WASHINGTON--Researchers terminated the treatment portion of the Breast Cancer Prevention Trial (BCPT) in late March, 14 months earlier than expected, after the studys independent monitoring committee determined that patients receiving tamoxifen(Drug information on tamoxifen) (Nolvadex) had a 45% reduction in breast cancer incidence, compared to the placebo arm.
"This is the first time in history that we have evidence that breast cancer can not only be treated, but also prevented," said Bernard Fisher, MD, scientific director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which conducted the study. "This is an extremely emotional experience for me, probably the most emotional of my entire career. In the beginning of my career, to have thought of doing a prevention trial would have been considered entirely fanciful."
In addition to fewer breast cancers, women taking tamoxifen also had fewer bone fractures, attributed to the drugs estrogen-like effects on bone density. However, women in the tamoxifen arm did have a significant increased risk of endometrial cancer, pulmonary embolism, and deep vein thrombosis. Researchers will continue to follow the women who took part in the trial.
"The results of this study are remarkable," NCI director Richard D. Klausner, MD, said at a press conference called to announce the findings. "This study provides an estimate of the magnitude of the reduction of risk, and significant information about important and serious side effects of taking tamoxifen."
"Tamoxifen heralds a new era of preventive maintenance therapy for breast cancer," V. Craig Jordan, PhD, DSc, a leading tamoxifen researcher, told Oncology News International. "This really swings the scales from treatment toward prevention of breast cancer." Dr. Jordan is director of the Breast Cancer Research Program, Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago.
The biology of tamoxifens action has been well known for decades. The reduction in cancers realized in the Breast Cancer Prevention Trial was the culmination of over 20 years of steady work with the drug, said the British-born Dr. Jordan. He first studied tamoxifen in 1972, as a means of preventing mammary tumors in rats. Its uses have moved in a steady continuum: "Weve gone from lab rats in the 1970s to preventive trials today. Theres no doubt that the benefits far outweigh the risks."
Dr. Klausner and others stressed that no blanket recommendation could be made about using tamoxifen to prevent breast cancer and that women need to discuss their individual situations with their physicians.
"The decision to begin tamoxifen is a complex one," said Leslie Ford, MD, NCI associate director for the Early Detection and Community Oncology Program. "Even for women with a high risk of developing breast cancer, tamoxifen may not be the appropriate choice."
Tamoxifen was initially approved in the United States in 1978 for the treatment of patients with advanced breast cancer. It won approval as an adjuvant therapy following surgery and/or radiation for early stage breast cancer in 1985. Evidence that tamoxifen not only prevented recurrence of original tumors but also prevented new cancers in the opposite breast led to the BCPT.
The $50 million double-blinded, randomized, placebo-controlled BCPT study enrolled the first of its 13,388 patients on June 1, 1992. Researchers at more than 300 centers in the United States and Canada randomized 6,681 women to receive 20 mg of tamoxifen daily and 6,707 women to get a placebo. Each woman was to take two pills a day for 5 years. At the time the BCPT released its results, 57% had completed 4 years or more on the study.
All Age Groups Benefited
All the women admitted to the study were deemed at high risk of developing breast cancer. About 40% of the women were ages 35 to 49; 30% were in their 50s, and another 30% were age 60 or older. All the age groups taking tamoxifen had similar reductions in breast cancer. Women in the 35 to 49 age group showed no excess risk of adverse effects from tamoxifen.
Although the study suggested that women older than age 50 might gain greater benefit from the drug than those younger than 50, this difference was not significant. Moreover, women age 50 and above had a greater risk for some of the more serious side effects observed.
The women on tamoxifen developed 85 cases of invasive breast cancer, 45% fewer than the 154 cases that occurred in the placebo group. The tamoxifen women also had fewer noninvasive breast cancers, such as ductal carcinoma in situ (DCIS). The drug group experienced 31 cases of noninvasive cancer vs 59 cases among the women taking the placebo. Eight women in the study died of breast cancer, three in the tamoxifen group and five in the placebo arm.
"We have found that tamoxifen is highly effective for preventing cancer, not only invasive breast cancer, but also noninvasive breast cancer," said Joseph Costantino, DrPH, associate professor of biostatistics at the University of Pittsburgh Graduate School of Public Health.
Women taking tamoxifen suffered fewer fractures of the hip, wrist, and spine, 47 compared to the 71 fractures in the placebo group. Previous studies have indicated that the drug maintains bone density and decreases the extent of osteo-porosis. No difference occurred in the number of heart attacks.
However, women on tamoxifen did suffer significantly more endometrial cancers--33 vs 14 in the placebo arm (about 37% of the women in each group had had a hysterectomy). This increased risk was approximately the same as seen in women taking a single agent for estrogen replacement therapy. All but one of these endometrial cancers was detected at an early stage.
The tamoxifen women also had a greater danger of pulmonary embolism--17 cases in the treatment group vs 6 among placebo takers--and suffered more deep vein thrombosis, 30 cases in the tamoxifen arm vs 19 cases among the controls.
BCPT participants have been asked to continue their follow-up examinations. Those who did not complete 5 full years on tamoxifen can continue until they do; women in the placebo arm can seek tamoxifen from their private physician, if they choose.
"These women have only been followed for a certain amount of time, and there is much we do not know about how long the protection will last, details about how long the drug will have to be taken, and what will happen in the future," Dr. Klausner noted.