NIH Press Release
NATIONAL INSTITUTES OF HEALTH
National Cancer Institute

FOR RESPONSE TO INQUIRIES
Monday, April 6, 1998

NCI Press Office
(301) 496-6641

Questions and Answers:
The Breast Cancer Prevention Trial

This document describes preliminary results from the Breast Cancer Prevention Trial. It is divided into three sections:

Background and Study Design (questions 1-12);

Preliminary Trial Results/Notifications (questions 13-24); and

Public Concerns (questions 25-37).

BACKGROUND AND STUDY DESIGN

1. What is the Breast Cancer Prevention Trial?

The Breast Cancer Prevention Trial (BCPT) is a clinical trial (a research study conducted with people) designed to see whether taking the drug tamoxifen (Nolvadex®) can prevent breast cancer in women who are at an increased risk of developing the disease. The BCPT is also looking at whether taking tamoxifen decreases the number of heart attacks and reduces the number of bone fractures in these women. The study began recruiting participants in April 1992 and closed enrollment in September 1997; 13,388 women ages 35 and older are enrolled. Researchers with the National Surgical Adjuvant Breast and Bowel Project (NSABP) are conducting the study in more than 300 centers across the United States and Canada. The study is funded by the National Cancer Institute (NCI), the United States' primary agency for cancer research.

2. What is tamoxifen?

Tamoxifen is a drug, taken by mouth as a pill. It has been used for 25 years to treat patients with advanced breast cancer. Since 1985 it has also been recommended in the United States for adjuvant, or additional, therapy, following surgery and/or radiation for early stage 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. For this reason, tamoxifen is often called an "anti-estrogen." In treatment, the drug slows or stops the growth of these cancer cells.

3. Why was tamoxifen tested to prevent breast cancer?

Research has shown that taking tamoxifen as adjuvant therapy for breast cancer not only helps prevent the original breast cancer from returning but also helps to prevent the development of new cancers in the opposite breast. Researchers believed that tamoxifen might have a similar beneficial effect for women at increased risk of breast cancer. While tamoxifen acts against the effects of estrogen in breast tissue, it acts like estrogen in other body systems. Tamoxifen's estrogen-like effects include the lowering of blood cholesterol and the slowing of bone loss.

4. Who participated in the BCPT?

Women at increased risk for developing breast cancer participated in the study. These included women 60 years of age and older who qualified to participate based on age alone, and women between the ages of 35 and 59 with an increased risk of breast cancer equivalent to or greater than that of a 60-year-old woman. At age 60, about 17 of every 1,000 women are expected to develop breast cancer within five years.

Of the 13,388 women on the trial, about 40 percent were ages 35 to 49, about 30 percent were ages 50 to 59, and about 30 percent were age 60 or older. About 3 percent of the participants were minorities, including African American, Asian American, Hispanic, and other groups.

5. Did every woman in the study receive tamoxifen?

No. Participants in the BCPT were randomized (selected by chance) to receive either tamoxifen or a placebo (an inactive pill that looked like tamoxifen). In a process known as "double blinding," neither the participant nor her physician knew which pill she was receiving. Setting up a study in this way allowed the researchers to clearly see what the true benefits and side effects of tamoxifen are without the influence of other factors. According to the design, all women in the study were to take two pills a day for five years, either a 20-mg dose of tamoxifen (two 10-mg pills) or placebo pills.

6. Why were women 60 years of age or older eligible for the BCPT based on age alone?

Many diseases, including breast cancer, occur more often in older persons. The risk of developing breast cancer increases with age, so breast cancer occurs more commonly in women over 60 years of age. The risk of developing heart disease or osteoporosis also increases with age, and those diseases are also being studied in the BCPT.

7. What factors were used to determine increased risk of breast cancer for the participants aged 35 to 59?

To enroll in the study, women between 35 and 59 years of age needed to have a risk of developing breast cancer within the next five years that was equal to or greater than the average risk for 60-year-old women. This increased risk was determined in one of two ways. Women diagnosed as having lobular carcinoma in situ, a condition that is not cancer but indicates an increased chance of developing invasive breast cancer, were eligible based on that diagnosis alone. The risk for other women was determined by a computer calculation based on the following factors:

For example, a 35-year-old woman would have to have two or more first-degree relatives with breast cancer AND a personal history of at least one benign breast biopsy OR a diagnosis of lobular carcinoma in situ.

A 45-year-old woman would have to have one or more first-degree relatives with breast cancer AND a personal history of at least one benign breast biopsy OR a diagnosis of lobular carcinoma in situ.

A 55-year-old woman would have to have one or more first-degree relatives with breast cancer OR a personal history of at least one benign breast biopsy OR a diagnosis of lobular carcinoma in situ.

8. What proportion of women in the United States are estimated to be at the level of risk required for participation in the BCPT?

At age 35, about three women in 1,000 or .3 percent, would have qualified for the study based on their estimated breast cancer risk.

9. Did other factors affect eligibility for the study?

Certain existing health conditions affected eligibility for the study. For example, women at increased risk for blood clots could not participate. Also, women taking hormone replacements and women using oral contraceptives ("the pill") could not take part in the trial unless they stopped taking these medications. Those who stopped taking these hormones were eligible for the study three months after they discontinued the drugs.

Women who were pregnant or who planned to become pregnant were not eligible to participate. Animal studies have suggested that the use of tamoxifen during pregnancy might harm the fetus. Premenopausal women participating in the BCPT were required to use some method of birth control other than oral contraceptives. Oral contraceptives may change the effects of tamoxifen and may also affect the risk of breast cancer.

10. Were the participants required to have any medical exams?

Participants were required to have blood tests, a pelvic exam, a mammogram, and a physical exam before being accepted into the study. Women 55 years of age and older needed to have an electrocardiogram or ECG (a test to measure the heart's muscular activity), in addition to the other tests. Screening endometrial sampling (an examination of cells from the lining of the uterus) was required at entry for participants joining the study beginning in October 1994 and was strongly recommended annually for all women in the study. These tests were repeated periodically.

11. Who paid for these medical exams?

Most physicians' fees and the costs of medical tests were charged to the participant as if she were not part of the study; however, the costs for these tests were often covered by the participant's insurance company. Screening endometrial samplings were provided without charge. For women over 55, the required electrocardiograms were also done at no cost. Every effort was made to contain the costs specifically associated with participation in this study, and a fund was available to cover costs for participants without the ability to pay.

12. How much did the tamoxifen cost the participants?

There was no charge to participants for the tamoxifen or the placebo. The company that manufactures tamoxifen, Zeneca Pharmaceuticals Group, of Wilmington, Del., (formerly ICI Americas, Inc.) provided both the tamoxifen and the placebo without charge.

PRELIMINARY TRIAL RESULTS/ NOTIFICATIONS


13. What are the initial results of the BCPT?

At this point (data to Jan. 31, 1998), women on the trial have been followed on the study for about four years. Results show 45 percent fewer diagnoses of invasive breast cancer in women who were randomized to take tamoxifen compared to women who were randomized to take the placebo (85 cases in the tamoxifen group versus 154 cases in the placebo group). Women on tamoxifen also had fewer diagnoses of noninvasive breast cancer, such as ductal carcinoma in situ (31 cases in the tamoxifen group versus 59 cases in the placebo group). Eight women have died of breast cancer, three women in the tamoxifen group and five women in the placebo group.

Women in the tamoxifen group had fewer bone fractures of the hip, wrist, and spine than women in the placebo group (47 cases in the tamoxifen group versus 71 cases in the placebo group). There was no difference in the number of heart attacks between the two groups.

Tamoxifen did increase the women's chances of three rare but serious health problems: endometrial cancer (cancer of the lining of the uterus) 33 cases in the tamoxifen group versus 14 cases in the placebo group; pulmonary embolism (blood clot in the lung) 17 cases in the tamoxifen group versus 6 cases in the placebo group; and deep vein thrombosis (blood clots in major veins) 30 cases in the tamoxifen group versus 19 cases in the placebo group.

14. What were the participants' chances of developing endometrial cancer?

BCPT participants who were randomized to the tamoxifen group had more than twice the chance of developing endometrial cancer compared with women on placebo (based on 33 cases in the tamoxifen group versus 14 cases in the placebo group). The increased risk of endometrial cancer was equal to the risk that was expected and is in the same range as (or less than) the endometrial cancer risk for postmenopausal women taking single-agent estrogen replacement therapy. Estrogens and agents that act like estrogens are known to increase the risk of endometrial cancer.

All the participants were informed about the possibility of increased risk of endometrial cancer before they entered the study. Like all cancers, endometrial cancer is potentially life-threatening. All but one (in the placebo group) of the endometrial cancers that occurred during the study were found at an early stage, when treatment is very effective. However, one participant (also in the placebo group) died of endometrial cancer. About 37 percent of BCPT participants in both groups had a hysterectomy (surgery to remove the uterus) for a variety of health reasons before joining the study. Therefore, these women were not at any risk for endometrial cancer.

15. What was done to help diagnose endometrial cancer early?

Pap smears are very effective at detecting cancer in the cervix but are not useful for detecting endometrial cancer. Therefore a screening endometrial sampling - removal of cells in the lining of the uterus for examination under a microscope - was used in the BCPT to detect abnormalities in the endometrium. Women who joined the study after October 1994 were required to have a screening endometrial sampling before entering the study if their uterus had not been removed. All women in the study were strongly urged to have screening endometrial sampling done annually throughout the study (at no cost to them), but could decline if they chose. In addition to these annual tests, women in the BCPT were told to see their physicians if they experienced abnormal vaginal bleeding or pain. The vast majority of the endometrial cancers that were diagnosed in the BCPT caused such symptoms.

16. What were the participants' chances of getting blood clots?

Women taking tamoxifen had almost three times the chance of developing a pulmonary embolism (blood clot in the lung) as women on placebo (based on 17 cases in the tamoxifen group versus 6 cases in the placebo group). Two women died from these embolisms, both in the tamoxifen group. Women in the tamoxifen group were also more likely to have deep vein thrombosis (a blood clot in a major vein) than women on placebo (30 cases versus 19 cases). Blood clots occur more often in people with high blood pressure (hypertension), diabetes, smokers, and in those who are obese.

17. Is there a relationship between tamoxifen use and the development of eye problems?

Women in the tamoxifen group, in general, had no more eye problems than women taking the placebo. However, women taking tamoxifen may be at a slightly increased risk for developing cataracts (a clouding of the lens inside the eye) according to other research. As women age, they are more likely to develop cataracts whether or not they take tamoxifen. Other eye problems, such as corneal scarring or retinal changes, have been reported in a few breast cancer patients in tamoxifen treatment trials.

18. Was tamoxifen associated with any other cancers?

Tamoxifen was not associated with an increased risk of any other cancer other than endometrial cancer.

19. What were the other adverse effects of tamoxifen?

Like most medications, whether over-the-counter medications, prescription drugs, or drugs in research studies, tamoxifen causes adverse effects in some women. The effects experienced most often by women in the tamoxifen group were hot flashes and vaginal discharge. Women in both groups reported sometimes having side effects - even though the placebo itself would not cause any symptoms. The side effects that some women in both groups reported included: vaginal dryness, itching, or bleeding; menstrual irregularities; depression; loss of appetite; nausea and/or vomiting; dizziness; headaches; and fatigue. Treatments that could minimize or eliminate most side effects were available to the participants.

20. Did any group of women benefit more from tamoxifen than others?

It is possible that the breast cancer benefit from tamoxifen could be greater in women over age 50, but older women are also at increased risk for some of the serious side effects (endometrial cancer, pulmonary embolism, and deep vein thrombosis).

21. Why was the study "unblinded," and who made that decision?

As part of the study design, the BCPT data were regularly reviewed by an independent Endpoint Review, Safety Monitoring, and Advisory Committee (ERSMAC). At its regularly scheduled meeting on March 24, 1998, the committee recommended to NSABP that the study be unblinded (inform the participants and their physicians what pills the participants had been taking) because of the clear evidence of a reduction of breast cancer incidence in the tamoxifen group. The NSABP presented the data and recommendation to the NCI on March 26 and together, NSABP and NCI researchers concurred with the committee's recommendation. This was based upon the assessment of all three groups that the effect of tamoxifen in the reduction of breast cancer had been demonstrated. It was agreed that any additional information that could be gained from continuing the study in its current form did not outweigh the benefits of making the treatment available to the participants in the placebo group and other women at an increased risk of breast cancer.

22. How were the participants notified?

At the inception of the study, the NSABP made a commitment to make every effort to notify the participants of major results prior to any public announcement. After notification to the BCPT Participant Advisory Board, a group of 16 women in the trial, a letter announcing initial results and details for participant "unblinding" was rapidly sent to BCPT investigators so that they could convey this information to BCPT participants.

23. What will the participants do now?

All participants are being asked to continue with their follow-up examinations. Women who have been randomized to the tamoxifen group who have not completed five years of tamoxifen therapy will have the opportunity to continue on therapy. Postmenopausal women who had been taking the placebo are being invited to participate in an upcoming trial that will compare tamoxifen to a different drug that could have similar breast cancer prevention properties, but might be associated with fewer adverse effects. Women of any age on placebo also have the option of seeking tamoxifen from their private health care providers.

24. Would it be beneficial for women to take tamoxifen for more than five years?

Not necessarily: Results of another NSABP study in which women with early stage breast cancer took tamoxifen for 5 years versus 10 years (called the B-14 trial) showed no greater benefit from the longer duration of tamoxifen and showed a trend toward more adverse effects.


PUBLIC CONCERNS


25. Was any special effort made to include minority women on the trial?

Throughout the trial, several strategies were used to increase participation of women from racial and ethnic minority groups. These strategies included placing study-related recruitment materials in businesses and churches located in minority communities; collaborating with a minority-owned public relations firm to develop a structured media campaign targeting racial and ethnic minorities; developing and broadly disseminating a Public Service Announcement that featured singer Nancy Wilson; and communicating information to study sites about how other sites successfully reached racial and ethnic minorities.

When the early strategies did not attract sufficient numbers of minority participants, the NSABP launched the Pilot Minority Recruitment Program in August 1996. The goal of the program was to increase participation by increasing awareness and educating minority populations about the trial. A multidimensional approach was used: Community Outreach Coordinators employed at five BCPT sites offered personalized presentations on breast cancer risk factors, incidence, and survival rates, and on clinical trial research at African-American churches, community hospitals and health clinics, health fairs, public housing sites, businesses, and local chapters of sororities, the Urban League, and minority medical societies. In less than a year, these strategies enabled the coordinators to establish many relationships in their communities. As a result of these efforts, the number of Risk Assessment Forms submitted by minority groups increased, and during this period, the BCPT experienced the highest level of randomizations from racial and ethnic minority groups since the trial began. The Pilot Minority Recruitment Program has been the most effective strategy to date and will serve as the model for minority recruitment for future prevention trials.

26. Will the study results be published?

Further analyses of the data are under way. A manuscript will be prepared and submitted to a peer-reviewed journal.

27. Based on the BCPT results, should women who are at increased risk of breast cancer take tamoxifen?

Women who are at increased risk of breast cancer now have the option to consider taking tamoxifen to reduce their chances of developing breast cancer. As with any medical procedure or intervention, the decision to take tamoxifen is an individual one in which the benefits and risks of the 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. Therefore even if a woman is at increased risk of breast cancer, tamoxifen therapy may not be appropriate for her. Women who are considering tamoxifen therapy should talk with their health care provider.

28. How can a woman learn more about the next breast cancer prevention trial?

The NSABP is planning a new breast cancer prevention trial, tentatively scheduled to begin in fall 1998. The trial would involve postmenopausal women who are at least 35-years-old and are at increased risk for developing breast cancer. The study would compare tamoxifen to another drug.

There are several ways to be placed on a mailing list for more information on this upcoming trial - by Internet, by mail, or by fax. On the Internet, the NSABP homepage http://www.nsabp.pitt.edu has a form available. By regular mail, send a letter or post card with name, mailing address, and a note specifying interest in future breast cancer prevention trials to: NSABP, Box 21, Pittsburgh, Pa. 15261. Or fax the same information to NSABP at (412) 330-4664. When information about the next prevention trial is available, it will be mailed to the people on this list.

29. How does a woman determine whether she is at increased risk of breast cancer?

BCPT participants had their risk for developing breast cancer calculated using age, family history, and medical information in a computer program that also estimated their likelihood of developing heart disease, endometrial cancer, and blood clots. Some private physicians use computer calculations in their practice to assess breast cancer risk, but because these are not identical to the program used in the BCPT, it is unclear how well those programs would identify women at increased risk. The NSABP and NCI plan to make information available which will assist a woman and her health care provider to determine whether her risk is comparable to the women who participated in the BCPT.

30. Will women with breast cancer gene alterations (BRCA1 and BRCA2) benefit from tamoxifen?

These two breast cancer gene alterations, which increase a woman's risk of the disease, were first identified after the BCPT began. Using blood samples taken from participants, analyses are under way to determine whether tamoxifen has the same relative effects on women whether or not they carry alterations in these genes. To maintain strict confidentiality, samples in this study have no identifying labels that could link them to individual women. Therefore, researchers will not be able to give individual results to a participant or her health care provider.

31. Is tamoxifen a good substitute for hormone replacement therapy?

No. Every woman has individual health risks that affect her need for interventions such as hormone replacement therapy or tamoxifen therapy. Hormone replacement therapy is intended to help women maintain bone density. It may also reduce the risk of heart disease in postmenopausal women, and many women benefit from a reduction in hot flashes and other problems that can affect quality of life. Some studies have suggested that hormone replacement therapy increases a woman's chances of developing breast cancer.

The BCPT results show that tamoxifen reduces breast cancer risk and may help slow or reduce bone loss, as evidenced by the reduced number of bone fractures, but it did not decrease heart disease risk. A woman with a large risk of heart disease may not have the same benefit from tamoxifen as from hormone replacement therapy.

32. Should women who are not at a demonstrated increased risk of breast cancer consider taking tamoxifen?

This question has not been studied. At this time, there is no evidence that tamoxifen is beneficial for women who do not have an increased risk of breast cancer.

33. Are there any women who should not take tamoxifen?

Animal studies have suggested that the use of tamoxifen during pregnancy might harm the fetus. Women who were pregnant or who planned to become pregnant were not eligible to participate in the BCPT. Premenopausal women participating in the BCPT were required to use some method of birth control other than oral contraceptives ("the pill") while taking tamoxifen. Oral contraceptives may change the effects of tamoxifen and may also affect the risk of breast cancer.

Women with a history of blood clots, hypertension, diabetes, and cigarette smoking must also consider that tamoxifen increases the risk for serious blood clots.

34. How much does a standard dose of tamoxifen cost?

A month's supply of tamoxifen costs about $80 to $100.

35. How much did the study cost?

The trial had been projected to cost $70 million, but the total cost is estimated at $50 million, including $10 million for two more years of follow-up. All except $3.5 million from the National Heart, Lung, and Blood Institute, was provided by NCI.

36. Why is the Breast Cancer Prevention Trial so important?

This year, more than 178,000 women in the United States alone will be diagnosed as having breast cancer, and about 43,500 will die of the disease. For many years, women at increased risk for developing breast cancer had no proven means to reduce their risk. Women had to rely on frequent checkups and periodic mammograms to detect breast cancer at an early stage. Doctors sometimes suggest that certain women at very high risk have preventive (prophylactic) mastectomies, which is surgery to remove breast tissue before cancer develops. However, the operation does not guarantee that breast cancer will be avoided, because it is almost impossible to remove all the breast tissue and the impact of prophylactic mastectomy on breast cancer risk is not known.

Because tamoxifen was successful in reducing the incidence of breast cancer, women at increased risk for developing the disease will have a choice other than more frequent exams or major surgery. Tamoxifen does not replace the need for regular mammography. In order to prove its value, tamoxifen had to be tested in a large research study to determine whether the benefits outweighed the risks.

37. What is the National Surgical Adjuvant Breast and Bowel Project?

The NSABP is a cooperative group 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, potentially prevented. Results of research studies 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. When a breast cancer prevention study was initially conceived, more than 30,000 women with breast cancer had participated in treatment studies conducted by NSABP investigators. A research study to prevent breast cancer was a logical next step for this research group.

NSABP was recently incorporated under the aegis of the NSABP Foundation, Inc., a Pennsylvania nonprofit membership organization with nearly 300 members in the United States, Canada, and Australia. More than 6,000 physicians, nurses, and other medical professionals in the NSABP, located in member institutions and their satellites are involved in the conduct of treatment and prevention trials. NCI provides funding for the two headquarters components of NSABP: the NSABP Operations Center at Allegheny University of the Health Sciences, Allegheny Campus, and the NSABP Biostatistical Center at the University of Pittsburgh, both located in Pittsburgh, Pa. NCI also provides funding directly or indirectly, to the medical center Members of the NSABP Foundation, Inc., who are responsible for implementation of NSABP studies.