**2.1 Endometrial cancer**

The rate of endometrial cancer was increased in the tamoxifen group by more than 2.5-fold (risk ratio = 2.53; 95% confidence interval = 1.35–4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older.


Table 1. Events and incidence rates of invasive and *in situ* endometrial cancer in the placebo and tamoxifen groups by age at study entry in the BCPT.

The average annual rate of invasive endometrial cancer per 1000 participants was 2.30 in the tamoxifen group and 0.91 in the placebo group. The increased risk was predominantly in women 50 years of age or older. The relative risk of endometrial cancer was 4.01 (95% CI 4 1.70–10.90) in women aged 50 years or older, and increase in incidence after tamoxifen administration was observed early in the follow-up period. Through 66 months of followup, the cumulative incidence was 5.4 per 1000 women and 13.0 per 1000 women in the placebo and tamoxifen groups, respectively. Fourteen (93%) of the 15 invasive endometrial cancers that occurred in the placebo group were International Federation of Gynecology and Obstetrics (FIGO) stage I, and one (7%) was FIGO stage IV. All 36 invasive endometrial cancers that occurred in the group receiving tamoxifen were FIGO stage I. Four *in situ* endometrial cancers were reported; three of these occurred in the placebo group and one in the tamoxifen group. The cumulative incidence of invasive endometrial carcinoma along with other side effects in the trial through seven years of follow-up is shown in Figure 1.

Through 66 months of follow-up, the cumulative incidence was 5.4 per 1000 women and 13.0 per 1000 women in the placebo and tamoxifen groups, respectively. These rates are shown in Figure 2. Fourteen (93%) of the 15 invasive endometrial cancers that occurred in the placebo group were International Federation of Gynecology and Obstetrics (FIGO) stage I, and one (7%) was FIGO stage IV. All 36 invasive endometrial cancers that occurred in the group receiving tamoxifen were FIGO stage I. Four in situ endometrial cancers were reported; three of these occurred in the placebo group and one in the tamoxifen group.

The rate of endometrial cancer was increased in the tamoxifen group by more than 2.5-fold (risk ratio = 2.53; 95% confidence interval = 1.35–4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women

**Type of cancer Placebo Tam Placebo Tam Diff RR‡ 95% CI** 

Invasive 17 53 0.68 2.24 −1.56 3.28 1.87 to 6.03

≤49 y at entry 9 12 0.82 1.16 −0.34 1.42 0.55 to 3.81

≥50 y at entry 8 41 0.58 3.08 −2.50 5.33 2.47 to 13.17

 *In situ* cancer 3 1 0.12 0.04 0.08 0.35 0.01 to 4.36

Table 1. Events and incidence rates of invasive and *in situ* endometrial cancer in the placebo

The average annual rate of invasive endometrial cancer per 1000 participants was 2.30 in the tamoxifen group and 0.91 in the placebo group. The increased risk was predominantly in women 50 years of age or older. The relative risk of endometrial cancer was 4.01 (95% CI 4 1.70–10.90) in women aged 50 years or older, and increase in incidence after tamoxifen administration was observed early in the follow-up period. Through 66 months of followup, the cumulative incidence was 5.4 per 1000 women and 13.0 per 1000 women in the placebo and tamoxifen groups, respectively. Fourteen (93%) of the 15 invasive endometrial cancers that occurred in the placebo group were International Federation of Gynecology and Obstetrics (FIGO) stage I, and one (7%) was FIGO stage IV. All 36 invasive endometrial cancers that occurred in the group receiving tamoxifen were FIGO stage I. Four *in situ* endometrial cancers were reported; three of these occurred in the placebo group and one in the tamoxifen group. The cumulative incidence of invasive endometrial carcinoma along with other side effects in the trial through seven years of follow-up is shown in

Through 66 months of follow-up, the cumulative incidence was 5.4 per 1000 women and 13.0 per 1000 women in the placebo and tamoxifen groups, respectively. These rates are shown in Figure 2. Fourteen (93%) of the 15 invasive endometrial cancers that occurred in the placebo group were International Federation of Gynecology and Obstetrics (FIGO) stage I, and one (7%) was FIGO stage IV. All 36 invasive endometrial cancers that occurred in the group receiving tamoxifen were FIGO stage I. Four in situ endometrial cancers were reported; three of these occurred in the placebo group and one in the tamoxifen group.

**Rate per 1000 women** 

**2.1 Endometrial cancer** 

aged 50 years or older.

Figure 1.

**No. of events** 

and tamoxifen groups by age at study entry in the BCPT.

Fig. 1. Comparison of relative risks (with 95% confidence intervals) of benefits and undesirable effects of tamoxifen from the initial and updated results of NSABP P-1. (Fisher 2005).

Fig. 2. Cumulative incidence of invasive endometrial carcinoma through seven years of follow-up.

After 7 years of follow-up, women who received tamoxifen still had a statistically significantly increased risk of invasive endometrial cancer (RR = 3.28, 95% CI = 1.87 to 6.03) (Fisher et al. 2005). Again, the risk was not increased in women aged 49 years or younger (RR = 1.42, 95% CI = 0.55 to 3.81), but there was a statistically significant increase in risk in women aged 50 years or older (RR = 5.33, 95% CI = 2.47 to 13.17). The cumulative rate of invasive endometrial cancer through 7 years of follow-up was 4.68 per 1000 women in the placebo group and 15.64 per 1000 women in the tamoxifen group, respectively (*P*<.001). Of the 70 cases of endometrial cancer (17 in the placebo group and 53 in the tamoxifen group), 67 cases (15 in the placebo group and 52 in the tamoxifen group) were International Federation of Gynecology and Obstetrics (FIGO) stage I. Of the remaining two cases in the placebo group, one was stage III and one was stage IV. The remaining case in the tamoxifen group was stage III. Four cases of endometrial cancer *in situ* were observed: three in the placebo group and one in the tamoxifen group. In addition to these cases of endometrial cancer, there were four cases of uterine sarcoma, one in the placebo group and three in the tamoxifen group.

#### **2.2 Gynecologic and vasomotor symptoms**

Vaginal discharge was reported in almost 55% of women on tamoxifen in the NSABP-P1 trial, and 78% of women on tamoxifen reported bothersome hot flashes during treatment. Results from the Italian trial, which included only women who had a hysterectomy, also showed a statistically significant increase in vaginal discharge for women taking tamoxifen (RR = 3.44; 95% CI, 2.90 to 4.09).17

#### **3. Raloxifene**

Raloxifene was the first of a benzothiophene series of antiestrogens to be labeled a SERM. Raloxifene has the ability to bind to and activate the estrogen receptor while exhibiting tissue-specific effects distinct from estradiol (Vogel 2007). As a result, raloxifene was specifically developed to maintain beneficial estrogenic activity on bone and lipids and antiestrogenic activity on endometrial and breast tissue. In December 1997, the U.S. Food and Drug Administration (FDA) labeled raloxifene for the prevention of osteoporosis. These agents work by inducing conformational changes in the estrogen receptor resulting in differential expression of specific estrogen-regulated genes in different tissues. Activation of the estrogen receptor by raloxifene may involve multiple molecular pathways that may result in gene expression of ligand-, tissue- and/or gene-specific receptors

Raloxifene undergoes extensive systemic biotransformation, but it does not appear to be metabolized by the cytochrome P450 pathway. Clinically significant interactions are unlikely to occur with drugs typically eliminated by this route. Raloxifene has a plasma elimination half-life of approximately 27 hours. This prolonged elimination half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling.

Raloxifene appears to lack proliferative effects on endometrial tissue. Data from both animal and human studies demonstrate that raloxifene has minimal effects on the uterus and causes no significant changes in the histologic appearance of the endometrium (Boss et al. 1997). Two six-month studies involving a total of 969 postmenopausal women showed that endometrial thickness did not differ between women receiving raloxifene (30 to 150 mg per day) and those receiving placebo (Delmas et al. 1997).

In healthy, postmenopausal women raloxifene (200 to 600 mg per day given over eight weeks) does not induce endometrial proliferation as measured by endometrial biopsies. By comparison, 77 percent of the women who receive unopposed estrogen (0.625 mg per day of conjugated estrogen) have moderate to marked estrogenic proliferation of endometrial tissue. Women who received conjugated estrogen were also noted to have a much higher incidence of vaginitis than those who received raloxifene or placebo.

A trial in 136 healthy postmenopausal women compared the stimulatory effects on the uterus of raloxifene (150 mg per day) and continuous hormone replacement therapy (0.625 mg per day of conjugated estrogen with 2.5 mg per day of medroxyprogesterone). After a period of 12 months, the women who received estrogen replacement therapy experienced significant changes in endometrial thickness and uterine volume. In contrast, the women who were treated with raloxifene exhibited no changes in either parameter. Additional short-term trials appear to support the view that raloxifene does not produce endometrial stimulation.

#### **3.1 MORE/CORE trials uterine events**

152 Cancer of the Uterine Endometrium – Advances and Controversies

After 7 years of follow-up, women who received tamoxifen still had a statistically significantly increased risk of invasive endometrial cancer (RR = 3.28, 95% CI = 1.87 to 6.03) (Fisher et al. 2005). Again, the risk was not increased in women aged 49 years or younger (RR = 1.42, 95% CI = 0.55 to 3.81), but there was a statistically significant increase in risk in women aged 50 years or older (RR = 5.33, 95% CI = 2.47 to 13.17). The cumulative rate of invasive endometrial cancer through 7 years of follow-up was 4.68 per 1000 women in the placebo group and 15.64 per 1000 women in the tamoxifen group, respectively (*P*<.001). Of the 70 cases of endometrial cancer (17 in the placebo group and 53 in the tamoxifen group), 67 cases (15 in the placebo group and 52 in the tamoxifen group) were International Federation of Gynecology and Obstetrics (FIGO) stage I. Of the remaining two cases in the placebo group, one was stage III and one was stage IV. The remaining case in the tamoxifen group was stage III. Four cases of endometrial cancer *in situ* were observed: three in the placebo group and one in the tamoxifen group. In addition to these cases of endometrial cancer, there were four cases of uterine

Vaginal discharge was reported in almost 55% of women on tamoxifen in the NSABP-P1 trial, and 78% of women on tamoxifen reported bothersome hot flashes during treatment. Results from the Italian trial, which included only women who had a hysterectomy, also showed a statistically significant increase in vaginal discharge for women taking tamoxifen

Raloxifene was the first of a benzothiophene series of antiestrogens to be labeled a SERM. Raloxifene has the ability to bind to and activate the estrogen receptor while exhibiting tissue-specific effects distinct from estradiol (Vogel 2007). As a result, raloxifene was specifically developed to maintain beneficial estrogenic activity on bone and lipids and antiestrogenic activity on endometrial and breast tissue. In December 1997, the U.S. Food and Drug Administration (FDA) labeled raloxifene for the prevention of osteoporosis. These agents work by inducing conformational changes in the estrogen receptor resulting in differential expression of specific estrogen-regulated genes in different tissues. Activation of the estrogen receptor by raloxifene may involve multiple molecular pathways that may

Raloxifene undergoes extensive systemic biotransformation, but it does not appear to be metabolized by the cytochrome P450 pathway. Clinically significant interactions are unlikely to occur with drugs typically eliminated by this route. Raloxifene has a plasma elimination half-life of approximately 27 hours. This prolonged elimination half-life has been attributed to

Raloxifene appears to lack proliferative effects on endometrial tissue. Data from both animal and human studies demonstrate that raloxifene has minimal effects on the uterus and causes no significant changes in the histologic appearance of the endometrium (Boss et al. 1997). Two six-month studies involving a total of 969 postmenopausal women showed that endometrial thickness did not differ between women receiving raloxifene (30 to 150 mg per

In healthy, postmenopausal women raloxifene (200 to 600 mg per day given over eight weeks) does not induce endometrial proliferation as measured by endometrial biopsies. By

result in gene expression of ligand-, tissue- and/or gene-specific receptors

the drug's reversible systemic metabolism and significant enterohepatic cycling.

day) and those receiving placebo (Delmas et al. 1997).

sarcoma, one in the placebo group and three in the tamoxifen group.

**2.2 Gynecologic and vasomotor symptoms** 

(RR = 3.44; 95% CI, 2.90 to 4.09).17

**3. Raloxifene** 

The MORE trial randomized 7,705 postmenopausal women younger than 81 years (mean age= 66.5 years) with osteoporosis to raloxifene or placebo (Cummings et al. 1999). The primary aim of the MORE study was to test whether 3 years of raloxifene reduced the risk of fracture in postmenopausal women with osteoporosis, and the occurrence of breast cancer was a secondary end point. Women were excluded if they took estrogens within 6 months of randomization and were not permitted to take concomitant estrogen replacement therapy with the study drug. With a median follow-up of 40 months, raloxifene reduced the risk of invasive breast cancer by 76% in postmenopausal women with osteoporosis, largely accounted for by a 90% reduction in ER-positive breast cancer. Raloxifene did not reduce the risk of ER-negative breast cancer. There was no apparent decrease in ER-negative cancers. In addition, raloxifene decreased the risk of vertebral fractures and decreased low-density lipoprotein cholesterol levels. Raloxifene did not increase the risk of endometrial cancer, endometrial hyperplasia or vaginal bleeding (Table 2) but was associated with a threefold increase in thromboembolic events. More women in the raloxifene group reported increased rates of hot flashes, leg cramps, and peripheral edema.

The Continuing Outcomes Relevant to Evista (CORE) trial was designed to evaluate the efficacy of an additional 4 years of raloxifene therapy in preventing invasive breast cancer in women who participated in the MORE trial (Martino et al. 2004). CORE was a multicenter, double-blind, placebo-controlled clinical trial. The CORE trial was conducted in the subset of the MORE women who agreed to participate in what was an extension of the MORE trial, with a change in the primary endpoint from vertebral fracture incidence to invasive breast cancer. A secondary objective of the CORE trial was to examine the effect of raloxifene (at 60 mg/day) on the incidence of invasive ER-positive breast cancer. Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n= 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n=1703). Women in the raloxifene group had a 59% reduction in the incidence of all invasive breast cancer compared with women in the placebo group and a 66% reduction in the incidence of invasive ER-positive breast cancers compared with women in the placebo group. By contrast, the incidence of invasive ER-negative breast cancer in women who received raloxifene was not statistically significantly different from that in women who received placebo. The overall incidence of breast cancer, regardless of invasiveness, was reduced by 50% in the raloxifene group


compared with the placebo group. Again, there was no observed increase in the risk of endometrial cancer attributable to raloxifene.

\* CORE = Continuing Outcomes of Relevant to Evista; MORE = Multiple Outcomes of Raloxifene Evaluation.

† Dose of 60 mg of raloxifene per day during the CORE trial.

‡ Based on two-sided Fisher's exact test.

§ Doses of 60 mg or 120 mg of raloxifene per day during the MORE trial and 60 mg of raloxifene per day during the CORE trial.

ǁ Includes only women who had an intact uterus at baseline of the MORE trial. For 4 years beginning at visit 1 of CORE, n = 1008 and n = 2138 for the placebo and raloxifene groups, respectively. For 8 years beginning at randomization in MORE, n = 1026 and n = 2167 for the placebo and raloxifene groups, respectively.

Table 2. Rates of adverse events among the CORE enrollees\*.

#### **3.2 RUTH Trial**

The Raloxifene Use and the Heart (RUTH) trial randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for coronary heart disease (CHD) to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years (Barrett-Connor et al. 2006). The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer.

As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events, and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor–positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke. Raloxifene reduced the risk of clinical vertebral fractures. Raloxifene did not significantly affect the risk of CHD. There was no significant difference between the treatment groups in the number of women with one or more reported adverse events. More women in the raloxifene group than in the placebo group permanently discontinued use of the study drug because of an adverse event.

Four common adverse events (an acute coronary syndrome, anxiety, constipation, and osteoporosis) were reported more frequently in the placebo group than in the raloxifene group, and seven (arthritis, cholelithiasis, dyspepsia, hot flush, intermittent claudication, muscle spasm, and peripheral edema) were reported more frequently in the raloxifene group than in the placebo group (P≤0.05). Hot flushes, leg cramps, peripheral edema, and gallbladder disease, all special search categories, were more common in women assigned to raloxifene than to placebo. The rates of cholecystectomy did not differ significantly between the treatment groups (P=0.25). The incidences of endometrial cancer and all cancers other than breast cancer did not differ significantly between treatment groups. Few details were provided about the endometrial cancers that were observed.

#### **3.3 STAR Trial**

154 Cancer of the Uterine Endometrium – Advances and Controversies

compared with the placebo group. Again, there was no observed increase in the risk of

4 years beginning at visit 1 of the CORE trial

> Raloxifene group†

CORE enrollees, % (No.)

Placebo

*P* ‡

0.20 (2) 0.19 (4) >.99 1.36 (14) 1.25 (27) .87

Adverse event (N = 1286) (N = 2725) (N = 1286) (N = 2725) *P* ‡

hyperplasia<sup>ǁ</sup> 0.20 (2) 0.05 (1) .24 0.29 (3) 0.37 (8) >.99 Endometrial cancer<sup>ǁ</sup> 0.30 (3) 0.19 (4) .69 0.39 (4) 0.32 (7) .75

§ Doses of 60 mg or 120 mg of raloxifene per day during the MORE trial and 60 mg of raloxifene per day

 Includes only women who had an intact uterus at baseline of the MORE trial. For 4 years beginning at visit 1 of CORE, n = 1008 and n = 2138 for the placebo and raloxifene groups, respectively. For 8 years beginning at randomization in MORE, n = 1026 and n = 2167 for the placebo and raloxifene groups,

The Raloxifene Use and the Heart (RUTH) trial randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for coronary heart disease (CHD) to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years (Barrett-Connor et al. 2006). The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary

As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events, and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor–positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke. Raloxifene reduced the risk of clinical vertebral fractures. Raloxifene did not significantly affect the risk of CHD. There was no significant difference between the treatment groups in the number of women with one or more reported adverse events. More women in the raloxifene group than in the placebo group permanently discontinued use of the study drug because of an

CORE = Continuing Outcomes of Relevant to Evista; MORE = Multiple Outcomes of Raloxifene

8 years beginning at randomization in the MORE trial

group Raloxifene group§

endometrial cancer attributable to raloxifene.

Vaginal bleeding<sup>ǁ</sup>

during the CORE trial.

Endometrial

Evaluation.

respectively.

**3.2 RUTH Trial** 

adverse event.

\*

ǁ

Placebo group

† Dose of 60 mg of raloxifene per day during the CORE trial.

Table 2. Rates of adverse events among the CORE enrollees\*.

‡ Based on two-sided Fisher's exact test.

syndrome) and invasive breast cancer.

The Study of Tamoxifen and Raloxifene (STAR Trial) was conducted to compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes (Vogel et al. 2006). It was carried out by The National Surgical Adjuvant Breast and Bowel Project Study and was a prospective, double-blind, randomized clinical trial conducted in nearly 200 clinical centers throughout North America. Patients were 19,747 postmenopausal women of mean age 58.5 years who had increased 5 year breast cancer risk. Women received either oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) daily over 5 years. Outcome measures included the incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, and thromboembolic events.

At the time of the planned, initial analysis, there were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs. 4.41 per 1000; RR = 1.02; 95% confidence interval [CI], 0.82-1.28). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR = 0.62; 95% CI, 0.35-1.08).

Fig. 3. Invasive uterine cancer and thromboembolic events in the STAR Trial.

After a median of 47 months of follow-up, there was a trend toward a decreased incidence of uterine cancer in the raloxifene group, but the difference was not statistically significant— 36 cases (tamoxifen) vs. 23 (raloxifene). Annual incidence rates were 2.00 per 1000 (tamoxifen) and 1.25 per 1000 women (raloxifene) (RR = 0.62; 95% CI, 0.35-1.08). Cumulative incidence rates through 7 years were 14.7 per 1000 (tamoxifen) and 8.1 per 1000 (raloxifene) (P = .07,). These events are shown in Figure 3. Only 1 case of uterine cancer occurred among women younger than 50 years, in a participant in the tamoxifen group. The majority of women who developed uterine cancer (56 [91%]) were diagnosed with stage I disease. Of the remaining cases, there was 1 case of stage II disease in each of the treatment groups, 2 with stage III disease in the raloxifene group, and 1 with stage IV disease in the raloxifene group. Two of these cases were mixed Mullerian cell type; both were in the tamoxifen group.

Table 3 shows that while there were no statistically significant differences with respect to risk of uterine cancer, there were differences between the treatment groups indicating that the effect of raloxifene on the uterus is less than that of tamoxifen. Among those who did not have a diagnosis of uterine cancer, there was a statistically significant difference between the groups in the incidence of uterine hyperplasia. The rates were 84% less in the raloxifene-treated group (14 cases) than in the tamoxifen-treated group (84 cases) (RR, 0.16; 95% CI, 0.09-0.29). This magnitude of difference between treatment groups was evident for hyperplasia both with and without atypia. For the tamoxifen and raloxifene groups, respectively, there were 12 cases and 1 case with atypia (RR, 0.08; 95% CI, 0.00- 0.55) and 72 and 13 cases without atypia (RR, 0.18; 95% CI, 0.09-0.32). There also was a statistically significant difference between the treatment 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 (RR, 0.44; 95% CI, 0.35-0.56).

After 81 months of follow-up, the incidence of invasive uterine cancer was significantly lower in the raloxifene group (Vogel et al. 2010). 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, 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 1,000; RR = 0.19; 95% CI, 0.12–0.29). The number of hysterectomies performed in the tamoxifen group, including those done for benign disease, was more than double that performed in the raloxifene group (RR = 0.45; 95% CI, 0.37–0.54).


Table 3. Uterine Events in the Study of Tamoxifen and Raloxifene (STAR Trial).

(tamoxifen) and 1.25 per 1000 women (raloxifene) (RR = 0.62; 95% CI, 0.35-1.08). Cumulative incidence rates through 7 years were 14.7 per 1000 (tamoxifen) and 8.1 per 1000 (raloxifene) (P = .07,). These events are shown in Figure 3. Only 1 case of uterine cancer occurred among women younger than 50 years, in a participant in the tamoxifen group. The majority of women who developed uterine cancer (56 [91%]) were diagnosed with stage I disease. Of the remaining cases, there was 1 case of stage II disease in each of the treatment groups, 2 with stage III disease in the raloxifene group, and 1 with stage IV disease in the raloxifene group. Two of these cases were mixed Mullerian cell type; both were in the tamoxifen

Table 3 shows that while there were no statistically significant differences with respect to risk of uterine cancer, there were differences between the treatment groups indicating that the effect of raloxifene on the uterus is less than that of tamoxifen. Among those who did not have a diagnosis of uterine cancer, there was a statistically significant difference between the groups in the incidence of uterine hyperplasia. The rates were 84% less in the raloxifene-treated group (14 cases) than in the tamoxifen-treated group (84 cases) (RR, 0.16; 95% CI, 0.09-0.29). This magnitude of difference between treatment groups was evident for hyperplasia both with and without atypia. For the tamoxifen and raloxifene groups, respectively, there were 12 cases and 1 case with atypia (RR, 0.08; 95% CI, 0.00- 0.55) and 72 and 13 cases without atypia (RR, 0.18; 95% CI, 0.09-0.32). There also was a statistically significant difference between the treatment 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 (RR, 0.44; 95%

After 81 months of follow-up, the incidence of invasive uterine cancer was significantly lower in the raloxifene group (Vogel et al. 2010). 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, 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 1,000; RR = 0.19; 95% CI, 0.12–0.29). The number of hysterectomies performed in the tamoxifen group, including those done for benign disease, was more than double that performed in the

Invasive Cancer 65 37 2.25 1.23 1.02 0.55 0.36–0.83 Hyperplasia 126 25 4.40 0.84 3.56 0.19 0.12–0.29 Without atypia 104 21 3.63 0.70 2.93 0.19 0.11–0.31 With atypia 22 4 0.77 0.13 0.64 0.17 0.04–0.51

during follow-up 349 162 12.08 5.41 6.67 0.45 0.37–0.54

Table 3. Uterine Events in the Study of Tamoxifen and Raloxifene (STAR Trial).

**Events,** *<sup>n</sup>* **Rate per 1,000 RR\* RR (95% CI) Tam Ralox Tam Ralox Diff** 

group.

CI, 0.35-0.56).

**Disease/uterine event** 

Uterine disease and hysterectomy

Hysterectomy

raloxifene group (RR = 0.45; 95% CI, 0.37–0.54).

Previous studies had shown that raloxifene does not increase the risk of uterine malignancy when compared with placebo. In the STAR trial, only 59 invasive uterine cancers were diagnosed in both study groups during more than 76,000 woman-years of follow-up. As noted above, approximately 25% fewer cases of uterine cancer were diagnosed in the raloxifene than in the tamoxifen group. Although uterine cancer of the mixed Mullerian type occurred in only 2 cases in the tamoxifen group of the STAR trial, there have been isolated case reports of this tumor associated with raloxifene. The rates of uterine cancer were 2.00 per 1000 (tamoxifen) and 1.25 per 1000 (raloxifene), but this difference did not reach statistical significance. Endometrial hyperplasia, however, a risk factor for endometrial cancer, was far more common in the tamoxifen-treated group than in the raloxifene group (RR, 0.16; 95% CI, 0.09-0.29). The number of participants undergoing a hysterectomy for non–cancer-related reasons was significantly reduced 56% in the raloxifene group. It is important to note that the difference between the treatment groups in non–cancer-related hysterectomies has likely caused an underestimate of the true magnitude of endometrial cancer risk associated with tamoxifen and an underestimate of the true magnitude of difference between the two treatment groups for this end point.

These data demonstrate that raloxifene is nearly as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a non-statistically significant higher risk of noninvasive breast cancer.

#### **3.3.1 Summary for uterine cancer, uterine hyperplasia, and hysterectomy for raloxifene and tamoxifen in the STAR Trial**

In the STAR Trial, there was a trend toward a decreased incidence of uterine cancer in the raloxifene group, but the difference was not statistically significant—36 cases (tamoxifen) vs. 23 (raloxifene). Annual incidence rates were 2.00 per 1000 (tamoxifen) and 1.25 per 1000 women (raloxifene) (RR, 0.62; 95% CI, 0.35-1.08). Cumulative incidence rates through 7 years were 14.7 per 1000 (tamoxifen) and 8.1 per 1000 (raloxifene) (P = 0.07,). Only 1 case of uterine cancer occurred among women younger than 50 years, in a participant in the tamoxifen group. At the time of analysis, clinicopathological stage was unknown for 3 cases (1 in the tamoxifen group, 2 in the raloxifene group). The majority of the others who developed uterine cancer (56 [91%]) were diagnosed with stage I disease. Of the remaining cases, there was 1 case of stage II disease in each of the treatment groups, 2 with stage III disease in the raloxifene group, and 1 with stage IV disease in the raloxifene group. As noted, two of these cases were mixed Mullerian cell type; both were in the tamoxifen group.

While there were no significant differences with respect to risk of uterine cancer in the STAR trial, there were differences between the treatment groups indicating that the effect of raloxifene on the uterus is less than that of tamoxifen. Among those who did not have a diagnosis of uterine cancer, there was a statistically significant difference between the groups in the incidence of uterine hyperplasia. The rates were 84% less in the raloxifenetreated group (14 cases) than in the tamoxifen-treated group (84 cases). This magnitude of difference between treatment groups was evident for hyperplasia both with and without atypia. For the tamoxifen and raloxifene groups, respectively, there were 12 cases and 1 case with atypia (RR, 0.08; 95% CI, 0.00-0.55) and 72 and 13 cases without atypia (RR, 0.18; 95% CI, 0.09-0.32). There also was a statistically significant difference between the treatment 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 (RR, 0.44; 95% CI, 0.35-0.56).

#### **3.3.2 STAR quality of life**

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 musculoskeletal problems, dyspareunia, and weight gain.

#### **3.4 Raloxifene summary**

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 cancer.

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 elevated risk for breast cancer.

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
