression of the estrogen and progesterone receptors.[10] The highest response rates were observed in tumors expressing both estrogen and progesterone receptors: Rates approaching 70% were observed in this group, compared with rates of less than 10% in patients whose tumors express neither receptor.

Effects in Other Tissues

Bone Density—Despite tamoxifen’s antiestrogenic effects on the breast, it has partial, estrogen-like effects elsewhere in the body. Although tamoxifen might be expected to result in bone mineral density loss, this was not found to be the case. Tamoxifen maintains bone density in preclinical models.[11,12] Likewise, in postmenopausal women, tamoxifen actually increases trabecular bone density and does not result in significant bone loss compared with controls, producing a trend toward reduced loss of cortical bone density.[13,14] Additionally, the National Surgical Adjuvant Breast and Bowel Project prevention trial (NSABP P-1) demonstrated a nonsignificant (50%) reduction in hip fractures in women treated with tamoxifen, compared with placebo.[1] Therefore, there is no evidence to suggest that tamoxifen significantly accelerates bone loss—it actually appears to prevent bone loss in postmenopausal women. In premenopausal women, however, tamoxifen results in a slight reduction in bone mineral density.[15]

Cardiovascular Effects—Another concern about tamoxifen’s preventive use in patients with early-stage breast cancer and in healthy women was that it might accelerate the development of coronary heart disease, possibly by a deleterious effect on the lipid profile. In adjuvant breast cancer trials, however, tamoxifen significantly reduces total cholesterol levels. Specifically, tamoxifen reduces low-density lipoprotein[16,17] while causing a slight increase in high-density lipoprotein,[16,18,19] suggesting that its effects on lipid profiles are not identical to those of estrogen. Tamoxifen also reduces fibrinogen,[18,19] lipoprotein(a),[18-20] and homocysteine[21]—all recognized risk factors for the development of coronary artery disease.

There is no clear indication, however, that tamoxifen’s effects on these cardiovascular risk factors translate into a reduction in coronary heart disease. A 25% reduction in cardiovascular mortality was noted in the 1992 overview analysis.[22] A number of other trials demonstrated nonsignificant trends toward reduced myocardial infarctions[23] or deaths from coronary heart disease[24] with 5 years of tamoxifen use. However, no significant reduction in the rates of myocardial infarction, coronary artery bypass, or angioplasty was found in the NSABP P-1 prevention trial.[1]

These findings can, perhaps, be explained by the recent demonstration that estrogen replacement therapy does not prevent the progression of coronary atherosclerosis, as previously thought.[25] In summary, while tamoxifen does not appear to protect against coronary artery disease, more importantly there is no evidence to suggest that tamoxifen increases the risk of coronary heart disease.

Endometrial Cancer—One of the most publicized and potentially serious side effects of tamoxifen is its association with an increased incidence of endometrial cancer. Overall, tamoxifen is associated with a two- to threefold increased risk of endometrial cancer.[2,26] Similar findings were noted in the NSABP P-1 prevention trial, but the increase was seen only in postmenopausal women, with no significant difference in endometrial cancer incidence among premenopausal women treated with tamoxifen or placebo (Figure 3).[1]

A retrospective analysis of tamoxifen-associated endometrial cancer noted an increased risk only for women with a high body mass index and/or a history of estrogen replacement therapy use.[27] Additionally, despite one study to the contrary,[28] tamoxifen is associated with low-grade and early-stage endometrial tumors and good prognosis.[1,2,26] The majority of endometrial tumors associated with tamoxifen occur after short durations of therapy, and it seems likely that tamoxifen stimulates the growth of preexisting cancer cells rather than causing endometrial cancer.