Six years after its inception, the Breast Cancer Prevention Trial (BCPT)shows a 45 percent reduction in breast cancer incidence among the high-riskparticipants who took tamoxifen (Nolvadex®), a drug used for the pasttwo decades to treat breast cancer.
As a result, investigators released the initial study results about 14months earlier than expected. They also notified the 13,388 women participantsof the findings so those women who had been taking the placebo could considerstarting tamoxifen therapy after consulting with their personal physicians. Participants will continue to be followed by the National Surgical AdjuvantBreast and Bowel Project (NSABP), the Pittsburgh-based research networkthat conducted the trial with support from the National Cancer Institute(NCI).
In this trial, healthy women assigned to take tamoxifen developed 85cases of invasive breast cancer compared to 154 cases in the women assignedto the placebo.
Tamoxifen did increase the women's chances of three rare but life-threateninghealth problems: there were 33 cases of endometrial cancer (cancer of thelining of the uterus) in the tamoxifen group versus 14 cases in the placebogroup; there were 17 cases of pulmonary embolism (blood clot in the lung)in the tamoxifen group versus 6 cases in the placebo group; and there were30 cases of deep vein thrombosis (blood clots in major veins) in the tamoxifengroup versus 19 cases in the placebo group.
Among these women at increased risk for breast cancer, women under age50 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 theoption to consider taking tamoxifen to reduce their chances of developingbreast cancer. As with any medical procedure or intervention, the decisionto take tamoxifen is an individual one in which the benefits and risks mustbe considered," said Leslie Ford, M.D., associate director for earlydetection 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, tamoxifentherapy may not be appropriate for her," continued Ford. "NSABPand NCI are developing information for individual decision making that willhelp women at increased risk of breast cancer consult with their healthcare providers to answer the question, 'Is tamoxifen the right choice forme?'"
The BCPT is a clinical trial designed to see whether the drug tamoxifenprevents breast cancer in women who are at an increased risk of developingthe disease. Women in the study were randomly assigned to receive tamoxifenor a placebo pill and neither participants nor their physicians were awareof the treatment assignment, a process called "double-blinding."
Launched in April 1992, the BCPT also looked at whether taking tamoxifendecreases the number of heart attacks and reduces the number of bone fracturesin these women. There was no difference in the number of heart attacksbetween the tamoxifen and placebo group, but women in the tamoxifen grouphad fewer bone fractures of the hip, wrist, and spine (47 cases in the tamoxifengroup versus 71 cases in the placebo group).
As part of the study design, the BCPT data were regularly reviewed byan independent Endpoint Review, Safety Monitoring, and Advisory Committee(ERSMAC). At its regularly scheduled meeting on March 24, 1998, the committeerecommended that the participants and their physicians be told what pillseach participant had been taking because of the clear evidence that tamoxifenreduced breast cancer risk.
NSABP presented the data to NCI on March 26 and, together, both NSABPand NCI researchers concurred with the committee's recommendation. Thisdecision was based upon their joint assessment that a reduction of breastcancer had been demonstrated. It was agreed that any additional informationthat might be gained from continuing the study did not outweigh the benefitsof making the treatment available to the participants in the placebo groupand other women at increased risk of breast cancer.
The women in the trial have taken tamoxifen or placebo daily for aboutfour years. In spite of extensive efforts to enroll minorities in the BCPT,African American, Asian American, Hispanic, and other groups together madeup only about 3 percent of the participants.
About 40 percent of the participants were ages 35 to 49, 30 percent wereages 50 to 59, and 30 percent were age 60 or older. All age groups showedsimilar reductions in breast cancer incidence from tamoxifen. There wasa suggestion that the breast cancer benefit from tamoxifen could be greaterin women over age 50, but older women are also at increased risk for someof the serious side effects (endometrial cancer, pulmonary embolism, anddeep 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 versus59 cases in the placebo group). Eight participants have died of breastcancer, three in the tamoxifen group and five in the placebo group.
"This advance represents the results of a long-term investmentin research," said NCI Director Richard Klausner, M.D. "Thisis a real advance, but it is no magic bullet. Only through continued researchwill we find preventions that are even more effective and with fewer sideeffects."
At the inception of the study, the investigators made a commitment tonotify 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 participantsat their sites.
"Our heartfelt gratitude is extended to the study participants,"said Norman Wolmark, M.D., chairperson of NSABP. "It is only becauseof their commitment that we were able to answer a question of extreme importanceto many women."
Sandy Kanicki, co-chair of the BCPT Participant Advisory Board, saidsimply, "The results are so profound that I'm speechless. We don'tknow where we are going from here but we have taken a major step to helpwomen reduce their 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 optionto participate in an upcoming trial that will compare tamoxifen to anotherdrug that could have similar breast cancer prevention properties, but whichmight be associated with fewer adverse effects. Women of any age on placeboalso have the option of seeking tamoxifen from their health care providers.
The BCPT researchers will be evaluating the study's results in greatdetail in coming weeks. The final analysis will be published in the scientificliterature.
The study began recruiting participants in April 1992 and closed enrollmentin September 1997. Researchers with the NSABP are conducting the studyin more than 300 centers across the United States and Canada.
"Since 1990 when I and my NSABP colleagues, together with membersof NCI, designed this study, there has been an unprecedented display ofteamwork by the participants, their physicians, study support staff, numerousgovernment agencies, and medical centers," said Bernard Fisher, M.D.,scientific director at NSABP. "That commitment to scientific investigationhas resulted in this landmark accomplishment. I am delighted to have hadan opportunity to make a contribution."
Only women at increased risk for developing breast cancer participatedin the study. Because the risk of breast cancer increases with age, women60 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 breastcancer within five years. Women between the ages of 35 and 59 who demonstratedan increased risk of breast cancer equivalent to or greater than that of an average 60-year-old woman were also eligible. This breast cancer riskwas determined by a computer calculation based on the following factors:
One of the most widely prescribed cancer drugs in the world, tamoxifenhas been the focus of more than 25 years of research on its actions, benefits,and risks. Zeneca Pharmaceuticals, Wilmington, Del., manufactures tamoxifenand provided both the drug and placebo pills for the prevention study withoutcharge.
NCI new comprehensive online resource center for clinical trials informationat http://cancertrials.nci.nih.gov
Charts and Graphs summarizing the BreastCancer Prevention Trial (BCPT)
Backgrounder: Questions andAnswers: The Breast Cancer Prevention Trial
Announcer Copy: Breast Cancer PreventionTrial Shows Major Benefit, Some Risk
Editor's Note: The original news release, with contact information, can be found at http://rex.nci.nih.gov/massmedia/pressreleases/prevtrial.htm.
Materials provided by National Cancer Institute. Note: Content may be edited for style and length.
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