Tamoxifen For Breast Cancer Prevention: FDA Approved, But Not Proven
The Events Leading to Approval For Breast Cancer Prevention
In 1998, a clinical trial was abruptly stopped and a flurry of press releases from its principals ensued. Its claims of 50% reduction in breast cancer rates of healthy women who took Tamoxifen for prevention, swept the airwaves and ethernet. Only very limited data that the authors of the study chose to release was available. Nevertheless, the organization's website told women everywhere to talk to their own physicians about using Tamoxifen to prevent breast cancer. While it had not been officially approved as a preventive drug for breast cancer, because it is already was already approved for breast cancer treatment, any physician could prescribe it for any purpose if, in the doctor's
judgement, there is scientific support. Typically, this is done when
there are several studies published in peer-reviewed (looked at by
a panel of doctors) journals supporting the new use for the drug.
But, in this case all the evidence rested solely on one study and its
unreviewed results, not to mention a lot of media coverage.
The group, called the National Surgical Adjuvant Breast and Bowel Project (NSABP) was later criticized for its use of the media to publicize their results. It allowed them to promote the good aspects of thier work, while sheilding them from any criticism about bad, becasue they simply did not release the data. Its motives and its financial relationships with the drug's manufacturer also came under fire. Estronaut found several negative aspects, such as equal death rates, and raised other questions. It seemed to cause as much disease as it prevented. Neverthless, it was approved for breast cancer prevention in women believed (but not proven) to be at high risk for breast cancer, in October of 1998 by the Food and Drug Administration.
Overall disease rates were comparable between the groups.
The study took more than 13,000 women who were classified as
being at high risk for breast cancer. The women were divided into two groups. One group
got Tamoxifen and the other group took placebos (a sugar pill with
no drug in it). The final numbers for breast cancer were 156 women not
taking the drug, and only 86 of
those taking Tamoxifen. This is
how researchers reached the conclusion that Tamoxifen will
reduce a woman's risk of breast cancer by nearly one half.
Take Tamoxifen: Get A Different Disease
What is usually glossed over are the higher rates of endometrial cancer and blood clot diseases (pulmonary embolism, deep vein thrombosis, strokes) and cataracts caused by the drug. These can off-set any gain due to decrease in breast cancer. Overall, the number of women who not taking the drug that got any disease? 919. The number taking Tamoxifen? 909. No difference.
Take Tamoxifen: Die Differently
There was not statisically significant differences in the chance of dying whether or not a woman took Tamoxifen, during the course of the study. Nor, was there a difference in breast cancer deaths. There were projections of long-term improvements in survival, but they are only projections. If one takes out unknown, unrelated, or non-gyny cancers, the exact same number of women died in both groups.
Other Benefits Were Not Found
It was hoped that Tamoxifen could act as a substitute for hormone replacement. However, it did not show that heart attacks and disease nor fractures decreased.
Endometrial Cancer Data Raised Several Questions
Endometrial cancer is of particular interest because Tamoxifen is so clearly implicated in its development. Not surprising, it was significantly higher in those who took Tamoxifen. But, this increase was seen only in the over 50 population. The more independent FDA reviewers said that the control group had unusually high rates of endometrial cancer. It was also concerned that the control group did not show the typical increase in endometrial cancer after 50. It suggested that the overlap in risk factors for endometrial and breast cancer were likely the cause.
The increase in the over 50 year old group was staggering. It was about 4.5 times more likely in the Tamoxifen group. If it turns out there was randon bias in the control group, then the increases could be even worse.
Current Conclusions on Tamoxifen For Breast Cancer Prevention
The rate of breast cancer decrease was the same as before (about 50%) in high risk women. There were no new health benefits (heart and osteroporosis) discovered. The old risks (endometrial cancer and blood clots) were confirmed.
Estronaut's assessment of this drug is same. Taking Tamoxifen preventively simply trades one disease for another, one cause of death for another. The disease a woman trades for may be worse beyond the absolute numbers. Blood clots can cause immediate death and permanent disability. With breast cancer there is the possiblity of cure or at more years of life.
The models used to assess predict high risk for breast cancer are not well developed. Worse yet, when they do pick up high risk breast cancer they are also picking up those at high risk for endometrial cancer. Women over 50 with a uterus have a particularly poor risk/benefit outlook.
It is also known that minority
women were not well represented in this study, in spite of efforts to
do so. So whatever the final results may be, they may not apply to
The Future of Tamoxifen For Breast Cancer Prevention
Recent studies show that a much lower dose, about 1/4, will get the same results. Presumably the lower dose will spell less disease caused, such as the endometrial cancer and the blood clots. This would improve the risk/benefit assessment.
But what happens in about 15 year? What if everyone has a uterus? As noted, above, the over 50 crowd has a very dramatic increase in endometrial cancer with Tamoxifen. This generation also has a high rate of hysterectomy. With each hysterectomy in this study, there is a woman who might have otherwise gotten endometrial cancer. With new treatments and the trend away from hysterectomy, the percentage of women over 50 with uteruses will likely increase. Imagine we take today's data and extrapolate and pretending that everyone over 50 has a uterus. The Tamoxifen group has 1) a higher overall disease rate by 5% 2) breast cancer is still 50% off 3) gynecological cancers are only 20% lower. If there was an unusally high rate of endometrial cancer in the current control group, the overall disease would go up, the gyny cancer rates begin to equalize.
As time goes on we may learn what the long-term effects of
taking Tamoxifen are in healthy women. Is there an overall
decrease in disease in women who take it? Is there an overall
increase in life span?
Women may not have to wonder about Tamoxifen much longer. There are trials comparing Tamoxifen with Relaxifen, in hopes that latter has a better risk/benefit profile.