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Understanding Breast Cancer Risk
Andrew Joe, MD
When estimating the baseline risk of a healthy woman developing
breast cancer, the statistic often quoted is 1 out of 8. This
often leads to much anxiety, since a 12.5% risk of developing
cancer is frighteningly high. However, this is a cumulative risk
over one's lifetime, and half of this risk actually occurs after
a woman reaches the age of 65 years.
The following represents a broad overview of factors associated
with breast cancer risk, methods to measure breast cancer risk,
and options available to women at high risk of developing the
disease. Many of these topics are discussed in greater detail
in other feature articles in the November Focus and will be discussed
throughout the month during Healthology Live audio broadcasts.
We encourage you to read on and tune in.
I. Risk Factors
Age is a well-known risk factor for breast cancer with the greatest
risk occurring after the age of 55 years. There are many other
known endogenous (i.e., related to one's individual body) and
exogenous (i.e., related to lifetime exposures, including toxins,
environmental changes, and medicines) risk factors for female
breast cancer.
A. Hormonal Factors
The major breast cancer risk factors are "hormonal" and related
to a woman's reproductive history. The greatest risk results following
long periods of uninterrupted menstrual or ovulatory cycles. This
is because breast tissue, in these situations, is consistently
exposed to estrogen. Thus, the early onset of menarche and the
late onset of menopause both will increase the number of menstrual
cycles in a woman's lifetime and therefore, increase her risk.
Pregnancy will interrupt menses and is therefore protective; a
woman who delivers her first child at an early age will have less
risk, whereas a woman who has never given birth, is at a much-increased
risk of developing breast cancer. Events which delay the onset
of, (e.g. extreme physical activity) or eliminate (e.g. oophorectomy,
the removal of one's ovaries) regular menstrual cycles will also
decrease cancer risk. Abortion, either miscarriage or voluntary,
does not have an effect on cancer risk. It is possible that prolonged
breastfeeding may decrease risk in premenopausal women.
Because breast tissue exposure to estrogen increases cancer risk,
there has been much interest in evaluating the risk of oral contraceptives
and hormone replacement after menopause. The risk of using oral
contraceptives was previously controversial, but most would now
agree that they do not increase a woman’s risk of developing breast
cancer. There is possibly a small increased risk with using hormone
replacement. However, there are now well-characterized benefits
of hormone replacement therapy for both cardiovascular disease
and osteoporosis. Therefore, a woman’s relative risks of breast
cancer, cardiovascular disease, and osteoporosis must all be factored
when considering hormone replacement therapy during menopause.
B. Genetic Factors
As with other medical conditions, there is a growing belief that
the etiology of cancer is, in part, genetic and environmental.
Most of the major discoveries supporting the genetic basis of
cancer have been in colon cancer and breast cancer.
Over the past decade, two breast cancer susceptibility genes have
been discovered and characterized, BRCA-1 and BRCA-2. Certain
changes, known as mutations, in either of these genes will increase
a woman’s risk of breast cancer and may also increase the risk
of other types of cancer, including ovarian, in affected family
members. Mutations of these two genes are much more common in
the Ashkenazi Jewish population. There are other genes which may
confer an increased risk of breast cancer, including p53, and
probably multiple other, as-of-yet undiscovered breast cancer
susceptibility genes. However, as a group, those with a well-documented
genetically inherited predisposition to breast cancer only account
for about 5-10% of cases diagnosed in the United States. A personal
history of early-onset breast cancer, bilateral breast cancer,
or both breast and ovarian cancer, suggests the presence of the
mutation in one of these genes. Furthermore, if a woman has more
than three relatives with breast or ovarian cancer, it is possible
that the mutation may exist within the family members.
In addition to these gene-based, hereditary breast cancer syndromes,
there are much more common non-hereditary syndromes in which there
is an abnormally high frequency of breast cancer within a family.
In these families, there are generally more than one affected
first degree relative, and cancer often occurs in women younger
than 50 years of age. However, in contrast to hereditary cancer,
affected women have a much lower individual risk of developing
cancer that rarely exceeds 30%.
C. Environmental and Lifestyle Factors
In addition to the better characterized hormonal and genetic factors
that increase the risk of developing breast cancer, there are
several known environmental and lifestyle risk factors. The best
data exist for alcohol, obesity and physical activity, and high
doses of radiation. In contrast, there is no convincing data supporting
an increased risk with cigarette smoking.
There is a linear relationship between heavy alcohol consumption
and breast cancer incidence: with greater intake, there is a greater
risk. This does not appear to hold true for mild-to-moderate levels
of consumption, which potentially offers some benefits in fighting
cardiovascular disease.
Obese women are generally at an increased risk of developing breast
cancer. The theoretical basis for this association is that fatty
tissue raises estrogen levels and increases estrogen activity
in the setting of obesity. Therefore, factors that promote or
decrease obesity are likely to affect breast cancer risk as well.
For example, physical activity, both at the workplace and during
leisure time, has been shown to decrease the risk of breast cancer.
It is likely that dietary fat does not by itself lead to a significantly
increased risk of breast cancer, but does increase risk by contributing
to obesity.
High levels of radiation exposure will increase the risk of developing
breast cancer. Examples of these exposures include atomic bomb
radiation and treatment exposures, such as radiation treatment
of Hodgkin’s disease. Regarding other common environmental concerns,
although some studies have reported a possible relationship, there
is no definitive data linking either organochlorine pesticides
or electromagnetic fields to an increased risk of breast cancer.
Silicone breast implants do not increase the risk of breast cancer.
Furthermore, there has been recent concern over the apparently
increased incidence of breast cancer in women who reside on Long
Island. This incidence does not appear to differ much from other
urban and suburban areas of the northeastern United States. An
ongoing study is evaluating the actual incidence and risk factors
that characterize this region.
D. Benign Breast Disease
Certain benign, or non-cancerous, breast diseases may confer an
increased risk of developing breast cancer. These abnormalities
are discovered either by physical examination or during mammography.
Biopsies of these abnormal areas reveal microscopic findings that
are definitely outside the boundaries of normal breast tissue,
but are not considered actual "cancers". Some of these microscopic
changes, such as "atypical hyperplasia" and "lobular carcinoma-in-situ"
will place a woman at an increased cancer risk.
II. Estimating Risk
Breast cancer is the most widely publicized cancer among the general
population. Great public awareness of this disease has led to
significant advances in its management due to increased funding
of research, widespread formation of support groups for victims
and survivors, and the assumption of a more active role of patients
in their treatment. This heightened public awareness, however,
has also led to much anxiety and the concern that breast cancer
has reached "epidemic" proportions. Caution must be placed when
women and their physicians are discussing potential risk factors
for breast cancer in order to avoid overestimation of actual risk.
The Gail model, as proposed by Mitchell Gail at the National Cancer
Institute, is a clinical tool used to mathematically estimate
a woman’s risk of developing breast cancer. This risk estimate
is based on known risk factors, including age at menarche, age
at the first live birth, the number of first-degree relatives
afflicted with breast cancer, and the number of previous benign
breast biopsies. However, one has to remember that in approximately
half of those women who develop breast cancer, there is no apparent
risk factor aside from female sex and age. Furthermore, there
is no general consensus on what should be done for a woman who
is found to be at an increased risk and there are no established
strategies for preventing the development of cancer in high-risk
individuals.
III. Options for Women with Increased Risk Estimates
Cancer prevention is a relatively new and growing area in oncology.
Unfortunately, once a woman is found to have an increased risk
of developing breast cancer, there are no standard recommendations
of what she and her physician should do with this information.
Options that are available include careful surveillance, prophylactic
mastectomy, and enrollment in clinical prevention trials. However,
clinical trials demonstrating clinical benefits with any of these
modalities are very limited.
Careful surveillance and screening may include breast self-examinations
and physician clinical examinations every four-to-six months.
Annual mammograms may also be offered to "higher-risk" women at
an earlier age, even as early as thirty-five years old. Although
logically there is a potential of detecting lesions at an early
stage, there is no proven benefit with such surveillance.
Prophylactic bilateral mastectomy is also an option for a woman
at increased risk. However, even after such a procedure, the risk
of developing breast cancer is not zero. There is often some breast
tissue remaining and a continued risk of cancer in this tissue.
This is also, of course, an operation associated with tremendous
psychological and emotional issues along with significant physical
side effects.
A woman who is found to be at an increased risk may also decide
to participate in a clinical prevention trial similar to the recently
reported Breast Cancer Prevention Trial conducted by the National
Surgical Adjuvant Breast and Bowel Project and the National Cancer
Institute. This large-scale trial targeted women who were estimated
to have a breast cancer risk equivalent to that of a woman in
her sixties. Risk estimates were based on the Gail model and included
factors such as early menarche, no childbirth or delayed childbirth,
affected first-degree relatives, and a history of abnormal breast
biopsies. Although tamoxifen was found to significantly decrease
the incidence of breast cancer in this population, further confirmatory
studies are required to establish the preventive role of this
agent.
IV. Conclusion
Breast cancer is clearly a common disease and the most common
type of cancer in women. It is also the second most common cause
of cancer-related death in women. It is important, therefore,
for women to think about their risk of breast cancer and discuss
these risks with their physicians. This dialogue is extremely
important for a number of reasons. First, most women overestimate
their risk of breast cancer and believe that the average lifetime
risk of the disease in the United States is far higher than the
actual 11%. This overestimation of risk can be associated with
tremendous anxiety and stress, which can lead to denial and avoidance
of risk-reducing strategies. Second, it is unfortunately the women
at above-average risk that frequently don't recognize their risk.
With exciting advances made over the past year, both doctors and
the general public are continuing to understand more about the
management of this disease. Therefore, it has never been more
important and more potentially beneficial to acknowledge, understand,
and act upon breast cancer risk.
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