Does Tamoxifen Prevent Breast Cancer?

Wondering About a Wonder Drug
By SUSAN LOVE
The New York Times
August 3, 1999
For women with breast cancer or a high risk of developing it, the drug tamoxifen has been seen as a life saver. The drug is able to counter the cancer-promoting effects of the hormone estrogen, which has been shown to aid the growth of about half of breast cancers. But according to a new study, tamoxifen can reverse its colors and stimulate the growth of cancer cells after two to five years of use.

These latest findings are troubling and confusing news for the many women who are taking the drug. Didn't we just read reports that Tamoxifen should be given to healthy women to prevent breast cancer? What is going on here?

What is going on is yet another example of the fact that medicine and science are a work in progress.

In fact, this new research, done by scientists at Duke University Medical Center and the Novalon Pharmaceutical Corporation in Durham, N.C., does not contradict any of the previous studies. Rather, it suggests the explanation for the observation made in several previous studies that that taking Tamoxifen for 10 years is no better and maybe worse than taking it for 5 years. If you keep on taking Tamoxifen beyond five years the drug can develop a way to start acting like estrogen rather than blocking it. A little is good but more isn't better.

Whenever a new finding is announced, scientists and clinicians are doing nothing more than making their best guess at the moment. We have to stay tuned, because with more studies we can make an even better guess. Unfortunately people often infer (and the media often give the impression) that these guesses and hypotheses are the "truth."

I was once told by a television interviewer that the problem was that women needed "the answers" on breast cancer. I replied that I thought it was the media that required "the answers" and that women are perfectly able to make the best decision possible based on inadequate information. They do this all day every day. And women are capable of understanding that the answers may change with further data.

Tamoxifen is a perfect example of how medical knowledge develops. It was first developed in 1962 as a "morning after" birth-control pill that was effective in rats. In humans, however, tamoxifen had the opposite effect: it was found to be a fertility drug. Luckily a British doctor, Arthur Walpole, thought to test tamoxifen in women with breast cancer. It was known that many cancers were sensitive to estrogen, and he hypothesized that an antiestrogen agent might help. Indeed it did.

More recently, clinicians have been surprised again by this "antiestrogen" which they had assumed blocked estrogen throughout the body. They found that it did block estrogen in the breast and brain but amazingly seemed to act like estrogen in the bones, liver and uterus. This observation led them to develop a whole new category of drugs called selective estrogen receptor modulators.

Researchers then set out to design a drug which would be even better than tamoxifen: one that would not cause uterine cancer but would prevent osteoporosis and heart disease as well as breast cancer. Scientists are currently studying the first of these designer selective estrogen receptor modulators, Raloxifene.

In a National Cancer Institute study of more than 13,000 women concluded last year, tamoxifen was shown to decrease the incidence of breast cancer by 49 percent in high-risk healthy women. But the number of women in the study who did get cancer was relatively small: 4.3 percent of women developed breast cancer in the placebo group, while 2.2 percent were diagnosed with breast cancer in the tamoxifen group. This means that 95.7 percent of these high-risk women took tamoxifen with no benefit and risked side effects including a small increase in uterine cancer in postmenopausal women and, more important, a small but real increase in deaths from clots to the lung.

The women in this study who had had biopsies showing atypical hyperplasia (precancerous changes in the cells lining the milk ducts) and who took tamoxifen reduced their risk of developing breast cancer by 86 percent. If it were easy to identify which women will develop these changes we could select which women are most likely to benefit from tamoxifen. But as of now there is no equivalent of a Pap smear for breast cancer.
Or, if we had a way to monitor women on tamoxifen, we might be able to detect when the cells are beginning to become resistant before they have a chance to do damage. Researchers are studying devices to do just this. Let's hope this is the next piece of progress.

Thus the real message for women is not that tamoxifen is bad or good, but that it is a very interesting drug that we do not fully understand. Taking it for five years after a breast cancer diagnosis is worthwhile. Taking it longer may not be better. In high-risk women, the risks and potential benefits of taking it beyond five years should be considered. Raloxifene, on the other hand, has yet to be proved to decrease breast cancer in high-risk women.
Once again, we have been disappointed that what we regarded as the "truth" about cancer. A miracle drug is a miracle for some and not others, and we don't yet know enough to figure out which group is which. But the more research and the more clinical trials, the better, no matter how conflicting their results. We may not ever have the "truth," but our best guesses will only get better.

Susan Love, a breast surgeon, is the author of "Dr. Susan Love's Hormone Book."

Why Tamoxifen (breast cancer drug) stops working
NEW YORK, Jul 30, 1999 (Reuters Health) -- Breast cancer patients generally develop resistance to the drug tamoxifen 2 to 5 years into treatment, but new study results suggest there may be a way to prevent tamoxifen resistance.   Normally, tamoxifen blocks estrogen receptors found on breast cancer cells, thus thwarting the growth-promoting effects of the female hormone. 

About half of breast cancers have such estrogen receptors, and tamoxifen treatments can be very successful at blocking continued cancer growth.  Over time the tamoxifen stops being effective as an anti-estrogen agent and begins to act on the cell like estrogen itself. 

According to a report in the July 30th issue of Science, researchers now think they know the reason
why this occurs. Apparently, the tamoxifen begins to change the shape of the estrogen receptor, which forms an additional ``pocket'' that can bind to peptides, or short proteins inside the cell. The action of these other proteins seems to change how the cell perceives tamoxifen, Dr. Donald McDonnell, of Duke University Medical Center in Durham, North Carolina, and colleagues from the Novalon Pharmaceutical Corporation in Durham explain.
The full article can be found at:
http://dailynews.yahoo.com/headlines/hl/story.html?s=v/nm/19990730/hl/tam11_1.ht

10/06/1998 Reuters Health
Dangerous side-effects of tamoxifen might be reduced by cutting the dose of the drug, Italian researchers reported today. Reporting in the Journal of the National Cancer Institute, the researchers said they found tamoxifen seems to work well in much smaller doses than usually given.   “Up to a 75 percent reduction in the conventional dose of tamoxifen does not affect the activity of the drug,” Andrea Decensi and colleagues at the European Institute of Oncology in Milan, Italy, wrote.
Tamoxifen, produced under the name Nolvadex by a subsidiary of Britain’s Zeneca Group, is already the most commonly used drug against breast cancer.   For  more information, click on: 
http://www.abcnews.go.com/sections/living/DailyNews/tamoxifen981006.html

July 21, 1998
From: bettym19@mindspring.com (betty martini)
To: dorietz@awod.com (Dave Rietz)

Dear Dave:  I'm sending this to you to put on the list.  You recall I wrote the article Tamoxifen, Terror and Tears and made mention that Tamoxifen has been declared a carcinogen by the World Health Organization of the United Nations, and that Tamoxifen does not kill cancer but targets other organs,
is a pro-hormonal, not anti-estrogen. 

U.S. Researchers sparked a transatlantic debate this spring when they announced that the drug tamoxifen can prevent women from developing breast cancer.  Researchers in Britain responded that longer studies were necessary to justify that conclusion.

Now, two teams of European researchers offer some support for those critics.  In the July 11 Lancet, both groups report preliminary findings that indicate tamoxifen -- a widely prescribed medication for limiting breast cancer recurrence - provides no significant protective effect.

Like the U.S. researchers, teams in England and Italy examined whether the drug reduces the number of new cases of cancer among healthy women with no previous breast cancer but who were, for a variety of reasons, at high risk of contracting the disease. 

Neither study found a significant difference in cancer incidence between women who took an inactive substance, or placebo, and those who received tamoxifen.  In contrast, the U.S. Breast Cancer Prevention Trial had found that among participants diagnosed with invasive breast cancer, almost twice
as many were taking the placebo as tamoxifen (SN: 4/11/98,p.228).

Citing statistical shortcomings in their own data, the European investigators stop short of dismissing tamoxifen's preventative effects and instead call for further research.  The British team, led by Trevor Powles of the Royal Marsden NHS Trust in Surrey,England, reports a chance of about 1 in 10 that their study erred in failing to observe the effect reported by the U.S. team.  The finding in the Italian Tamoxifen Prevention Study, by researchers at the European Institute of Oncology in Milan, appears less powerful still.

The NCI halted its study last March, after finding what they termed dramatic evidence of tamoxifen's protective benefit. "I have seen nothing in either of those (Lancet) articles which would lead me to change our conclusions in any way," says Bernard Fisher of Allegheny University of the Health Sciences in Pittsburgh, who directed the U.S. trial.

The latest reports have nevertheless renewed discussion about whether any protective benefit of tamoxifen outweighs its side effects, which can include uterine cancer and life-threatening blood clots.  "What cautious people thought was, we shouldn't jump to act based on that one (U.S.) study," says Cynthia Pearson of the National Women's Health Network in Washington, D.C.

Significant differences between the participants in the U.S. and European studies may explain the contrasting results, Fisher says.  More women in the U.S. study had passed menopause, which is associated with an increased risk of breast cancer.  Also, the European researchers allowed participants
to treat symptoms of menopause with estrogen-like drugs, which Kramer says could have distorted the results.  Estrogen helps breast cancer cells grow and tamoxifen blocks its action. 

In a commentary in the same issue of Lancet, Kathleen I. Pritchard of the University of Toronto says the U.S. findings "seem robust."  But, she adds, the disparate results suggest that tamoxifen may only initially suppress the growth of small, difficult to detect tumors.  In the longer term, those cancers may grow if they become resistant to tamoxifen or if a woman stops preventative therapy."