Reflections on the Tamoxifen Breast Cancer Prevention Trial

NEW YORK—The observation in the early 1970s that an estrogen-receptor modulator called tamoxifen (Nolvadex) could decrease breast tumor recurrences and secondary primaries launched trials that continue to yield remarkable results, D. Lawrence Wickerham, MD, said at a teleconference for patients, sponsored by Cancer Care, Inc. Tamoxifen became the most commonly prescribed breast cancer drug, and now it has become the first to be approved for reducing the incidence of breast cancer in high-risk women.

Dr. Wickerham, associate professor of human oncology, Allegheny University, Pittsburgh, is the associate chairperson of the National Surgical Adjuvant Breast and Bowel Project (NSABP), the cooperative group that has evaluated tamoxifen as adjuvant therapy and prevention.

He called the trials that led up to the approval of tamoxifen for breast cancer prevention a 30-year success story. “Science tends to be very slow and deliberate, and sometimes it’s hard to get a full perspective on how important a new approach can be. But here we have an example of an initial finding in the laboratory pointing to the treatment of advanced disease, the treatment being proved in the adjuvant setting, and now it is being shown that the treatment can prevent cancer.”

The tamoxifen prevention trial, which began in 1992 and involved 13,388 subjects whose risk for breast cancer was about five times that of a similar population, showed a 49% reduction in the incidence of invasive and noninvasive cancers among those on tamoxifen, compared with placebo. The benefit occurred in all age and risk groups. The impressive findings justified an early end to the trial in April 1998.

Effects Appear Early

“This difference between tamoxifen and placebo appears very early on in treatment. We can see it occurring as early as 1 year, and it also continues for the entire duration of follow-up, and we have women now who are well out into their sixth year of follow-up,” Dr. Wickerham said.

This suggests two things are occurring: that there may well be some effect of tamoxifen on early breast cancers that were already present but not detectable by physical exam or mammogram, and that tamoxifen is having some preventive effects. “It certainly results in fewer clinically detectable breast cancers,” he said.

In the prevention trial, the breast cancers that did occur in the tamoxifen group tended to be smaller and were more likely to be node negative. “There was no indication that these cancers were more aggressive, and the cancers that were ER negative were no more frequent in the tamoxifen group than in the placebo group,” he said.

However, some uncertainties remain about tamoxifen, such as its long-term efficacy and who should take it, and that is to be expected, he said. “Any clinical trial worth a pinch of salt results in more questions than it answers, and that’s the case here. It doesn’t mean that the studies are flawed. It simply means that you can’t answer every question with one evaluation, and there are some unanswered ones here.”

A Question About ER-Negative Tumors

At the Cancer Care teleconference, a patient asked Dr. Wickerham if tamoxifen (Nolvadex) could benefit women with receptor-negative breast cancers. “That is an area of active research,” he said. ‘The value of tamoxifen has not been established in ER-negative breast cancers. The trials in this area to date are relatively limited and small in scope, but a recent overview analysis, combining the results of all the studies of tamoxifen around the world, showed no suggestion of benefit within that group, with the exception of reducing the risk of opposite breast cancers, as we see in the prevention population.

“However, there are situations where the ER evaluations on primary tumor come into question. It may be that even in tumors that are characterized as ER negative, there are a number of ER-positive cells that can benefit from tamoxifen. So its use in women with ER-negative breast cancer is still an open question.”

It’s clear that tamoxifen appears to reduce the incidence of breast cancer, he said. “Is that true prevention or are we merely delaying cancer development?” he asked. “We’re going to continue following these women. Our expectation from treatment trials is that this is a real benefit that will continue for a long time.”

Five years of tamoxifen is currently being recommended for women at high risk who seek preventive therapy. “Would a longer period be of greater benefit?” he asked. “We don’t know that for a fact in prevention, but we certainly feel that 5 years is sufficient in breast cancer treatment and is likely to be the same in prevention.” As for the drug’s effect on breast cancer in women with inherited breast cancer mutations, he said that trials examining this are underway and should be yielding results in a year.

Dr. Wickerham mentioned one other concern: “Are we merely preventing ‘good’ breast cancers, those that are ER positive—though I’m not sure I’ve ever met a good breast cancer. There were certainly concerns about similar things when adjuvant therapy initially came into use. With time, we’ve shown that these early results with adjuvant therapy have been maintained. We expect the same to occur with prevention. But, at present, we don’t know.”

The NCI’s Breast Cancer Risk Assessment Tool makes it possible to calculate a woman’s 5-year and lifetime risk of developing breast cancer, and Dr. Wickerham pointed out that the “risk disk,” as it has come to be known, also can determine a woman’s risk-eligibility for the NSABP’s newest prevention trial comparing tamoxifen and raloxifene (Evista), a selective ER modulator approved for use in osteoporosis.

“Participating in the second prevention trial is a real option for these women,” Dr. Wickerham said. “But not every woman will choose it. It becomes an issue of weighing risks and benefits.”