**4. Lasofoxifene**

158 Cancer of the Uterine Endometrium – Advances and Controversies

groups in the number of hysterectomies performed during the course of follow-up. Among women who were not diagnosed with endometrial cancer, there were 244 hysterectomies performed in those assigned to tamoxifen compared with 111 in those assigned to raloxifene

No significant differences existed between the tamoxifen and raloxifene groups in patientreported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function (Land et al. 2006). Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)–approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased the risk of endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05–1.47) and for noninvasive disease, 1.22 (95% CI, 0.95–1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast

With follow-up extended to 81 months in the STAR Trial, toxicity relative risks (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36–0.83; *P* = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12–0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60–0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with

Invasive uterine cancer and uterine hyperplasia are well-established toxicities associated with tamoxifen treatment. When compared with tamoxifen, raloxifene does not have such a profile. The incidence of invasive uterine cancer is significantly lower in the raloxifene group (*P* = 0.003). The annual average rate per 1,000 was 2.25 in the tamoxifen group compared with 1.23 in the raloxifene group (RR = 0.55; 95% CI, 0.36–0.83). In the original report of the STAR trial (Vogel et al. 2006), the difference between treatment groups for the rate of invasive uterine cancer was not statistically significant. The average annual incidence rate of uterine hyperplasia, the majority of which was hyperplasia without atypia, was 5 times higher in the tamoxifen group (4.40 per 1,000) than in the raloxifene group (0.84 per

(RR, 0.44; 95% CI, 0.35-0.56).

**3.3.2 STAR quality of life** 

**3.4 Raloxifene summary** 

elevated risk for breast cancer.

cancer.

musculoskeletal problems, dyspareunia, and weight gain.

Lasofoxifene is a nonsteroidal selective estrogen-receptor modulator that decreases bone resorption, bone loss, and low-density- lipoprotein (LDL) cholesterol in postmenopausal women. It is a potent third-generation SERM that was developed because of its potentially attractive pharmacological profile as an agent for risk reduction of fractures, breast cancer, and heart disease in postmenopausal women at increased risk of osteoporotic fractures. Preclinical laboratory evidence showed that lasofoxifene reduced bone loss and cholesterol, prevented experimental breast cancers, and did not cause endometrial hyperplasia (Cummings et al. 2010). Early clinical studies confirmed its potency relative to raloxifene in reducing bone loss and serum cholesterol, whereas neither agent increased the risk for endometrial hyperplasia.

As we have seen, currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene reduced the risk of estrogen receptor–positive breast cancer, non-vertebral and vertebral fractures, coronary artery disease, and stroke.

The effects on total breast cancer (invasive and ductal carcinoma in situ, ER- positive and estrogen receptor–negative) and ER- positive invasive breast cancer were also assessed. Postmenopausal women (n = 8556) aged 59–80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and non-vertebral fractures at 5 years (LaCroix et al. 2010). A nested case–control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER- positive invasive breast cancer by baseline serum estradiol and sex hormone–binding globulin levels. Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail breast cancer risk score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs. those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79).

These data confirm that a 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER-positive invasive breast cancer in postmenopausal women with osteoporosis.

Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, is associated with reduced risks of vertebral fracture, non-vertebral fracture, ER-positive breast cancer, coronary heart disease events, and stroke. Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, is associated with reduced risks of vertebral fracture and stroke. Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events, respectively. Endometrial cancer occurred in 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 prevention of both osteoporosis and invasive breast cancer.

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 placebo, for 5 years.


\*Statistically significant difference from placebo.

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 women.
