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Review Essay Discusses The “Big Picture” About Risk Factors For Breast
Cancer
[Editor’s Note: We are reprinting a very readable and
comprehensive article on breast cancer written by Albert Einstein
epidemiologist Geoffrey Kabat which recently appeared in
Forbes. We contacted Dr. Kabat to get permission to reprint his essay
and to ask him about what prompted the article.
He told the The Epidemiology Monitor he was motivated
to write the piece when he realized that most recent
epidemiologic studies tend to focus on one or a small number of risk
factors (in the past, studies tended to be broader in their approach),
and there are increasingly pooled analyses looking at a single risk
factor, such as physical activity or alcohol consumption.
Questions
He
was interested in trying to answer the question---What proportion of
breast cancer incidence is explained by known risk factors and what
proportion remains unexplained? In the early 1990s there were
attempts to answer this admittedly difficult question, but it appeared
that the field had become increasingly fragmented. Many studies tend
to be focused on one aspect of the problem – hormones, reproductive
factors, obesity, genetics, diet, environmental exposures, etc. He
had the impression that there were few attempts to integrate all the
different risk factors, many of which are quite modest and many of
which are inter-correlated. Such an undertaking would help by
conveying their relative magnitudes.
Methods
Kabat
sent e-mails to a dozen prominent breast cancer epidemiologists asking
their view on two questions: 1) what proportion of breast cancer is
explained by known risk factors? and 2) what do you consider to be
established environmental risk factors for breast cancer above and
beyond the hormonal factors (OCs, HRT, DES, etc.), ionizing radiation,
and alcohol consumption?
Kabat said he heard back from three researchers, but,
interestingly, in even this small sample people had very different
views – some believing that most of breast cancer can be explained by
known risk factors and others feeling that there is a lot that remains
unexplained. The three respondents did not address the second
question.
According to Kabat, “When you try to see the big picture – that is,
what we really know about these risk factors -- you realize that there
are a lot of inconsistencies and a lot we don’t know. But somehow
this is not the message that is relayed to the public.”]
"After 40 Years Of Research, What Do We Know About
Preventing Breast Cancer?"
By:
Geoffrey Kabat
Hundreds of scientific articles are published each year
about risk factors for breast cancer and about prevention of the
disease. However, the most basic questions about what we really know
get very little attention. How much of the occurrence of breast
cancer can be explained by our current knowledge? What can women do to
reduce their risk? And where should we look for the remaining pieces
of the puzzle?
Recently, a federal inter-agency task force issued
a report
emphasizing
the need to redouble research efforts focused on the prevention of
breast cancer. And another
report
claimed that between 12 and 18% of breast cancer deaths are
attributable to alcohol consumption. These and many similar studies
focus our attention on specific risk factors or possible risk
factors. But rarely are we given a critical overview of what we
actually know and how useful this information is for the prevention of
breast cancer. As a result, there is widespread confusion on this
most important question.
Risk Factors
Breast cancer is the most commonly occurring cancer in
women both in this country, as well as worldwide. In the U.S. breast
cancer accounts for nearly one-in-three cancers among women.
Epidemiologic studies over the past 40 years have
identified numerous risk factors for breast cancer, including: older
age, an early age at menarche, a late age at first full-term birth,
not having children, a family history of breast cancer in a
first-degree relative, greater height, higher circulating estrogen
levels, postmenopausal hormone use, breast density, history of breast
biopsies, obesity (for postmenopausal breast cancer), and exposure to
ionizing radiation.
Other, probable risk factors are alcohol intake,
physical activity (protective), and breast feeding (protective). Many
other factors that have been studied do not seem to affect the risk of
breast cancer (dietary fat intake, cigarette smoking, past oral
contraceptive use, exposure to electromagnetic fields).
Risk Comparisons
Known risk factors for breast cancer are relatively
weak, contributing only a small elevation in risk. Even having a
family history of breast cancer in a first degree relative carries
about a twofold increase in risk. And the more recently discovered
breast density is the strongest with roughly a 4-fold increase in
risk. Thus, these breast cancer risk factors are nothing like
cigarette smoking as a risk factor for lung cancer, where a current
smoker has roughly a 15-fold increased risk compared to that of
someone who never smoked, and a heavy smoker might have a 40 or
50-fold increased risk. Smoking accounts for the vast majority of
lung cancer cases.
(The strongest risk factors for breast cancer are older
age and being female: women between the ages of 65 and 69 have 15
times greater breast cancer incidence compared to women between the
ages of 30 and 34, and women have more than one hundred times the
incidence of breast cancer compared to men.)
Mechanisms
The “classical” reproductive and hormonal risk factors
are generally explained by the effects of exposure of breast tissue to
ovarian hormones, primarily estrogen but also progesterone. The
greater the interval between menarche and menopause, the greater the
number of menstrual cycles with spikes in exposure to these
hormones. Following menopause, the main source of estrogen is from
fat deposits, and this is believed to explain the association of
obesity with postmenopausal breast cancer. Finally, current or recent
use of postmenopausal hormones modestly increases the risk of
postmenopausal breast cancer.
The protective effect of an early pregnancy is thought
to be due to the fact that a first, full-term pregnancy stimulates the
full differentiation of the cells lining the milk ducts, where most
breast cancers arise.
Thus, from the point of view of reducing breast cancer
risk, having a later onset of menstruation followed by an early
pregnancy and a large number of children is beneficial. This was the
pattern 150 years ago in this country and more recently in Asia, where
rates of breast cancer have been about one-fifth of rates in the U.S.
An understanding of the hormonal nature of breast
cancer has led to the development of highly effective treatments for
the most common form of breast cancer in postmenopausal women.
Prevention
Unfortunately, our extensive knowledge about risk
factors affords little basis for women to reduce their risk, since
most of these factors (family history, reproductive factors, etc.) are
not modifiable.
And this knowledge does not enable us to accurately
predict who will develop breast cancer and who will not.
Furthermore, this knowledge does not fully account for
changes in breast cancer incidence. For example, on the basis of
known risk factors, one would expect women of the “baby boom”
generation to have increasing rates of breast cancer due to delayed
child-bearing, having fewer children, and greater use of hormone
therapy. But, in fact, breast cancer rates among women of this
generation have declined.
Regarding the possible impact of environmental
exposures (in the more narrow sense, e.g., pesticides, industrial
pollutants, etc.), studies to date have not yielded any strong
signals. However, most studies have focused on exposures in adulthood
rather than in earlier periods when susceptibility may be greater.
New Developments
Over the past twenty years, thinking about the causes
and prevention of breast cancer has advanced in important ways, and
the picture has become much more complicated than the overly simple
focus on the “classical” risk factors allows for.
First, the discovery of rare, high-penetrance germ-line
mutations of BRCA1 and BRCA2 identified a small subset of women with a
very high life-time risk of breast and ovarian cancer. However, only
1-2 percent of breast cancer is accounted for by these mutations.
Second, there is an increasing awareness that
experiences starting in the womb may influence future risk of disease,
that there are “windows of vulnerability,” and that the timing of
exposures may affect future risk. Such periods include: in utero
exposure, puberty, and the period between menarche and a first
full-term pregnancy. Thus, the timing of exposure to hormones and
other factors at different points in the life-span can have very
different effects.
For example, obesity actually appears to be protective
for premenopausal breast cancer, whereas it is a risk factor for
postmenopausal breast cancer. Furthermore, follow-up of women exposed
to the atomic bomb at Hiroshima showed that exposure during
adolescence (during breast development) carried a much higher risk of
breast cancer than exposure later in life. The association of adult
height with increased risk suggests that exposures during childhood
and early adolescence (possibly a calorie-dense diet) may influence
the risk of breast cancer.
Third, researchers have focused on so-called
gene-environment interactions, reasoning that some exposures that have
relatively weak associations with breast cancer in the general
population may have a much stronger effect in subgroups with a
specific genetic make-up. This line of research has to date yielded
few instances of important interactions.
Enormous efforts have gone into examining the contribution of other
normally-occurring genetic variants (single nucleotide polymorphisms,
or SNPs), but these studies have only identified a few SNPS with very
slight increases in risk. It is now believed that there may be as
many as a hundred genes that each contributes a small added increment
to a woman’s risk of breast cancer.
Further complicating the landscape is the realization
in the past decade that, rather than being a single disease, breast
cancer is at least five distinct diseases, with (to some extent at
least) different risk factors, pathology, prognosis, and treatment.
Bottom Line For Now
Where does this leave us?
First, while we know a good deal about breast cancer,
knowledge of established risk factors provides few opportunities for
reducing risk. Therefore, it is important to realize that there is
still a great deal we don’t know about what causes breast cancer.
Some of what we know may be useful. For example, avoiding, or
minimizing, weight gain and engaging in physical activity may reduce a
woman’s risk.
Second, it should be noted that breast cancer incidence
rates are not increasing, and mortality rates have been decreasing in
all age groups over the last two decades as result of improved
treatment.
As research increasingly addresses the roles of early
life events and interactions between a variety of factors in relation
to specific types of breast cancer, we may acquire significant new
knowledge that lends itself to prevention.
In the meantime, it is important to focus on the bigger
picture. For cultural and psychological reasons, breast cancer has a
special status and is a focus of enormous anxieties and confusion.
However, women should bear in mind that heart attacks kill 6 times
more women than breast cancer does. We have identified more
modifiable risk factors for heart disease than for breast cancer.
These include: serum cholesterol level, high blood pressure, smoking,
obesity, and sedentary behavior. Owing in large part to changes in
these risk factors, heart disease rates have declined dramatically
over the past 50 years. And a heart-healthy pattern may also carry
benefits for breast cancer risk.
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