The news made headlines across the country last month. Tamoxifen, a drug prescribed for over two decades to prevent recurrences in women with breast cancer, has now been shown to prevent the disease in some healthy but high-risk women. The National Cancer Institute stopped its clinical trial earlier than expected because there were 45% fewer cases of breast cancer among the women taking tamoxifen as compared with those taking an inactive placebo. Media reports hailed the finding as a breakthrough, yet they also included the appropriate cautions regarding the drugs risks. The women taking tamoxifen had more than twice the rate of endometrial (lining of the uterus) cancer and nearly three times the rate of pulmonary embolism (blood clot in the lung).

Lost in most of the media reporting, however, were the two deaths from pulmonary embolism among the women taking the drug.Tamoxifen may have prevented some cases of breast cancer, but the drug, thus far, has not been shown to save lives. There were five deaths in the tamoxifen group (three from breast cancer, two from pulmonary embolism) and five deaths in the placebo group (all from breast cancer).

The tamoxifen study, known as the Breast Cancer Prevention Trial, has been under attack since its conception for a variety of reasons. Chief among them is the charge that tamoxifen, a known carcinogen, might be appropriate for people with a life-threatening disease like breast cancer but not for healthy womenno matter what their risk of breast cancer. Tamoxifens most serious complicationsendometrial cancer and blood clotswere well known from the numerous studies of breast cancer patients given the drug to reduce their odds of developing cancer in the other breast. The drug was also shown to cause liver cancer in rats, 43% of whom developed the disease after six months. Furthermore, some breast cancer advocates would prefer to see Federal research dollars invested in finding dietary, lifestyle, or environmental causes of breast cancer rather than in a costly drug that must be taken for years. (A months supply of tamoxifen costs $80-100.)

The Breast Cancer Prevention Trial involved 13,000 participants, half took tamoxifen daily and half took an inactive placebo. The trial was originally supposed to continue for five years but stopped 14 months early because there were 45% fewer cases of breast cancer among the women taking tamoxifen: 154 cases in the placebo group and 85 cases in the tamoxifen group. The National Cancer Institute researchers were criticized by their British counterparts for ending their trial prematurely and raising false hopes. British scientists who are conducting a similar trial argued, rightly, that only long-term follow-up will demonstrate whether the benefits of tamoxifen are outweighed by the risks. At a press conference, the British scientists charged that American researchers will be unable to establish whether tamoxifen actually saves lives (see below). Answers are expected from an ongoing British-led international study.

The decision to stop the trial early was also criticized by some American activists. The Washington-based National Womens Health Network said in a press release that there are many questions that still need to be answered: What additional risks, if any, will be found as the participants are followed longer? Will there be fewer deaths among tamoxifen-treated women in the long run? And what are the implications for women not at high risk for breast cancer? Other activists argued that the widely reported 45% reduction in breast cancer cases is actually less than meets the eye. All we know now is that for a very small number of women, the drug delays the onset of breast cancer, wrote Barbara Brenner, executive director of Breast Cancer Action in San Francisco, in a letter to the editor of The New York Times.
Tamoxifen is a synthetic hormone that can block the female hormone estrogens potentially cancer-causing effect on the breast. It has an adverse effect on the uterus, however, because the drug mimics estrogens tumor-stimulating activity. On the other hand, tamoxifen imitates some of estrogens beneficial effects, and the drug was expected to reduce bone fractures and heart attacks. The Prevention Trial showed a lower rate of the former but not the latter. Tamoxifens more common side effects include hot flashes, headaches, depression, vaginal discharge, and fatigue.

The data from the Breast Cancer Prevention Trial have yet to be reviewed by independent experts or published in a medical journal. This is one of numerous breast cancer clinical trials conducted as part of the National Surgical Adjuvant Breast Project, directed by Dr. Bernard Fisher. For more information about the Prevention trial, visit the National Cancer Institutes web site (http://rex.nci.nih.gov).

By Maryann Napoli

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