The Fear of Breast Cancer—And Its Link to Estrogen Use—Causes Many Women to Decline Or Discontinue Estrogen Replacement Therapy
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MANAGEMENT Integrating Practice Management With Patient Care The fear of breast cancer—and its link to estrogen use—causes many women to decline or discontinue estrogen replacement therapy. SERMs offer many of the same benefits with fewer risks, broadening the options for protecting long-term health. BY ANTHONY A. LUCIANO, MD 52 OBG MANAGEMENT • JANUARY 2002 COVER STORY lthough it was initially considered a female cancer mortality.6 The fear of this dis- female sex hormone, estrogen is ease causes many women to decline or dis- A now recognized as a systemic sub- continue ERT, a decision that can profoundly stance that affects every organ system and affect their long-term health.7 Hence, the con- appears to be important for both men’s and troversy regarding ERT centers on weighing women’s health.1-4 At puberty, elevated circu- the risk-benefit balance, i.e., trying to select lating estrogen levels transform girls into patients who are more likely to benefit from young women and shape their feminine fig- the hormone and less likely to suffer from its ures. In boys, estrogen is important in the clo- adverse effects. sure of the epiphyseal plates to arrest post- Physicians—particularly gynecologists pubertal growth and support bone health who devote their care exclusively to throughout life. It also may have Anthony A. Luciano, MD women’s health—have longed for beneficial actions on the male car- the ideal estrogen that will impart diovascular system.2 all of the benefits without the As a systemic hormone, estrogen risks. This ideal estrogen would is important in women for the relieve women of vasomotor and health of the skeleton, the heart, urogenital symptoms and prevent the integuments, and the brain.1,3 the dire consequences of osteo- Women who suffer the loss of porosis, accelerated atherosclero- estrogen through surgery, illness, sis, neurogenic deficit, and colla- or early menopause often are gen loss from the skin, without advised to consider estrogen thera- increasing the risk of cancer and py to protect these organs from thromboembolic phenomena. premature failure. Tamoxifen use Some experts believe this ideal Unfortunately, estrogen re- may be found in the new class of placement therapy (ERT) is a dou- confers a compounds referred to as selec- ble-edged sword, with significant 47% reduction tive estrogen receptor modulators benefits in some organs and sig- (SERMs). Although several SERMs nificant risks in others. ERT pro- in contralateral with desirable estrogenic proper- tects against vasomotor symp- breast cancer. ties are available, none is ideal. toms, urogenital atrophy, osteo- Nevertheless, this new class of porosis, cardiovascular disease, ••• estrogenic substances—with mul- and perhaps Alzheimer’s dis- tiple beneficial effects and fewer ease.1,3 Unfortunately, it also increases the risks—represents an important pharma- risk of venous thromboembolic events, cotherapeutic advance in the care of post- recurrent myocardial infarction and cardiac menopausal women. death5 (in diseased hearts), and cancers of the uterus and breast.4 Tamoxifen Of the many diseases that impact the lives Tamoxifen citrate (Nolvadex; AstraZeneca, of American women, none is more feared Wilmington, Del) has wide clinical applica- than breast cancer, the most common cancer tions in the treatment and prevention of breast in females and the second leading cause of cancer. In 1980, tamoxifen was approved by the FDA for postmenopausal women with Dr. Luciano is professor of OBG at the node-positive breast cancer and for pre- University of Connecticut School of Medicine and menopausal women with estrogen-receptor director of the Center for Fertility and Women’s (ER) positive advanced breast cancer. In 1990, Health, New Britain General Hospital, New the FDA extended the approval of tamoxifen Britain, Conn. to include pre- and postmenopausal women JANUARY 2002 • OBG MANAGEMENT 53 COVER STORY with node-negative, ER-positive breast cancer. In ER-positive tumors, tamoxifen is In patients with node-positive breast can- believed to exert its anti-tumor effects by cer, the 10-year-survival rate improves from inhibiting the estrogen-dependent secretion 50% in control subjects to 61% in patients of growth factors and angiogenic factors by treated with tamoxifen for 5 years. Similar the tumor cells, and by inducing programmed improvements in survival have been report- death of the tumor cells.9 An understanding ed with tamoxifen therapy in node-negative of this mechanism, along with the observa- breast cancer patients. After 5 years of tion that tamoxifen-treated breast cancer tamoxifen therapy and a median follow-up patients not only experience a reduction in of 10 years, the reduction of breast cancer breast cancer recurrence but also a 47% recurrence and death with tamoxifen treat- reduction in contralateral breast cancer, led to ment compared with placebo are 47% and the launch of the tamoxifen chemoprevention 26%, respectively.8 trials in North America and Europe. For women with ER-positive tumors (about In 1992, the National Surgical Adjuvant 70% of all breast cancers), tamoxifen therapy Breast and Bowel Project (NSABP) Tamoxifen of at least 1 year’s duration results in statisti- Breast Cancer Prevention Trial was launched cally significant recurrence and survival bene- in the United States and Canada. The results fits. These results increase with the duration of of this trial were released early because of the treatment up to 5 years. Among ER-positive compelling evidence of tamoxifen’s therapeu- women treated with tamoxifen for 5 years— tic efficacy. The drug was found to reduce the the optimal length of therapy—the annual incidence of breast cancer by 44%, 51%, and recurrence rate is cut in half and the annual 55% in women aged 35 to 49, 50 to 59, and 60 death rate is reduced by 28% (Figure 1).9 or older, respectively. Tamoxifen also was Treatment beyond 5 years does not accrue found to reduce ductal carcinoma in situ by additional benefits and is associated with 50%. Although tamoxifen decreased the over- increased adverse events.10 Tamoxifen has lit- all occurrence of ER-positive tumors by 69%, tle effect on animal tumors and ER-negative it did not have a significant impact on the inci- tumors in cell cultures and confers little or no dence of ER-negative tumors.11 benefit to women with ER-negative tumors.9 Based on these results, the FDA approved the use of tamoxifen for the primary preven- Key points tion of breast cancer in high-risk women. It is important to limit the use of tamoxifen to ■ Among ER-positive breast cancer patients high-risk women because of the potential for treated with tamoxifen for 5 years, the annual serious side effects, which include endometri- recurrence rate is cut in half and the annual al cancer, pulmonary embolism, deep vein death rate is reduced by 28%. thrombosis (DVT), and cataract formation.9-11 ■ Tamoxifen has been shown to reduce the The issue of whether tamoxifen inhibits the incidence of breast cancer by 44%, 51%, and initial development of a tumor or suppresses 55% in women aged 35 to 49, 50 to 59, and 60 an occult tumor remains unresolved. It is pos- and older, respectively. sible that both mechanisms are involved. This ■ Raloxifene mimics the effects of estrogen on is not merely an academic concern. Questions the skeleton and lipids, but acts as a complete remain as to whether a suppressed tumor may estrogen antagonist in the breast and uterus. develop resistance to tamoxifen or even be ■ Recent data indicate that 4 years of ralox- stimulated by the drug, becoming more viru- ifene therapy reduces the risk of all ER-positive lent during or after discontinuation of therapy. breast cancers by 72% compared with placebo. However, given the extensive data and long- term clinical experience and follow-up with ■ The ideal candidate for raloxifene is a post- menopausal woman with osteopenia or osteo- tamoxifen, this scenario seems unlikely. In porosis, no increased risk of thromboembolism, fact, the reduction in the incidence of breast and few or no vasomotor symptoms. cancer appears to continue for years after the therapy is discontinued.12,13 continued on page 57 54 OBG MANAGEMENT • JANUARY 2002 COVER STORY Raloxifene 1 Effect of tamoxifen on Raloxifene hydrochloride (Evista; Eli Lilly ER-positive breast cancer and Company, Indianapolis, Ind) was origi- FIGURE nally investigated for the treatment of breast cancer and was found to be similar to tamox- ifen in its anti-tumor activity. Raloxifene was subsequently studied for its skeletal effects and was approved for osteoporosis preven- tion in postmenopausal women in December 1997, and for fracture prevention in 1999. The agent mimics the effects of estrogen on the skeleton and lipids. However, it acts as a complete estrogen antagonist in the breast and the uterus, making it a more desirable SERM in the management of menopausal events of Number women with an intact uterus. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, Follow-up year placebo-controlled, multicenter study involv- Placebo Tamoxifen ing 7,705 postmenopausal women with Adapted from: Osborne CK. Tamoxifen in the treatment of breast can- osteoporosis at baseline. Although bone cer. N Engl J Med. 1998;339:1609-1618. metabolism and fractures were the primary endpoints, many other outcomes were evalu- women randomized to placebo versus 6.6% ated, including uterine and endometrial of women receiving 60 mg raloxifene daily. effects, bleeding, breast cancer incidence, Although raloxifene decreased the risk of new lipid levels, clotting factors, patient tolerance, vertebral fractures regardless of whether a and adverse events.14-18 The results of these spinal fracture was present at baseline, the studies support the classification of raloxifene absolute percentage decrease in the fracture as a SERM with several desirable estrogen- rate was higher in women who did not have agonistic and -antagonistic effects.