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Menopause Matters

Breast Cancer and Selective Estrogen Receptor Modulators: Who Should Use Them, and Why?

Wendy Y. Chen, MD, MPH

The prospect of breast cancer chemoprevention offers hope to so many women, but it raises some basic questions as well—eg, who can benefit, which agent is better for which patient, and what is the risk/benefit profile?

Given that breast cancer is the most common cancer among women, with an estimated 178,000 new cases annually,1 a chemoprevention agent could clearly have a significant impact. Currently, 2 selective estrogen receptor modulators (SERMs) are FDA-approved for this indication: tamoxifen and raloxifene.

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TAMOXIFEN

On the basis of the landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen has been approved for the reduction of breast cancer risk in women at higher risk of developing this disease. The P-1 trial randomized 13,388 women to either tamoxifen or placebo, demonstrating a 43% decrease in the incidence of invasive and noninvasive estrogen-receptor (ER)–positive breast cancer in the tamoxifen arm.2 Other large, randomized, placebo-controlled trials have confirmed these findings. Notably, in studies with longer follow-up, the protective effect of tamoxifen extended into the posttreatment period, suggesting that tamoxifen was truly preventing cancers rather than simply suppressing their growth.2-4 However, the use of tamoxifen for chemoprevention has been limited due to concerns regarding potential adverse effects and general unfamiliarity with the drug, which is primarily considered an oncology agent.

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RALOXIFENE

Because of tamoxifen’s adverse effects (eg, increased risk of uterine cancer and thromboembolic events), attention shifted to raloxifene. This SERM had only limited efficacy in the treatment of metastatic breast cancer,5 but was FDA-approved to treat osteoporosis. Three randomized, placebo-controlled trials evaluated the impact of raloxifene on breast cancer incidence, and all showed a similar 44% to 72% reduction in the incidence of invasive breast cancer compared with placebo.6-8 Lastly, the Study of Tamoxifen And Raloxifene (STAR) trial randomized 19,747 postmenopausal women to tamoxifen or raloxifene.9 After an average follow-up of 4 years, rates of invasive breast cancer were similar in both arms. The data from these 4 trials led to the approval of raloxifene by the FDA in September 2007 for the reduction of breast cancer risk among postmenopausal women with osteoporosis and/or at high risk for invasive breast cancer.

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COMPARISONS

The main advantage of raloxifene over tamoxifen is a more favorable side-effect profile (Table). First, whereas tamoxifen has been widely associated with an increased risk of uterine cancer,10,11 raloxifene has not been shown to increase the risk of uterine cancer compared with placebo.6-8 When compared directly with tamoxifen, there was a nonsignificantly lower risk of uterine cancer with raloxifene (relative risk [RR] 0.62, 95% confidence interval [CI] 0.35 to 1.08), but statistically significant differences in the risks of uterine hyperplasia (RR 0.16, 95% CI 0.09 to 0.29) and number of hysterectomies performed (RR 0.44, 95% CI 0.35 to 0.56) favoring raloxifene. Secondly, although raloxifene increased the risk of thromboembolic events (defined as deep venous thrombosis or pulmonary emboli) compared with placebo, the risk was lower than that associated with tamoxifen.9 Thirdly, cataract risk was higher with tamoxifen; unlike tamoxifen, the placebo-controlled trials demonstrated no increase in cataract risk with raloxifene.2,8,12 In the STAR trial, the risk of cataracts with raloxifene was significantly lower than with tamoxifen (RR 0.79, 95% CI 0.68 to 0.92).9 It should be noted that these comparisons refer mainly to postmenopausal women because the raloxifene trials were restricted to this population. In the P-1 trial, the adverse effects of tamoxifen appeared to be less in women younger than 50 years of age compared with women over age 50. However, as the absolute event rate was so small in the younger age group, it was unclear whether the risks truly differed.2 Finally—in contrast to tamoxifen—ObGyns and primary care physicians are already comfortable prescribing raloxifene, which is widely used to treat osteoporosis.

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TABLE. Adverse Effects of Tamoxifen Compared With Raloxifene*†

However, raloxifene does have several disadvantages compared with tamoxifen. Raloxifene can only be used in postmenopausal women, as few data exist on long-term safety in premenopausal women. On the other hand, tamoxifen has been shown to be effective in the adjuvant treatment and primary prevention of breast cancer in both premenopausal and postmenopausal women. Another advantage of tamoxifen is its effectiveness against noninvasive cancers.2,13 For reasons that are unclear, raloxifene appears mainly to decrease the risk of invasive, but not noninvasive, cancers.6,9 Nevertheless, since minimization of harm is key for prevention, raloxifene would be preferred in postmenopausal women due to its more favorable side-effect profile. Tamoxifen would be preferred for premenopausal women.

In terms of quality of life and patient-reported symptoms, raloxifene and tamoxifen were similar overall. Although some minor differences were seen between the two in the STAR trial, they did not reach clinical significance.14 However, compared with placebo, women taking raloxifene reported more hot flashes, leg cramps, and peripheral edema.6-8 Compared with placebo, the most common side effects reported by tamoxifen users are hot flashes/night sweats and vaginal discharge.15

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RISK ASSESSMENT

The most challenging issue for clinicians is to determine who would most benefit from breast cancer prevention with SERMs and how to make that evaluation during a routine office visit. Several investigators have assessed ways to identify women with the optimal risk/benefit ratio for breast cancer prevention.10,15 Gail et al10 estimated that for white women younger than 50 years of age, the benefits of tamoxifen would outweigh the risks regardless of presence/absence of a uterus because of the lower adverse-event rate in this population. For postmenopausal women older than age 70, they thought it unlikely that tamoxifen would be associated with a beneficial effect given the higher adverse-event rate and competing, non-breast-cancer causes of mortality.10 A separate analysis was also performed specifically focusing on women aged 50 to 70 years who would be likely candidates for both breast cancer chemoprevention and raloxifene to treat osteoporosis. Among women in their early 50s, only those in the highest decile of breast cancer risk had a favorable risk/benefit ratio, whereas 50% of the women in the 65-to-69-year age group would potentially benefit from raloxifene.16

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RECOMMENDATIONS

So who should be considered for breast cancer chemoprevention, and which agent should be used? Raloxifene has been shown in randomized, placebo-controlled trials to decrease the incidence of invasive breast cancer among postmenopausal women with only a small increase in thromboembolic risk. For women in their 70s, neither raloxifene nor tamoxifen would likely be associated with an overall benefit given the higher risks of adverse events and competing causes of mortality. For premenopausal women, the only option is tamoxifen, and the decision to pursue chemoprevention would be based on the underlying breast cancer risk, as adverse events rates are low in women younger than 50 years. For postmenopausal women aged 50 to 70 years, raloxifene may be more appealing because of the decreased risk of adverse effects compared with tamoxifen. Again, the decision for chemoprevention would be based on the underlying breast cancer risk but it should be remembered that breast cancer risk increases with age. Therefore, women in their 60s are more likely to derive benefit from raloxifene than women in their 50s, mainly due to the higher incidence of breast cancer as women age.

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CONCLUSION

When discussing breast health with postmenopausal women, it is crucial to consider their underlying risk factors, especially family history of breast cancer or personal history of benign breast disease. The Gail model is a useful tool for risk estimation (www.cancer.gov/bcrisktool). For many postmenopausal women aged 50 to 70, raloxifene as a breast cancer prevention agent should be considered. In addition, when considering treatment options for osteoporosis, the possible benefits of raloxifene in terms of breast cancer prevention should be considered as well.

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Wendy Y. Chen, MD, MPH, is Assistant Professor in Medicine, Channing Laboratory, Brigham and WomenÕs Hospital, Harvard Medical School; and in the Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School; both in Boston, MA.

References

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16. Chen WY, Rosner B, Colditz GA. Moving forward with breast cancer prevention. Cancer. 2007; 109(12):2387-2391.

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