NEW YORKThe 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 its 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
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 thats the case
here. It doesnt mean that the studies are flawed. It simply
means that you cant 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
However, there are situations where the ER evaluations on
Its 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. Were
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 dont 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 drugs 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
positivethough Im not sure Ive ever met a good
breast cancer. There were certainly concerns about similar things
when adjuvant therapy initially came into use. With time, weve
shown that these early results with adjuvant therapy have been
maintained. We expect the same to occur with prevention. But, at
present, we dont know.
The NCIs Breast Cancer Risk Assessment Tool makes it possible
to calculate a womans 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
womans risk-eligibility for the NSABPs 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.