VIENNA, AustriaThe substantial drop in breast cancer
incidence reported in the NSABP P-1 trial of prophylactic tamoxifen
(Nolvadex) contrasted sharply with the negative findings of the
earlier Royal Marsden and Italian trials. Whether the P-1 results can
be confidently and routinely applied to all high-risk women was the
focus of a debate between Royal Marsden investigator Trevor Powles,
MD, and NSABP investigator Bernard Fisher, MD, at the 10th European
Cancer Conference (ECCO 10).
There is absolutely no doubt that tamoxifen given to healthy
women will reduce the incidence of early breast cancer, Dr.
Powles acknowledged. But, he said, the 50% reduction amounted to only
86 fewer breast cancers. Thus, certain questions arise:
Does this reduction balance favorably against the toxicity of
- Is this balance of benefit and risk maintained
beyond 4 years?
- Is the treatment of tens of thousands of healthy
women better than the treatment of hundreds of patients with breast
- Is the reduction in early incidence a treatment of
occult disease or is it a permanent prevention of a disease that
- Are there groups of women who are resistant to
tamoxifen and should therefore not receive it?
Unfortunately, Dr. Powles said, answers to these critical questions
will not be forthcoming from the NSABP P-1 study. I would like
to put forward the case that (1) we are not yet ready to give
tamoxifen to large numbers of healthy women and (2)
placebo-controlled trials should continue in Europe, he said.
Dr. Powles pointed out that P-1 study enrollees who had atypical
ductal hyperplasia or lobular carcinoma in situ achieved the most
substantial gains with tamoxifen. In fact, he observed, if women with
histologic abnormalities are excluded from the study analysis, the
risk reduction afforded by tamoxifen drops from 50% to 42%.
If some subgroups of women are particularly sensitive to tamoxifen,
Dr. Powles suggested, there may also be other, as yet unidentified
subgroups who benefit less or not at all. This may explain why
the Italian trial and our own trial showed absolutely no effect of
the use of tamoxifen in about 7,500 healthy women, he proposed.
Of concern, he said, is that we gave 52,000 patient-months of
tamoxifen, which would cost about $1.5 million in the United States,
and we didnt prevent a single cancer over a 6-year period. If
there are large groups of women who are resistant, as in our study
and the Italian study, then we cant just extrapolate the
results of the P-1 trial and say that, yes, all women will benefit.
Examining the actual benefits and risks of tamoxifen prophylaxis in
the 6,681 participants in the NSABP P-1 study, Dr. Powles said that
the prevention of 86 invasive breast cancers was achieved at a cost
of 21 extra endometrial cancers, 14 strokes, 67 cataracts, 12
pulmonary embolisms, 3 acute myocardial infarctions, and 13 deep vein
Since the trial was stopped after 4 years, he noted, it is not
possible to determine exactly how the balance of benefits and risks
might shift over the long term. But there is no doubt in my
mind that the benefits are going to get better and the risks are
going to get worse, he said.
Dr. Powles said that although an FDA committee recommended approval
of tamoxifen for short-term risk reduction, the same committee
unanimously agreed that the NSABP P-1 data failed to demonstrate a
favorable benefit-to-risk ratio for prevention of breast cancer in
high-risk women as defined by the study.
Similarly, an ASCO technology assessment concluded that prophylactic
tamoxifen may be offered to women who have a 5-year risk of 1.6% or
more, while at the same time cautioning that there was insufficient
evidence to show an overall health or survival benefit.
Dr. Fisher Responds
Responding to the criticism of the NSABP trial, Dr. Bernard Fisher
said, Not one bit of data has been presented to challenge the
He pointed out that ample laboratory and clinical evidence to justify
the use of tamoxifen came from the earlier NSABP B-14 study, which
showed that 5 years of treatment with tamoxifen reduced the incidence
of contralateral breast cancer for 10 years.
Dr. Fisher maintained that the prophylactic benefits documented in
the P-1 study held across the board, in young women (44% reduction in
risk ) as well as older women (53% reduction), and in very-high-risk
women (66%) as well as moderate-risk women (63%).
You cannot make these numbers disappear, and you cant
ignore them, he said. Most important, Dr. Fisher said, the
reduction in breast cancers was related to the estrogen-receptor
positivity of the tumors.
The National Cancer Institute estimated that there were 29
million women in the United States who met the eligibility criteria
of this study, and one can see that over a 5-year period, if these
women had received tamoxifen, there could have been a reduction of
almost 500,000 invasive breast cancers and another 200,000 or 300,000
noninvasive breast cancers, Dr. Fisher said.
He called the major life-threatening toxicities of tamoxifen
highly overrated for many reasons, some of which are political,
some of which are economic, and some of which are pure bias. He
noted that vascular adverse events were rare in patients under the
age of 49 and that all cases of endometrial cancer were localized.
The mortality and morbidity associated with breast cancer are
likely to exceed those associated with the adverse effects of
tamoxifen, he stressed.
Potential candidates for tamoxifen prophylaxis, Dr. Fisher advised,
include premenopausal women with a risk profile comparable to that in
the P-1 study, women with a history of lobular carcinoma in situ or
atypical hyperplasia, women who have undergone hysterectomy, and
women with a history of ductal carcinoma in situ.
I personally believe that tamoxifen provides an alternative to
bilateral mastectomy in women with a BRCA1 or BRCA2 mutation,
Dr. Fisher said, while conceding that there is as yet insufficient
information upon which to base this statement.
Not all women are at increased risk, Dr. Fisher said, but
tamoxifen provides those who are at increased risk with an option to
prevent breast cancer. Thousands of women who are receiving so-called
effective treatment die of invasive breast cancer, and I do not
believe that we can afford to deny those women who are at increased
risk the opportunity to receive tamoxifen.
Dr. Fisher urged that future studies be conducted to assess the
impact of agents that affect ER-negative tumors and the potential
benefits of selective estrogen receptor modulators (SERMs) with
different mechanisms of action. We have begun to nibble away at
areas below the limits of detection of mammography, and this is where
the action must be, he concluded.