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Information on Protocol P-1

Breast Cancer Prevention Trial Shows Major Benefit, Some Risk
Six years after its inception, the Breast Cancer Prevention Trial (BCPT) shows a 45 percent reduction in breast cancer incidence among the high-risk participants who took tamoxifen (Nolvadex®), a drug used for the past two decades to treat breast cancer.

As a result, investigators released the initial study results about 14 months earlier than expected and notified the 13,388 women participants of the findings so those women who had been taking a placebo could consider starting tamoxifen therapy after consulting with their personal physicians. Participants will continue to be followed by the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Pittsburgh-based research network that conducted the trial with support from the National Cancer Institute (NCI).

In this trial, healthy women assigned to take tamoxifen developed 85 cases of invasive breast cancer compared to 154 cases in the women assigned to the placebo.

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

Among these women at increased risk for breast cancer, women under age 50 appeared to suffer no excess risk of adverse effects from use of tamoxifen.

"Women who are at an 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 must be considered," said Leslie Ford, M.D., associate director for early detection and community oncology in NCI's Division of Cancer Prevention. "The choice will vary depending on a woman's age, personal history, family history, and how she weighs the benefits and risks.

"Even if a woman is at increased risk of breast cancer, tamoxifen therapy may not be appropriate for her," continued Ford. "NSABP and NCI are developing information for individual decision making that will help women at increased risk of breast cancer consult with their health care providers to answer the question, 'Is tamoxifen the right choice for me?'"

The BCPT is a clinical trial designed to see whether the drug tamoxifen prevents breast cancer in women who are at an increased risk of developing the disease. Women in the study were randomly assigned to receive tamoxifen or a placebo pill and neither participants nor their physicians were aware of the treatment assignment, a process called "double-blinding."

Launched in April 1992, the BCPT also looked at whether taking tamoxifen decreases the number of heart attacks and reduces the number of bone fractures in these women. There was no difference in the number of heart attacks between the tamoxifen and placebo group, but women in the tamoxifen group had fewer bone fractures of the hip, wrist, and spine (47 cases in the tamoxifen group versus 71 cases in the placebo group).

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 that the participants and their physicians be told what pills each participant had been taking because of the clear evidence that tamoxifen reduced breast cancer risk.

NSABP presented the data to NCI on March 26 and, together, both NSABP and NCI researchers concurred with the committee's recommendation. This decision was based upon their joint assessment that a reduction of breast cancer had been demonstrated. It was agreed that any additional information that might be gained from continuing the study did not outweigh the benefits of making the treatment available to the participants in the placebo group and other women at increased risk of breast cancer.

The women in the trial have taken tamoxifen or placebo daily for about four years. In spite of extensive efforts to enroll minorities in the BCPT, African American, Asian American, Hispanic, and other groups together made up only about three percent of the participants.

About 40 percent of the participants were ages 35 to 49, 30 percent were ages 50 to 59, and 30 percent were age 60 or older. All age groups showed similar reductions in breast cancer incidence from tamoxifen. There was a suggestion 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).

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 participants have died of breast cancer, three in the tamoxifen group and five in the placebo group.

"This advance represents the results of a long-term investment in research," said NCI Director Richard Klausner, M.D. "This is a real advance, but it is no magic bullet. Only through continued research will we find preventions that are even more effective and with fewer side effects."

At the inception of the study, the investigators made a commitment to notify study participants of major results prior to any public announcement. The BCPT Participant Advisory Board, a group of 16 women in the trial, was notified by conference call. Letters were sent to BCPT researchers, and they in turn mailed letters or made other plans to notify the participants at their sites.

"Our heartfelt gratitude is extended to the study participants," said Norman Wolmark, M.D., chairperson of NSABP. "It is only because of their commitment that we were able to answer a question of extreme importance to many women."

Sandy Kanicki, co-chair of the Participant Advisory Board, said simply, "The results are so profound that I'm speechless. We don't know where it's going to go from here but we have taken a major step to help women reduce the incidence of breast cancer."

Women in the study will continue to be monitored by BCPT investigators. Postmenopausal women who had been taking the placebo may have the option to participate in an upcoming trial that will compare tamoxifen to another drug that could have similar breast cancer prevention properties, but which might be associated with fewer adverse effects. Women of any age on placebo also have the option of seeking tamoxifen from their health care providers.

The BCPT researchers will be evaluating the study's results in great detail in coming weeks. The final analysis will be published in the scientific literature.

The study began recruiting participants in April 1992 and closed enrollment in September 1997. Researchers with the NSABP are conducting the study in more than 300 centers across the United States and Canada.

"Since 1990 when I and my NSABP colleagues, together with members of NCI, designed this study, there has been an unprecedented display of teamwork by the participants, their physicians, study support staff, numerous government agencies, and medical centers," said Bernard Fisher, M.D., scientific director at NSABP. "That commitment to scientific investigation has resulted in this landmark accomplishment. I am delighted to have had an opportunity to make a contribution."

Only women at increased risk for developing breast cancer participated in the study. Because the risk of breast cancer increases with age, women 60 years of age and older qualified to participate based on age alone. At age 60, about 17 of every 1,000 women are expected to develop breast cancer within five years. Women between the ages of 35 and 59 who demonstrated an increased risk of breast cancer equivalent to or greater than that of an average 60-year-old woman were also eligible. This breast cancer risk was determined by a computer calculation based on the following factors:

  • Number of first-degree relatives (mother, daughters, or sisters) who have been diagnosed as having breast cancer;
  • Whether a woman has any children and her age at her first delivery;
  • The number of times a woman has had breast lumps biopsied, especially if the tissue was shown to have a condition known as atypical hyperplasia;
  • The woman's age at her first menstrual period;
  • Whether a woman has had a type of noninvasive breast cancer known as lobular carcinoma in situ.
One of the most widely prescribed cancer drugs in the world, tamoxifen has been the focus of more than 25 years of research on its actions, benefits, and risks. Zeneca Pharmaceuticals, Wilmington, Del., manufactures tamoxifen and provided both the drug and placebo pills for the prevention study without charge.

The National Cancer Institute's Cancer Information Service (CIS) is a nationwide information and education network for cancer patients and their families, the public, and health professionals. The CIS can provide information about breast cancer prevention, detection, treatment, and research. One toll-free number, 1-800-4-CANCER (1-800-422-6237) connects English- and Spanish-speaking callers all over the country with the office that serves their area. The number for callers with TTY equipment is 1-800-332-8615.