In January, an international team of researchers published a huge analysis of the success of various post-surgical, or adjuvant, therapies for breast cancer. Drawing on 133 randomized trials from around the world, their data identified tamoxifen -- a synthetic hormone -- as the ascendant star.
Unlike standard chemotherapeutic agents -- which kill dividing cells throughout the body, not just in the cancer -- tamoxifen kills nothing. It routs cancers by starving them of the estrogen that can promote their growth.
Hailed as nothing less than a wonder drug, tamoxifen has proved so successful in stalling or preventing breast cancer recurrence that researchers in the United States stand poised to begin large-scale trials of the drug this week in healthy women at high risk of the disease. A related trial could begin any day in the United Kingdom, with others slated in Europe and Australia. Their goal: prevention of breast cancer -- the most common malignancy in women.
New toxicological studies, however, hint that tamoxifen may itself cause cancer. These findings are seeding doubts about the wisdom of administering the potent anti-estrogenic drug for years -- perhaps for life -- to healthy women.
The new data have already held up the U.K. cancer-prevention trial involving tamoxifen. On March 12, as the study's leaders planned to begin recruiting an estimated 13,000 additional volunteers for a scaled-up five-year program, Britain's Medical Research Council (MRC) withdrew its support for the study as currently designed, pending further toxicological studies. The two remaining sponsors -- the Imperial Cancer Research Fund and the Cancer Research Campaign -- decided to continue the trial on their own, provided the U.K.'s Department of Health approves. At press time, that agency was taking a second look at the study design.
A U.S. tamoxifen trial for breast cancer prevention, funded by the National Cancer Institute (NCI), remains on track. NCI has scheduled a press conference for April 29 to announce details of this study, slated to eventually involve 16,000 healthy, high-risk women age 35 and over, half of whom will get the drug.
MRC Secretary Dai A. Rees explained his agency's decision to withdraw from the U.K. study in the March 28 BRITISH MEDICAL JOURNAL. Unpublished data by tamoxifen's manufacturer indicate that the drug induces liver tumors in rats, he notes. Because of the way it accumulates in the human body, doses of the drug responsible for producing cancers in rats appear "similar to those to be used in the trial," Rees says. As a result, "there is no dose or safety margin."
Rees also cites a study reported in the March 1 CANCER RESEARCH showing that tamoxifen produces potentially carcinogenic DNA alterations -- known as adducts -- in the livers of at least two types of rodents. Finally, though researchers have studied tamoxifen's effects in thousands of women, few of those patients have received the drug for more than five to seven years; that's less time than it usually takes for carcinogens to induce liver tumors in humans, Rees notes.
Worldwide, breast cancer rates are increasing (SN: 4/21/90, p.245). This disease, which will strike one in nine U.S. and Canadian women sometime during their lives, kills almost 45,000 each year in the United States alone.
MRC "has no wish to spread alarm among women taking tamoxifen for proved breast cancer," Rees says; for them, tamoxifen "is a well-tried and effective treatment" (see sidebar). However, until potentially life-threatening side effects can be ruled out, he says, MRC cannot justify administering this drug, as planned, to healthy women under age 40.
But not all researchers regard the new animal data as particularly revealing about tamoxifen's threat to humans. "Rat experiments seem to be the first stage, used to try to decide whether to use a drug or not," says Richard Peto, director of the cancer studies unit at Oxford University in England. …