The Study of Tamoxifen and Raloxifene (STAR): Questions and Answers

1. What is the Study of Tamoxifen and Raloxifene (STAR)?
   The Study of Tamoxifen and Raloxifene (STAR) is a clinical trial (a research study conducted with people) comparing the drug raloxifene (Evista®) with the drug tamoxifen (Nolvadex®) in reducing the incidence of breast cancer in postmenopausal women who are at an increased risk of developing the disease. Researchers with the National Surgical Adjuvant Breast and Bowel Project (NSABP) are conducting the study at more than 500 centers across the United States, Canada, and Puerto Rico. The study is funded primarily by the National Cancer Institute (NCI) - part of the National Institutes of Health. NCI is the U.S. Government's main agency for cancer research.

2. Who participated in STAR?
   Women at increased risk of developing breast cancer, who had gone through menopause, and were at least 35 years old took part in STAR. STAR began enrolling participants in 1999. Enrollment was closed on November 4, 2004, with 19,747 women recruited.

   All STAR participants had to have an increased risk of breast cancer equivalent to or greater than that of an average 60- to 64-year-old woman. In that age group, 1.66 percent of women -- or about 17 of every 1,000 women -- would be expected to develop breast cancer within five years. The average risk of breast cancer in the women who chose to enter STAR was about twice as high as this minimum risk.

   The breast cancer risk of women when they joined STAR was:
    

   Five Year Breast Cancer Risk	Women in STAR Who Fell Into This Risk Category
   1.66 – 1.99%	11.0% (2,176)
   2.0 - 2.99%	30.2% (5,962)
   3.0 - 4.99%	31.5% (6,229)
   Greater than 5.0%	27.2% (5,380)

3. What increases a woman's risk of breast cancer? How was it determined that a STAR participant was at increased risk of breast cancer?
    

   A woman's risk of developing breast cancer is determined by many factors. The factors that most affect a woman's risk of the disease are:

   • Age,
   • Number of first-degree relatives (mother, daughters, or sisters) diagnosed with breast cancer,
   • Whether a woman has had any children and her age at her first delivery,
   • The number of breast biopsies a woman has undergone, especially if the tissue showed a condition known as atypical hyperplasia,
   • The woman's age at her first menstrual period, and
   • The woman's age when she reached menopause.
   
   STAR researchers used the Breast Cancer Risk Assessment Tool, developed by scientists at NCI and NSABP, to estimate a woman's risk of breast cancer using most of the above factors. In addition, for STAR, women diagnosed as having lobular carcinoma in situ (LCIS), a condition that is not cancer but indicates an increased chance of developing invasive breast cancer, were eligible based on that diagnosis alone, as long as their treatment for the condition was limited to local excision.

4. What is tamoxifen?
   Tamoxifen is a drug, taken by mouth as a pill. It has been used for more than 30 years to treat patients with breast cancer. Tamoxifen works against breast cancer, in part, by interfering with the activity of estrogen, a female hormone that promotes the growth of breast cancer cells. In October 1998, the U.S. Food and Drug Administration (FDA) approved the use of tamoxifen to reduce the incidence of breast cancer in women at increased risk of the disease based on the results of the NSABP Breast Cancer Prevention Trial (BCPT). The known, serious side effects of tamoxifen are uterine cancer, blood clots, strokes, and cataracts. Other side effects of tamoxifen include menopause-like symptoms such as hot flashes and vaginal discharge or bleeding.

   Findings from the BCPT were reported in the September 16, 1998, issue of the Journal of the National Cancer Institute and showed tamoxifen reduced breast cancer risk by about 50 percent.

   To read the FDA labels for either drug, visit the Drugs@FDA Web site at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

5. What is raloxifene?
   Raloxifene is a drug, taken by mouth as a pill. In December 1997, it was approved by the FDA for the prevention of osteoporosis in postmenopausal women. In October 1999, it was also approved as an osteoporosis treatment. Studies testing its effectiveness against osteoporosis have shown that women taking the drug developed fewer breast cancers than women taking a placebo. On September 14, 2007, the FDA announced approval of raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer based on the initial results of STAR and results of osteoporosis trials. Raloxifene is not used as a treatment for breast cancer. The known, serious side effect of raloxifene is blood clots. Other side effects include menopause-like symptoms such as hot flashes and vaginal dryness as well as joint pain or leg cramps.

   To read the FDA labels for either drug, visit the Drugs@FDA Web site at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

6. What were the STAR results in terms of reducing invasive breast cancer risk?
   The initial results of STAR showed that raloxifene and tamoxifen were equally effective in reducing invasive breast cancer risk in postmenopausal women at increased risk of the disease after an average of 47 months.

   After an average of 81 months, (5 years of medication and 21 months of followup) women in the tamoxifen group had 247 cases of invasive breast cancer in 9,736 women and women in the raloxifene group had 310 cases of invasive breast cancer in 9,754 women. This means that in raloxifene reduces risk of invasive breast cancer by about 38 percent compared to tamoxifen reducing breast cancer by about 50 percent over almost 7 years; or, raloxifene is about 76 percent as effective as tamoxifen in reducing risk for invasive breast cancer over almost 7 years.

7. Did raloxifene reduce the incidence of lobular carcinoma in situ or ductal carcinoma in situ (non-invasive breast cancers)?
   Not initially, but with longer followup, raloxifene seems to have some effect on these diagnoses. Tamoxifen has been shown to reduce the incidence of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) by half. (LCIS and DCIS are sometimes called noninvasive or stage 0 breast cancers.) At 81 months, among the 9,736 women in the tamoxifen group, 111 developed LCIS or DCIS, compared to 137 of 9,754 women in the raloxifene group. This means that raloxifene reduces risk of non-invasive breast cancer by about 38 percent compared to tamoxifen reducing risk for this type of cancer by about 50 percent; or raloxifene is about 78 percent as effective as tamoxifen in reducing the risk of noninvasive breast cancer over almost 7 years.
8. How many participants developed uterine cancer?
   In STAR, more than half of the women entered the trial having had a hysterectomy. Women without a uterus are not at risk of uterine cancer. For those women in the trial with a uterus, the women in the raloxifene group developed 45 percent fewer uterine cancers during the trial, a statistically significant reduction: 65 of 4,739 women in the tamoxifen group developed uterine cancers compared to 37 of the 4,717 women in the raloxifene group. Tamoxifen is known to increase a woman's chance of developing uterine cancer (mostly in the lining of the uterus or endometrium) by two to three times compared to a woman not taking the drug The annual incidence rate of uterine cancer is 2.25 per 1,000 women taking tamoxifen and 1.23 per 1,000 women taking raloxifene after almost 7 years. --
9. How many participants developed blood clots?
   Both tamoxifen and raloxifene are known to increase a woman's chance of developing blood clots by up to three times that of women who are not taking either drug. In STAR, women in the raloxifene group had 28 percent fewer deep-vein thromboses (blood clots in a major vein) and 20 percent fewer pulmonary embolisms (blood clots in the lung) than women on tamoxifen: 118 of 9,736 women in the tamoxifen group had a deep-vein thrombosis compared to 86 of 9,754 women in the raloxifene group. In addition, 84 of 9,736 women in the tamoxifen group had a pulmonary embolism compared to 68 of 9,754 women in the raloxifene group. The average annual rate of either kind of blood clot was 3.3 per 1,000 women taking tamoxifen and 2.5 per 1,000 women taking raloxifene after almost 7 years.

10. How many participants developed other cardiovascular problems?
    The numbers of myocardial infarctions (heart attacks), strokes, and transient ischemic attacks (strokes that last only a few minutes) were essentially equivalent between the tamoxifen group and the raloxifene group.

    Women at increased risk of cardiovascular problems were not eligible to participate in STAR. This includes women who had uncontrolled high blood pressure or uncontrolled diabetes and those with a prior stroke, transient ischemic attack, or atrial fibrillation (a kind of abnormal heart rhythm).

11. How many women had bone fractures during the trial?
    In the initial report on STAR, women in the tamoxifen group and women in the raloxifene group had similar numbers of bone fractures of the hip, wrist, and spine: 104 of 9,726 women in the tamoxifen group had a bone fracture during the trial compared to 96 of 9,745 women in the raloxifene group. Raloxifene is currently FDA-approved and used for the treatment and prevention of osteoporosis, and data from the BCPT showed that women on tamoxifen have fewer fractures of the hip, wrist, and spine compared to women on placebo. These particular fracture sites were evaluated in the study because they are associated with osteoporosis.
12. Does having taken raloxifene change what a woman could do if she developed LCIS or DCIS?
    No. Treatment options for LCIS and DCIS would not change if a woman had been taking raloxifene prior to her diagnosis. For more information, see the PDQ® Breast Cancer Treatment summary.
13. How many participants developed a cataract during STAR?
    In the BCPT, women in the tamoxifen group had a 14 percent increased risk of developing a cataract. During STAR, 739 of 9,736 women in the tamoxifen group developed a cataract compared to 603 of 9,754 women in the raloxifene group. Overall, women taking raloxifene were about 20 percent less likely to develop a cataract compared to women taking tamoxifen.
14. Did any group of women benefit more from raloxifene than others?
    No. Raloxifene reduced breast cancer risk regardless of age, race, family history, or other known breast cancer risk factors.
15. Should postmenopausal women at increased risk of breast cancer take raloxifene or tamoxifen based on these results?
    Postmenopausal women who are at increased risk of breast cancer should consider taking either raloxifene or tamoxifen to reduce their risk. As with any medical procedure or intervention, the decision to take one of these drugs is an individual one in which the benefits and risks of therapy must be considered. The balance of these benefits and risks will vary depending on a woman's personal health history and how she weighs the benefits and risks. Even if a woman is at increased risk of breast cancer, raloxifene or tamoxifen therapy may not be right for her. Women who are considering breast cancer prevention therapy should talk with their health care provider.
16. What can premenopausal women at increased risk of breast cancer do to reduce their risk of breast cancer?
    Tamoxifen has already been shown to reduce a premenopausal woman's risk of developing breast cancer by half in the BCPT and the drug is approved by the FDA to reduce breast cancer risk in premenopausal women. In the BCPT, women under age 50 did not have an increased risk of the most serious side effects seen with tamoxifen use: uterine cancer, blood clots, strokes, and cataracts. Premenopausal women at increased risk of breast cancer can discuss tamoxifen therapy as an option with their physicians. Raloxifene is not FDA-approved for use in premenopausal women.
17. Are there women who should not take raloxifene or tamoxifen?
    Raloxifene is not approved by the FDA for use in premenopausal women for any indication, so premenopausal women should not take raloxifene. Postmenopausal women with a history of blood clots, hypertension, diabetes, and cigarette smoking must consider that both raloxifene and tamoxifen increase the risk of serious blood clots. Women at increased risk of cardiovascular problems were not eligible to participate in STAR: This included women who had uncontrolled high blood pressure or uncontrolled diabetes and those with a prior stroke, transient ischemic attack, or atrial fibrillation (a kind of abnormal heart rhythm.)

Background Information

18. What factors affected eligibility for STAR?
    Certain existing health conditions affected eligibility for the study. Health professionals at each STAR site discussed these with each potential participant. For example, women with a history of cancer (except basal or squamous cell skin cancer), blood clots, stroke, or certain types of heartbeat irregularities could not participate. Women with uncontrolled high blood pressure or diabetes were not eligible to participate.

    Also, women taking menopausal hormone therapy (estrogen or an estrogen/progesterone combination) could not take part in the trial unless they stopped taking this medication. Those who stopped taking these hormones were eligible for the study three months after they discontinued the drugs. Women who had taken tamoxifen or raloxifene for no more than three months were eligible for the study, but they also had to stop the medication for three months before joining STAR.

19. What determined which participants received tamoxifen or raloxifene?
    Participants in STAR were randomized (assigned by chance) to receive either tamoxifen or raloxifene. In a process known as "double blinding," neither the participant nor her physician knows which pill she is receiving. Setting up a study in this way allows the researchers to directly compare the true benefits and side effects of each drug without the influence of other factors. All women in the study were scheduled to take two pills a day for five years: half took active tamoxifen and a raloxifene placebo (an inactive pill that looks like raloxifene); the other half took active raloxifene and a tamoxifen placebo (an inactive pill that looks like tamoxifen). All women receive one of the active drugs; no one in STAR received only the placebo. The dosages are 20 mg of tamoxifen and 60 mg of raloxifene per day.
20. Were participants required to have any medical exams? Who paid for these exams?
    Participants had to have blood tests, a mammogram, a breast exam, and a gynecologic exam before they were accepted into the study. These tests are repeated at intervals during the trial. Physicians' fees and the costs of medical tests are charged to the participant in the same fashion as if she were not part of the trial; however, the costs for these tests generally are covered by insurance because the tests are part of routine care for postmenopausal women. Every effort is made to contain the costs specifically associated with participation in this trial, and financial assistance is available for women facing financial hardship.
21. Was any special effort made to include minority women in the trial?
    Throughout the trial, many approaches were used to increase participation of women from racial and ethnic minority groups. The majority of women in STAR were white (93.4 percent or 18,446 women). Six percent of women were from racial and ethnic minority groups (2.5 percent African American or 488 women; 2.0 percent Hispanic or 394 women and 2.1 percent other ethnicities or 419 women), an improvement over the 4 percent that participated in BCPT. These categories were determined based on how the women identified themselves when they applied to take part in the trial.
22. What is the National Surgical Adjuvant Breast and Bowel Project?
    The NSABP is a cooperative group funded by NCI with a 40-year history of designing and conducting clinical trials, the results of which have changed the way breast cancer is treated and, now, prevented. Results of clinical trials conducted by NSABP researchers have been the dominant force in altering the standard surgical treatment of breast cancer from radical mastectomy to lumpectomy plus radiation. This group was also the first to demonstrate that adjuvant therapy could alter the natural history of breast cancer, thus increasing survival rates and it was the first to demonstrate that healthy women at increased risk of breast cancer could reduce their risk of developing the disease by taking daily medication.
23. Where did women take part in STAR?

    UNITED STATES		UNITED STATES
    AL-Alabama	98	NE-Nebraska	208
    AR-Arkansas	70	NH-New Hampshire	40
    AZ-Arizona	199	NJ-New Jersey	95
    CA-California	1369	NM-New Mexico	87
    CO-Colorado	349	NV-Nevada	99
    CT-Connecticut	307	NY-New York	808
    DC-District of Columbia	64	OH-Ohio	959
    DE-Delaware	149	OK-Oklahoma	233
    FL-Florida	389	OR-Oregon	200
    GA-Georgia	185	PA-Pennsylvania	1301
    HI-Hawaii	159	PR-Puerto Rico	76
    IA-Iowa	352	SC-South Carolina	343
    ID-Idaho	38	SD-South Dakota	161
    IL-Illinois	1108	TN-Tennessee	271
    IN-Indiana	222	TX-Texas	1624
    KS-Kansas	337	UT-Utah	83
    KY-Kentucky	199	VA-Virginia	170
    LA-Louisiana	146	VT-Vermont	79
    MA-Massachusetts	616	WA-Washington	552
    MD-Maryland	302	WI-Wisconsin	388
    ME-Maine	52	WV-West Virginia	68
    MI-Michigan	1032
    MN-Minnesota	584	CANADA
    MO-Missouri	795	AB-Alberta	145
    MS-Mississippi	44	BC-British Columbia	112
    MT-Montana	122	MB-Manitoba	139
    NC-North Carolina	915	ON-Ontario	324
    ND-North Dakota	82	PQ-Quebec	898
    		TOTAL	19,747

Selected References

Vogel VG: Costantino JP; et al; for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Update of the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer. Cancer Prev Research 2010. Published online April 19, 2010.

Vogel VG; Costantino JP; et. al.; for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA. 2006;295:2727-2741. Published online June 5, 2006. Land SR; Wickerham DL; et.al. Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA. 2006;295:2742-2751. Published online June 5, 2006.

Land SR; Wickerham DL; et.al. Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA. 2006;295:2742-2751. Published online June 5, 2006.