**5. Population risks and benefits of SERM therapy**

The risks associated with tamoxifen therapy are shown in Table 5. Using the rates shown in the table, we can calculate that among the more than 65 million women aged 35–79 years without reported breast cancer in the United States in 2000, 10 million women (Freedman et

three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Endometrial cancers were diagnosed in two women in each lasofoxifene group and three women in the placebo group. Endometrial hyperplasia was confirmed in two women in the higher-dose lasofoxifene group, three women in the lower-dose lasofoxifene group, and no women in the placebo group. This SERM may represent a much safer option than either tamoxifen or raloxifene for the

A prospective study established the gynecological effects of 5 years of treatment with lasofoxifene versus placebo in postmenopausal osteoporotic women (Goldstein et al. 2011). The results are shown in Table 4. A total of 8,556 women aged 59 to 80 years with femoral neck or spine bone mineral density T scores of -2.5 or lower were randomly assigned to receive either lasofoxifene 0.25 mg/day, or lasofoxifene 0.5 mg/day, or

**Lasofoxifene** 

1.9%\* 1.6% 1.2%

**0.50 mg/day Placebo** 

prevention of both osteoporosis and invasive breast cancer.

**Lasofoxifene 0.25 mg/day** 

**(number of cases)** 2 2 3

**(number of cases)** 3 2 0

**(percent)** 2.2%\* 2.6%\* 1.3%

**(percent)** 8.8%\* 5.5\* 3.3%

Table 4. Rates of gynecological events among postmenopausal women taking lasofoxifene. Endometrial cancer was confirmed for two women in each lasofoxifene group and for three women in the placebo group. Endometrial hyperplasia and vaginal bleeding occurred in more women treated with either 0.25 mg/day or 0.5 mg/day lasofoxifene than in women treated with placebo. Lasofoxifene treatment resulted in a small increase in endometrial thickness versus placebo. Similar numbers of women required surgery for pelvic organ prolapse or urinary incontinence in the placebo and 0.5 mg/day lasofoxifene groups. These findings indicate that 5 years of lasofoxifene treatment result in benign endometrial changes that do not increase the risk for endometrial cancer or hyperplasia in postmenopausal

The risks associated with tamoxifen therapy are shown in Table 5. Using the rates shown in the table, we can calculate that among the more than 65 million women aged 35–79 years without reported breast cancer in the United States in 2000, 10 million women (Freedman et

placebo, for 5 years.

**Endometrial cancer** 

**Uterine hyperplasia** 

**Endometrial polyps** 

\*Statistically significant difference from placebo.

**5. Population risks and benefits of SERM therapy** 

**Vaginal bleeding** 

**Surgery for prolapsed or incontinence (percent)** 

women.

al. 2003) would have been eligible for tamoxifen chemoprevention. The percentage of U.S. women who would be eligible varied dramatically by race, with 18.7% (95% CI = 17.8% to 19.7%) of white women, 5.7% (95% CI = 4.3% to 7.5%) of black women, and 2.9% (95% CI = 2.1% to 3.9%) of Hispanic women being eligible. Of the 50 million white U.S. women aged 35–79 years, more than 2.4 million (would have a positive benefit/risk index for tamoxifen chemoprevention. Of the 7 million black U.S. women aged 35–79 years, only 42,000 would have a positive benefit/risk index. Among white women, more than 28,000 breast cancers would be prevented or deferred if those women who have a positive net benefit index took tamoxifen over the next 5 years.: A substantial percentage of U.S. women are eligible for chemoprevention according to FDA criteria, and a percentage of them would have an estimated net benefit. Nevertheless, this latter percentage corresponds to more than two million women.

Revised estimates show that of the more than 9 million white U.S. women in 2010 who would be eligible for tamoxifen chemoprevention, about one-third would derive a net benefit from taking the drug on the basis of their age and breast cancer risk factors (Freedman et al. 2011). Among the white women who would benefit from tamoxifen, approximately more than 58,000 invasive breast cancers will develop over the next 5 years. If all 2 431 911 women in the US with an estimated net benefit/risk index took tamoxifen over the next 5 years, and if the risk reduction of 49% applies, then 28 492 of these breast cancers would be prevented, or deferred, which would be a substantial achievement.


Table 5. Numbers of non-breast cancer events prevented (positive number) or caused (negative number) in 5 years among 10,000 women treated with tamoxifen (Gail et al. 1999). For non-Hispanic white women age 50 years or older with a uterus, raloxifene displays a better benefit/risk profile than tamoxifen overall (Freedman et al. 2011). For tamoxifen, women age 50 to 59 years with a 5-year risk of invasive breast cancer of 4.5% to 6.5% showed moderate evidence of net positive benefit, and women with risk of 7.0% or higher showed strong evidence. For women age 50 to 59 years with a 5-year risk of invasive breast cancer less than 4.0%, the risks outweighed the benefits. The risks outweighed the benefits for women age 60 years or older, regardless of IBC risk. In contrast, for raloxifene, there was strong evidence that benefits outweighed risks, compared with placebo, for women age 50 to 59 years with a 5-year breast cancer risk of 3.5% or higher and for women age 60 to 69 years with an risk of 6.5% risk or higher. There was moderate evidence of a net benefit for women age 50 to 59 years with a 5-year risk of 2.0% to 3.0%, women age 60 to 69 years with a 5-year risk of 3.0% to 6.0%, and women age 70 to 79 years with a 5-year IBC risk of 4.0% or higher. For postmenopausal black and Hispanic women with a uterus, raloxifene also displayed a better benefit/risk profile than tamoxifen and in a similar pattern to that for whites. Net benefit indices tended to be larger in Hispanic women and smaller in black women than in white women, however.

#### **6. American Society of Clinical Oncology (ASCO ) recommendations for breast cancer risk reduction**

In premenopausal women, tamoxifen for 5 years reduces the risk of breast cancer for at least 10 years, particularly estrogen receptor (ER) –positive invasive tumors. Women ≤ 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign and malignant uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in risk of breast cancer from either agent translates into reduced BC mortality.

#### **6.1 2009 Recommendation for the Use of tamoxifen to reduce the risk of developing breast cancer**

Five years of tamoxifen (20 mg/d) may be offered to women at increased risk of breast cancer to reduce their risk of estrogen receptor (ER) –positive invasive breast cancers for up to 10 years (Visvanathan et al. 2009). Eligible women include those with a 5-year projected breast cancer risk ≥ 1.66% (according to the National Cancer Institute [NCI] Breast Cancer Risk Assessment Tool based on the Gail model23 —available at http://www.cancer.gov/bcrisktool) or women with LCIS. The benefit of taking tamoxifen for more than 5 years is unknown. The greatest clinical benefit and the fewest side effects were derived from the use of tamoxifen in younger (premenopausal) women 35 to 50 years of age who are unlikely to experience thromboembolic sequelae or uterine cancer, women without a uterus, and women at high risk of breast cancer (Newman and Vogel 2007). Vascular and vasomotor side effects were observed to decline post-treatment across all ages. Tamoxifen is not recommended in women with a prior history of deep vein thrombosis (DVT), pulmonary embolus (PE), stroke, or transient ischemic attack. Combined use of tamoxifen for breast cancer prevention and hormone therapy (HT) is currently not recommended. Follow-up should include a baseline gynecologic examination before initiation of treatment and annually thereafter, with a timely work-up for abnormal vaginal bleeding. The risks and benefits of tamoxifen should be given careful consideration during the decision-making process. There has been no mortality differences observed in the tamoxifen prevention trials so far, most likely because these trials were not powered to detect such outcomes. Nevertheless, a reduction in breast cancer incidence is considered to be an important health outcome in and of itself.

#### **6.2 ASCO 2009 recommendation for the use of raloxifene to reduce the risk of developing breast cancer**

For postmenopausal women at increased risk for breast cancer, raloxifene (60 mg/d) for 5 years may be offered as another option to reduce the risk of ER-positive invasive breast cancer. Raloxifene has been shown to be equally efficacious to tamoxifen in reducing breast cancer risk in postmenopausal women. However, raloxifene was not as effective in reducing the incidence of noninvasive breast cancer compared with tamoxifen, although the association was not statistically significant. In the STAR trial, raloxifene was associated with a more favorable side-effect profile compared with tamoxifen, including a statistically significant lower risk of thromboembolic disease, benign uterine complaints, and cataracts as compared with tamoxifen. Raloxifene, like tamoxifen, is not known to have an effect on overall or breast cancer–specific mortality in women at increased risk of breast cancer. However, the risk reduction trials were not powered to detect a reduction in breast cancer incidence rather than mortality, as it was felt to be an important end point in and of itself. Raloxifene may be used for longer than 5 years in women with osteoporosis in whom breast cancer risk reduction is an additional potential benefit. Raloxifene is not recommended in premenopausal women or in women with a prior history of DVT, PE, stroke, or transient ischemic attack. In postmenopausal women, the risks and benefits of both tamoxifen and raloxifene, including risks of noninvasive breast cancer, adverse events, and impact on quality of life, should be discussed in detail with women before coming to a decision about risk reduction strategies.
