Beware This Breakthrough!

By MICHAEL D. LEMONICK

For Helene Wilson, the decision to participate in a clinical trial of tamoxifen took no thought at all. Scientists at the National Cancer Institute and the National Institutes of Health wanted to know if the drug, used for 25 years to treat breast cancer, could prevent the disease. The question was of more than academic interest to Wilson, 48, a North Wales, Pa., nurse and mother of two. Four close relatives, including her mother and grandmother, had died of breast cancer at an early age. Wilson herself had a history of benign lumps in her breast. She was, her doctor once bluntly told her, "a walking time bomb."

Perhaps now she has been defused. Last week researchers announced that they were halting the study 13 months early. Reason: tamoxifen, they've learned, does indeed prevent breast cancer. It's the first drug ever shown to do so. Said Dr. Harold Varmus, director of the NIH, in announcing the results: "This is a big deal."

More of a big deal than he'd expected, perhaps. Although Varmus and other officials were careful to stress that tamoxifen is a potentially deadly drug with serious risks and unpleasant side effects, that message was all but lost in the initial euphoria. Breast cancer justifiably terrifies American women--so badly that many latched on to the discovery and ignored the downside.

It didn't take long for the backlash to begin. Breast-cancer support groups weighed in almost at once. Why, they asked, would an otherwise healthy woman want to take a drug that can cause birth defects, trigger blood clots and double her chance of getting cancer of the uterus? Some questioned the drug's value even for the 29 million American women whose chances of getting breast cancer are, like Helene Wilson's, significantly higher than the 1-in-9 national average. Tamoxifen is already approved as a breast-cancer treatment, so physicians can prescribe it for prevention as well. But, says Fran Visco, president of the National Breast Cancer Coalition, "this is not a drug for the average woman. It's not the prevention that we've all been demanding."

It was those demands in the late 1980s that made University of Pittsburgh surgeon Dr. Bernard Fisher and others take a second look at tamoxifen, which had been in use for a decade as a milder alternative to chemotherapy for treating breast cancer. They noticed that it not only helped keep cancer from returning in the affected breast but also cut in half the number of new cancers in the other breast. Animal studies suggested that tamoxifen latches on to receptors in breast-cancer cells that would ordinarily take up the hormone estrogen--a substance known to fuel the growth of cancer. By keeping the estrogen out, tamoxifen essentially cuts off the cancer cells' fuel supply.

That being the case, Fisher and other researchers wondered whether this cell-starvation process could prevent breast cancer from taking hold in the first place. Thus in 1992 they began the federally funded, 13,388-participant, $50 million study of women at especially high risk; being over 60 was a qualification by itself. Participants could also be included if they had a combination of two or more close relatives who had had the disease, a first child late in life, and several previous biopsies of suspicious lumps.

Researchers knew--and made clear to participants going in--that the drug was not without danger. While tamoxifen acts as an estrogen blocker in the breast, it acts more like estrogen itself in other parts of the body. That's why the scientists were on the lookout for uterine cancer and effects on the circulatory system. And while such problems did show up, so did the hoped-for protection. Women who took the tamoxifen had a 45% lower incidence of breast malignancies than those who took placebos. Results were so dramatic that the scientists stopped the study and gave the placebo group a chance to consult with their doctors about switching to the genuine medication.

Whether the women in the study group--or any other women at high risk for breast cancer--should take tamoxifen is complicated not only by the potential side effects but also by another confusing trade-off. Tamoxifen causes the most serious side effects in women over 50. But those are the women who have the highest odds of getting breast cancer. So many factors have to be weighed in the choice that researchers plan to produce a chart or software that will help women decide what to do. Unfortunately, it won't be ready for at least three months.

Critics also point out that cutting off the study in midstream prevented doctors from learning a lot more about tamoxifen's longer-term effects. Will women have to take the drug for the rest of their life? Does the protective effect decrease over time? Will new side effects show up with long-term use? Will tumors that appear while a woman is on tamoxifen be harder to treat (preliminary studies suggest they may be)? Can other drugs confer comparable protection without side effects? And most important, did taking tamoxifen lengthen or shorten these women's life?

These questions will be answered by future research. But what's more important, Fisher believes, is that science has finally demonstrated that breast cancer can be prevented. Most women, especially those at low risk, probably won't go on tamoxifen. But they may well end up taking the next generation of safer, tamoxifen-based drugs, which are already under development, or the generation after that. Until those drugs come along, Visco of the National Breast Cancer Coalition urges women to go slowly. "Wait," she says. "The best thing to do is wait."

--Reported by Dick Thompson/Washington

With reporting by Dick Thompson/Washington