Good morning, Members of the Caucus. I am Leslie Ford M.D.,
Associate Director of the Early Detection and Community Oncology
Program at the National Cancer Institute (NCI). I am pleased to
testify before you today about the Breast Cancer Prevention
Trial.
For the past six years, the National Surgical Adjuvant Breast and
Bowel Project (NSABP), an NCI funded national clinical trials
organization, has been carrying out an historic clinical trial -
called the Breast Cancer Prevention Trial or BCPT- to determine
whether women at increased risk of developing breast cancer can
prevent the development of that cancer by taking the drug
tamoxifen.
The BCPT enrolled 13,388 women at increased risk for developing
breast cancer. These included women 60 years of age and older who
qualified to participate based on age alone, and women between
the ages of 35-59 with an increased risk of breast cancer
equivalent to or greater than that of a 60 year old woman.
Of the 13,388 women on the trial, about 40 percent were ages
35-49, about 30 percent were ages 50 to 59, and about 30 percent
were age 60 or older. About 3 percent of the participants were
minorities, including African American, Asian American, Hispanic,
and other groups.
Participants in the BCPT were randomized to receive either
tamoxifen or a placebo. The trial was "double blinded" so that
neither the participant nor the researcher knew which pill she
was on. Setting up the study in this way allowed the researchers
to clearly see what the true benefits and side effects of
tamoxifen are without the influence of other factors.
As with all of our clinical trials, an independent Endpoint
Review, Safety Monitoring and Advisory Committee met regularly to
examine the data to monitor whether unacceptable or unexpected
toxicities had arisen or whether the trial had succeeded in
answering the questions it had been designed to answer. When this
committee last met on March 24, it was concluded that tamoxifen
can significantly reduce the incidence of breast cancer in women
at increased risk. Nevertheless, there were, as you have heard,
adverse effects of tamoxifen which may make the very personal
decision about taking tamoxifen complex. For all of these
reasons, the committee recommended that the participants of the
study be notified of these important results. It has been our
commitment to the participants from the very start to notify them
as soon as clear results had been achieved.
On March 26, the NSABP leadership presented these recommendations
and the data behind them to the NCI and we -- NCI and NSABP --
agreed to accept the recommendations of the independent advisory
committee. This morning, I will share this information with you,
describing the study, its results, and its implications, and very
importantly, place this study in the context of what we know and
don=t know about breast cancer prevention.
Study Results
- Results show 45 percent fewer diagnoses of invasive breast
cancer in women who were randomized to take tamoxifen
compared to women who were randomized to take the placebo
(85 cases in the tamoxifen group versus 154 cases in the
placebo group).
- Women on tamoxifen also had fewer diagnoses of noninvasive
breast cancer, such as ductal carcinoma in situ (31 cases in
the tamoxifen group versus 59 cases in the placebo group).
- The reduction in the incidence of breast cancer was seen
across all age groups.
- Women in the tamoxifen group had fewer bone fractures of the
hip, wrist and spine than women in the placebo group (47
cases in the tamoxifen group versus 71 cases in the placebo
group).
- The use of tamoxifen was also associated with infrequent but
potentially life-threatening adverse events. Although these
adverse events were no greater than had been predicted prior
to the initiation of the study, they must be given careful
consideration in determining the propriety and utility of
tamoxifen in reducing breast cancer risk.
- The risk of tamoxifen-associated adverse events was
predominant in women older than 49 years of age. In this age
group, there were 26 endometrial cancers (cancer of the
uterus) in the tamoxifen treated participants compared with
6 in the placebo group.
- There was also an excess of Avascular events@
(thromboembolic phenomena, stoke and transient ischemic
attacks), 81 in the tamoxifen group versus 53 in the placebo
group. The increased risk of Avascular events@ was similar
to that noted in postmenopausal women taking hormonal
replacement therapy. There was no increased incidence of
ischemic heart disease including myocardial infarction.
Risk Determination for Participants
The risk factors for the trial were determined using a
computerized model that was developed by Dr. Mitchell Gail of the
National Cancer Institute. This model took into account such
factors as the number of first degree relatives that had breast
cancer, --that's mothers, sisters, and daughters--the number of
biopsies that the woman might have had for suspicious lesions
herself; whether any of these biopsies had a diagnosis of
atypical hyperplasia , or a pre-invasive cancer called lobular
carcinoma in situ; her age when she started her periods, whether
she had any children, and how old she was when those children
were born.
A woman was eligible for the BCPT if her risk was at least as
great as that of the average 60 year old woman. For example:
-
- For the youngest women in the trial, they needed not only to
have two first degree relatives that had breast cancer, but
in addition, another risk factor, such as a personal history
of biopsies.
- As the woman reached age 40, two first degree relatives and
no live births would have given her sufficient risk to be
eligible for the trial. And by age 45, she could have two
first degree relatives or one affected first degree relative
and a personal history.
The important message here is twofold: First, that the number of
additional risk factors needed for eligibility decrease as age
increases, and second, there are thousands of combinations of
these risk factors that put a woman at increased risk of breast
cancer.
Risk in the General Population
A very important point to consider is that women, especially in
the younger age groups, tend to vastly overestimate their risk of
developing breast cancer. For this reason and other reasons
already mentioned, it is important to take all of these factors
into consideration when making a decision about using tamoxifen.
We estimate that overall in the United States, approximately 29
million women, or 21 percent of the population, might fit these
risk criteria. A large number of those, 26 million, would come
from just being over 60. This would also include women who had
the diagnosis of lobular carcinoma in situ, and approximately 3
million women between the ages of 35 and 59 who would have
additional risk factors that put them into the high risk group.
In the 35-39 year old group, only 3 out of 1,000 women would have
met the eligibility requirement. As a woman ages, that number
gets bigger, to about 27 out of 1,000 (age 40-44), 71 out of
1,000 (age 45-49) and about 10 percent of women ages 50-59 would
have met the criteria.
We are now in a position to give women an option. We can now
intervene prior to the detection of breast cancer, and really
reduce a woman's chance of developing the disease. But as with
any medication, the decision to began tamoxifen therapy is a very
complex one. There are no simple answers. Not all women are at
increased risk for breast cancer, and the balance of benefits and
risk varies with age and hysterectomy status. Even for women at
high risk for developing breast cancer, tamoxifen may not be an
appropriate choice.
Making a Choice: Risks and Benefits
To put these numbers into some context, imagine 1,000 women
between the ages of 35 and 49 who might meet the criteria for
this trial: what could we expect over a five year period based on
these results? Without tamoxifen, we would expect 31 cases of
breast cancer to develop; and with tamoxifen 14 (or 45 percent)
of these could be prevented. Also, with respect to non-invasive
breast cancers, about 11 of the 15 cases could be prevented. In
this age group, we see no difference in the rate of endometrial
or vascular events that have occurred.
However, in women 50 years old and over, it is more complex. If
all 1,000 of these women have a uterus, then they would all be at
risk for endometrial cancer. In that situation, we might prevent
17 out of the 33 expected cases of breast cancer, and 3 out of
the 10 expected cases of noninvasive breast cancer. But there
could be as many as 12 more cases of endometrial cancer.
We are looking at ways to help us better define who is at risk of
breast cancer and who is at risk for some of the unwanted side
effects that come with tamoxifen therapy, as well as with other
hormone replacement therapies. Great interest has been generated
about genetic predisposition to breast cancer, and we know that
some breast cancer is linked to certain mutations. It is likely
that some of the women in this study, especially those with very
strong family histories of breast cancer, carry such a genetic
predisposition. While it is reasonable that such women would also
experience a decreased risk of breast cancer with tamoxifen, no
specific gene testing has been done. As further analyses of the
data from this clinical trial are done, we hope to be able to
provide more information over the next 6-12 months as to whether
women with alterations in BRCA1 & 2, the two known genes whose
alterations predispose to breast cancer, were protected from
cancer in this trial. I would like to emphasize, however, that
there are many important considerations as to how new knowledge
about genetics can and should be made a part of medical
decision-making that further complicate this process.
The choice to take tamoxifen has to be a personal one, a decision
between a woman and her health care provider. We are feverishly
working to analyze this data so we can better define who is at
increased risk for breast cancer. For women whose risks of
developing breast cancer fall within the range of this study,
tamoxifen can provide, for the first time, an option to reduce
that risk, much as new cholesterol-lowering medication can reduce
the risk of heart attacks. But that option must be weighed
carefully and on an individual basis.
This emphasis on individual risk is extremely important. Our
ability to identify individuals at risk for disease and to begin
to rationally intervene, based upon our knowledge of the disease
process, is what medicine will become.
The NCI is committed to communicating the importance of research
findings to all women and their physicians in a clear and
understandable manner. NCI has solicited feedback about the
impact the Breast Cancer Prevention Trial announcement has had on
those who counsel women regarding their decision to take
tamoxifen for the prevention of breast cancer. The preliminary
findings from a survey of Cancer Center Directors, NCI=s Cancer
Information Service, Principal Investigators of the NSABP, and
the advocacy community indicate that it has been possible for
them to respond to most inquiries and counseling requests using
information already provided by NCI and NSABP. This information
was disseminated through existing NCI and NSABP communication
mechanisms before or at the time of the public announcement of
the trial=s early results. A new mechanism was also used. NCI
launched on the day of the announcement a new clinical trials web
site, which included information about the benefits and risks of
tamoxifen.
The feedback concerning the handling of the announcement and the
materials provided to date has been very positive. This feedback
is being used to assist NCI and the NSABP to develop tools to
help each woman, and her health care provider, when making a
decision about whether use of tamoxifen is appropriate for her.
Minority Recruitment
Throughout the trial, several strategies were used to increase
participation of women from racial and ethnic minority groups.
These strategies included placing study-related recruitment
materials in businesses and churches located in minority
communities; collaborating with a minority-owned public relations
firm to develop a structured media campaign targeting racial and
ethnic minorities; developing and broadly disseminating a Public
Service Announcement that featured singer Nancy Wilson; and
communicating information to study sites about how other sites
successfully reached racial and ethnic minorities.
When the early strategies did not attract sufficient numbers of
minority participants, the NSABP launched the Pilot Minority
Recruitment Program in August 1996. The goal of the program was
to increase participation by increasing awareness and educating
minority populations about the trial. A multidimensional approach
was used: Community Outreach Coordinators employed at five BCPT
sites offered personalized presentations on breast cancer risk
factors, incidence, and survival rates, and on clinical trial
research at African-American churches, community hospitals and
health clinics, health fairs, public housing sites, businesses,
and local chapters of sororities, the Urban League, and minority
medical societies. In less than a year, these strategies enabled
the coordinators to establish many relationships in their
communities. As a result of these efforts, the number of Risk
Assessment Forms submitted by minority groups increased, and
during this period, the BCPT experienced the highest level of
randomizations from racial and ethnic minority groups since the
trial began. The Pilot Minority Recruitment Program has been the
most effective strategy to date and will serve as the model for
minority recruitment for future prevention trials.
Conclusion
This study is not an end. It is rather a very propitious
beginning. But it tells us that it is possible to prevent breast
cancer. Tamoxifen is far from ideal. Its efficacy is only partial
and it has significant risks. To move forward will require new
agents and new clinical trials. Newer selective estrogen receptor
modifiers are being developed and will be tested. The NCI hopes
to be able to follow this study soon with additional clinical
trials to find answers to the many questions that remain.
Thank you for the opportunity to address the caucus. I will be
happy to answer any questions you may have.
