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7
Recommendations for
Future Research
A
lthough much has been learned about breast cancer and its rela-
tion to environmental exposures, much remains unclear. As the
preceding chapters have illustrated, this reflects a mixture of cir-
cumstances. First, the scientific community is faced with conflicting and
inconclusive results from past studies of some risk factors. Second, grow-
ing knowledge of the complex biology of breast cancer suggests a need to
reframe hypotheses by focusing more on exposures in early life, examining
associations with tumors of specific types, and considering mechanistically
driven gene–environment interactions. Third, for a wide array of exposures,
data are simply inadequate because exposure assessment methodologies
have not been developed, informative studies may be nearly impossible
to conduct in humans, and/or the existing tools and resources to conduct
relevant research in animals or in vitro systems are limited.
With the complexity of breast cancer as a disease and of the combina-
tions of biological and environmental factors that are potential contributors
to it, the committee is persuaded that no one perspective will be sufficient
to guide the future research that is needed to reduce the toll of this disease.
Bringing together the perspectives of many disciplines into a transdisci-
plinary approach will be needed to generate innovative and cost-effective
approaches to framing research questions, designing and conducting stud-
ies, developing new tools for data collection and analysis, and translating
the results of research on risk factors into interventions that can reduce the
risk of breast cancer.
Drawing on the insights developed in the previous chapters, the com-
mittee presents in this final chapter recommendations for research that
325
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326 BREAST CANCER AND THE ENVIRONMENT
range from further examination of elements of the biology of breast devel-
opment and carcinogenesis to tests of potential interventions to reduce risk.
Important components of the work recommended here provide support for
the research necessary to develop better tools for assessing the carcinogenic-
ity of chemicals and pharmaceuticals as well as tools needed to strengthen
epidemiologic research. The importance of a life course perspective runs
throughout these recommendations.
Many of these recommendations are directed to both researchers and
research funders. Researchers will have to conduct the work described here,
but they will need the resources that come from a variety of sources. The
National Institutes of Health and other federal agencies are major funders
of research on breast cancer or they have unique authority or responsibility
in certain areas. But the nation’s portfolio of research on breast cancer is
also shaped in important ways by funders and other organizations in the
private sector, such as Susan G. Komen for the Cure, that have the flexibility
to pursue research topics and approaches that federal agencies may not. The
committee urges effective and innovative collaborations to answer the many
unresolved questions about the causes of breast cancer.
APPLYING A LIFE COURSE PERSPECTIVE TO
RESEARCH ON BREAST CANCER
Progress has been made in understanding the biology of breast develop-
ment, molecular mechanisms of carcinogenesis, the influence of the tissue
microenvironment on breast cancer development, and some aspects of
risk and prevention. But gaps remain in understanding of the etiology of
breast cancer and the extent of environmental influences on breast cancer
development.
Most epidemiologic studies have been obliged to focus on events in the
few years or perhaps one to two decades before a breast cancer diagnosis.
As described in Chapter 5, however, growing evidence suggests that events
associated with breast carcinogenesis may occur much earlier—in young
adulthood, puberty, childhood, and in utero. The effect of radiation, for
instance, is greater when exposure occurs around the time of puberty or
earlier. Although information about some early life events, such as age when
first giving birth or age at menarche, can be reliably retrieved, few studies
have collected information on nonreproductive environmental exposures
that may influence the occurrence of clinically detectable breast cancer
many decades later.
To address gaps in knowledge about the origins of breast cancer, the
committee determined that research should increasingly focus on the influ-
ence of environmental factors during potential windows of susceptibility
over the life course. It is possible that some exposures later in life, after
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RECOMMENDATIONS FOR FUTURE RESEARCH
childbearing is complete, have little effect on breast cancer risk whereas
similar exposures, if incurred early in life, before completion of breast
development, may increase risk for breast cancer. On the other hand, expo-
sures later in life may increase the growth of cancerous cells that have lain
dormant for years and that would, without the exposure, have continued to
be dormant. Thus the committee recommends that future research address
the timing of exposures in relation to a woman’s life course and explore
vulnerable windows for specific exposures of concern.
Recommendation 1: Breast cancer researchers and research funders
should pursue integrated and transdisciplinary studies that provide
evidence on etiologic factors and the determinants of breast cancer
across the life course, with the goal of developing innovative prevention
strategies that can be applied at various times in life.
• Such studies should seek to integrate animal models that capture
the whole life course and human epidemiologic cohort studies that
follow individuals over long periods of time and allow for inves-
tigation of so-called “windows of susceptibility” wherein breast
tissue may be especially sensitive to environmental influences (e.g.,
prenatal, childhood, and adolescent, and childbearing periods).
Long-term follow-up of cohorts is critical because new, unexpected
evidence frequently arises with extended follow-up.
• Topics warranting attention include (but are not limited to) the
biology of breast development; the mechanisms of carcinogenesis
early in life, including the role of the tissue microenvironment in
tumor suppression and development, and differences that may
be related to tumor type; differences in risk by tumor type; the
potential contribution of timing of exposure to variation in risk;
and analytical tools for investigating the potential for interactions
among exposures and the impact of mixtures of environmental
agents on biologic processes.
Other work to aid investigation of environmental influences on breast
cancer risk includes
• identifying cellular, biochemical, or molecular biomarkers of early
events leading to breast cancer and validating their predictive value
for future risk for breast cancer;
• determining whether intermediate endpoints, such as indicators of
breast development or peak height growth velocity, are valid and
predictive biomarkers of risk for breast cancer so that research can
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328 BREAST CANCER AND THE ENVIRONMENT
effectively identify predictors of change in risk earlier in life or with
shorter study periods;
• investigating the role that environmental factors may have in the
origins of breast cancers of different types (e.g., estrogen or proges-
tin receptor positive [ER+, PR+] or receptor negative [ER–, PR–];
HER2/neu positive or negative; or triple negative, meaning being
negative for all three types of receptors) to better understand the
potential contribution of these factors to disparities in the incidence
of types of breast cancers among racial and ethnic groups;
• exploring the value of linking information across cohort studies
focused on different stages of life as a way to overcome the chal-
lenges of mounting single long-term follow-up studies; and
• ensuring that cohorts established primarily to study genetic deter-
minants of cancer and other diseases improve their capacity to
capture information about environmental exposures over the life
course.
TARGETING SPECIFIC CONCERNS
Rationale: From its examination of evidence on a selection of environ-
mental factors, the committee sees particular benefit in further research to
clarify the mechanisms underlying breast cancer.
Recommendation 2: Breast cancer researchers and research funders
should pursue research to increase knowledge of mechanisms of action
of environmental factors for which there is provocative, but as yet
inconclusive, mechanistic, animal, life course, or human health evi-
dence of a possible association with breast cancer risk.
High-priority topics include the following:
• Shift work: There is growing evidence that shift work resulting
in the disruption of circadian rhythm is probably associated with
increased risk for breast cancer. Currently, there are no known
effective interventions other than avoidance of shift work, which
will not be an option for many workers. The biological mecha-
nisms and the potential contribution of light exposure during nor-
mal sleep periods are poorly understood. More needs to be learned
about the biological processes and pathways through which shift
work and circadian rhythm disruption, or other factors arising
from shift work, relate to breast cancer. This includes investiga-
tion of hormonal effects of circadian disruption, the role of “clock
genes” and signaling pathways in breast tissue development, how
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RECOMMENDATIONS FOR FUTURE RESEARCH
disruption of those signaling pathways may contribute to initiation
or progression of breast tumors, developing more detailed and
standardized approaches to exposure assessment for use in epide-
miologic research, and developing and testing the effectiveness of
interventions that could mitigate the carcinogenic effects that may
be associated with shift work.
• Endocrine activity: Exposure to chemicals with estrogenic or other
properties relevant to sex steroid activity, such as bisphenol A
(BPA), polybrominated diphenyl ethers (PBDEs), zearalenone, and
certain dioxins and dioxin-like compounds, may influence breast
cancer risk, especially if those exposures occur at certain life stages
or in combination with exposure to other similar chemicals, certain
dietary components, or other factors. Although the evidence on the
association between breast cancer risk and individual chemicals
in this category is not conclusive, current mechanistic hypotheses
warrant further research to examine their activity, to investigate
additive or greater potency across multiple chemicals, to explore
the effects of timing of exposure, and to evaluate interactions with
diet, body mass index, and other factors that may influence the
relationship of these types of compounds to breast cancer risk.
• Genotoxicity: Animal studies have demonstrated that some muta-
genic chemicals are capable of inducing malignant mammary
tumors, and numerous animal models of breast carcinogenesis
routinely use the potent mutagens 7,12-dimethylbenz[a]anthracene
(DMBA) and N-methyl-N-nitrosourea (MNU) as reproducible ini-
tiators of those tumors. But these studies have shown that the effect
is highly sensitive to the timing of the exposures and can be influ-
enced by other factors. More research is needed to understand the
degree to which mutagenic chemicals, such as polycyclic aromatic
hydrocarbons (PAHs), benzene, and ethylene oxide, acting alone
or in combination with other exposures at specific life stages, may
contribute to breast cancer risk at current levels of exposure.
• Epigenetic activity: Recent studies have demonstrated that some
chemicals, including BPA, while not genotoxic per se, can have
important influences on gene expression that may be relevant to
breast cancer risk. Relatively little is known about the importance
for breast cancer risk of such epigenetic modifications by envi-
ronmental chemicals. More fundamental research on the role of
epigenetic modifications in breast cancer risk is needed.
• Gene–environment interactions: Although few such interactions
have been identified, to some extent this may reflect the small
number of discrete exposures for which relevant genes are cur-
rently identifiable. Limited evidence indicates, for example, that
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330 BREAST CANCER AND THE ENVIRONMENT
genes governing acetylation efficiency may describe a susceptible
subset of the population for which exposure to tobacco smoke has
substantial influence on breast cancer risk. Likewise, isozymes of
different enzymes involved in alcohol metabolism may affect breast
cancer risks, particularly among those with high alcohol intake.
EPIDEMIOLOGIC RESEARCH
Studies of Occupational Cohorts and Other Highly Exposed Populations
Rationale: Many known human carcinogens were first identified as a
result of studies carried out in occupational settings where workers were
subject to chemical and physical exposures that were typically higher than
those experienced by the general population. When many of the early
occupational studies were carried out, relatively few women were in the
workforce. Changes in the typical workplace and the presence of more
women in the workforce, both in the United States and internationally,
make it appropriate to revisit occupational studies as a possible means to
identify some exposures that increase risk for breast cancer. These studies
should account for not only comparisons of breast cancer incidence associ-
ated with various work assignments or job titles, but also the distribution of
known breast cancer risk factors among workers to ensure that the analyses
of exposure-related risk are not confounded by differences among types of
workers in the prevalence of these other known risk factors.
Outside the workplace, other events such as industrial accidents or
contamination episodes can lead to high exposures for specific population
groups. Sometimes these events provide opportunities to investigate the
impact of specific timing of exposures, as in the case of the survivors of the
atomic bombs in Hiroshima and Nagasaki, or the population living in the
vicinity of the industrial accident in Seveso, Italy, and exposed to high levels
of dioxin. High-dose or long-term medical exposures have also lent them-
selves to study through the assembly of cohorts from records of patients
treated for specific diseases or conditions.
Recommendation 3: Breast cancer researchers and research funders
should pursue studies of populations with higher exposures, such as
occupational cohorts, persons with event-related high exposures, or
patient groups given high-dose or long-term medical treatments. These
studies should include collection of information on the prevalence of
known breast cancer risk factors among the study population. Sup-
port for these studies should include resources for the development of
improved exposure assessment methods to quantify chemical and other
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RECOMMENDATIONS FOR FUTURE RESEARCH
environmental exposures potentially associated with the development
of breast cancer.
New Exposure Assessment Tools
Rationale: A life course perspective on breast cancer suggests that
critical periods of vulnerability may exist during in utero development, in
childhood, adolescence, and early adulthood, and at older ages. Exposure
assessment becomes particularly challenging if the interval between criti-
cal exposure events and the point at which breast cancer can be diagnosed
extends over decades.
If evidence of exposure is retained in either environmental media or
the human body, measurements made long after exposure may provide
an adequate basis for estimating an earlier exposure. To be able to do so
requires sufficient knowledge of the patterns of persistence of chemical
compounds and their metabolites, the determinants of variability in reten-
tion, and the variation in exposure levels over time. If evidence of exposure
is not retained, one-time measurements are unlikely to be an adequate basis
for assessing true exposure unless it is known that an individual’s exposure
is consistent over long periods.
To effectively study exposures over long time periods, research proto-
cols may need to obtain measurements of exposure at multiple time points.
However, because repeated measurements can be prohibitively burdensome,
it may be necessary to develop alternative strategies that rely on external
indicators of exposure. For instance, if, hypothetically, 50 percent of the
body burden of a chemical exposure is from consumption of liquids from
plastic bottles, then questionnaires about such behavior patterns may be
a more reliable basis for assessing exposure than measurements of urinary
metabolites. If, additionally, persons who consume fluids from plastic bottles
do so consistently over years or decades, then this approach may be reason-
able for establishing past exposures as well.
Recommendation 4: Breast cancer and exposure assessment researchers
and research funders should pursue research to improve methodologies
for measuring, across the life course, personal exposure to and biologi-
cally effective doses of environmental factors that may alter risk for or
susceptibility to breast cancer.
Such research should encompass
• improving measurements in the environment and assessing varia-
tion over time and space;
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332 BREAST CANCER AND THE ENVIRONMENT
• determining routes of exposures and how they vary over time and
over the life course;
• evaluating how products are used and the extent to which actual
usage deviates from label instructions (e.g., home pesticide applica-
tions) as a critical component of exposure assessment, and focusing
on the impact on personal exposures;
• incorporating use of advanced environmental dispersion model-
ing techniques with accurate emissions and air monitoring data to
characterize specific population exposures;
• measuring compounds and their metabolites in biospecimens,
including specimens obtained by noninvasive means;
• understanding pharmacodynamics and pharmacokinetics and how
they vary by lifestage, body weight, nutrition, comorbidity, or other
factors;
• developing other biomarkers of exposure through early biologic
effects (DNA adducts, methylation, tissue changes, gene expression,
etc.);
• using existing and yet-to-be-established human exposure biomoni-
toring programs (e.g., breast milk repositories) by geographic areas;
and
• validating exposure questionnaires through various strategies.
RESEARCH TO ADVANCE PREVENTIVE ACTIONS
Minimizing Exposure to Ionizing Radiation
Rationale: As discussed in Chapters 3 and 6 and Appendix F, some of
the strongest evidence reviewed by the committee indicated a strong causal
association between breast cancer and ionizing radiation. However, popu-
lation exposures to ionizing radiation in medical imaging are increasing.
Chapter 6 sets forth a series of steps that can be taken by various groups
and in various settings to reduce exposures to ionizing radiation and there-
fore reduce risks for breast and other cancers. However, many unknowns
remain about the best ways to achieve these reductions. This work might
include investigation of the feasibility of developing cost-effective forms
of imaging that do not rely on ionizing radiation. Further research is war-
ranted to clarify the extent of population risks, unnecessary uses of medical
radiography, and the best means to maximize its benefits and minimize its
harms.
Recommendation 5: The National Institutes of Health, the Food and
Drug Administration, and the Agency for Healthcare Research and
Quality should support comparative effectiveness research to assess
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RECOMMENDATIONS FOR FUTURE RESEARCH
the relative benefits and harms of imaging procedures and diagnostic/
follow-up algorithms in common practice. This research effort should
also assess the most effective ways to fill knowledge gaps among
patients, health care providers, hospitals and medical practices, indus-
try, and regulatory authorities regarding practices to minimize exposure
to ionizing radiation incurred through medical diagnostic procedures.
Developing and Validating Preventive Measures
Rationale: Some breast cancer risk factors appear to be modifiable,
but it is important to determine what modifications of these environmental
exposures can be most effective in reducing risk and when during the life
course these changes need to occur. For example, overweight and obesity
are recognized as increasing risk for postmenopausal breast cancer, but the
contribution of weight loss to reducing risk is much less clear.
Recommendation 6: Breast cancer researchers and research funders
should pursue prevention research in humans and animal models to
develop strategies to alter modifiable risk factors, and to test the effec-
tiveness of these strategies in reducing breast cancer risk, including
timing considerations and population subgroups likely to benefit most.
Particular aspects of prevention that require attention include
• when weight loss is most likely to be beneficial in reducing risk for
postmenopausal breast cancer;
• effective strategies for achieving and maintaining weight loss in
different risk groups;
• effective and sustainable methods to prevent obesity;
• the feasibility of interventions in early life and development that
may influence breast cancer risk in adult life such as prevent-
ing childhood obesity, increasing physical activity, and minimizing
exposures to potentially harmful environmental carcinogens;
• approaches to prevention that respond to the differing breast can-
cer experience of various racial and ethnic groups; and
• dissemination and adoption of effective prevention strategies.
Chemoprevention—Research on Medications
to Reduce Breast Cancer Risk
Rationale: Breast cancer is likely to remain a major source of morbid-
ity for many decades to come. However, if early life events are critical in
breast cancer carcinogenesis, then most women may have already had some
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334 BREAST CANCER AND THE ENVIRONMENT
critical exposures by mid-life, when the incidence of breast cancer increases.
Avoiding other exposures later in life, such as hormone therapy, may delay
or even prevent breast cancer in some women, but it may be that further
reductions in risk later in life are most efficiently achieved through phar-
maceutical interventions.
Research has demonstrated that drugs that alter responses to estrogen
(e.g., tamoxifen, raloxifene) or production of estrogen (e.g., aromatase
inhibitors) can substantially reduce risk of ER+ breast cancer (Cummings
et al., 2009; Nelson et al., 2009; Goss et al., 2011). The Food and Drug
Administration (FDA) has approved use of tamoxifen and raloxifene for
this purpose by women who are considered at increased risk of breast
cancer and are not at increased risk for cerebrovascular disease. Other
medications, such as bisphosphonates and metformin, are under study to
assess their potential role in reducing the risk of either ER+ or ER– breast
cancer (Cuzick et al., 2011). But relatively few eligible women have chosen
to use tamoxifen and raloxifene, at least in part because they are associated
with increased risk for serious adverse health effects, including endometrial
cancer and stroke (Fisher et al., 2005; Vogel et al., 2010).
The desirability of drugs that can reduce breast cancer risk must be bal-
anced against any potential dangers associated with the use of those drugs.
These dangers are of particular concern for the large numbers of women
who would not have developed breast cancer even without medication,
as well as for the smaller numbers of women who develop breast cancer
despite using them.
Additional research into medications that can reduce risk for breast
cancer with minimal added risk of other serious adverse health effects
should be fostered and accelerated. Studies should include sufficient follow-
up, both during the study when the medications are being used and after
what is anticipated to be the typical period of use, to provide an adequate
basis for determining the benefits and risks that may be associated with the
medication. Furthermore, because the approved drugs only reduce the risk
of ER+ breast cancer, research is critically needed to find effective ways to
reduce the risk of other forms of breast cancer, including triple negative
breast cancer and other hard-to-treat forms of breast cancer that may have
a disproportionate impact at younger ages or among African American,
Asian, or Hispanic women.
Recommendation 7: Breast cancer researchers and research funders
should pursue continued research into new breast cancer chemopreven-
tion agents that have minimal risk for other adverse health effects. This
work should include efforts to identify chemopreventive approaches for
hormone receptor negative breast cancer.
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RECOMMENDATIONS FOR FUTURE RESEARCH
Adequately sized primary prevention studies will be needed to allow
for estimation of both benefits and risks. Research plans should also
include long-term follow-up to identify any changes in risk patterns for
types of breast cancer or other effects that only become evident beyond
the time frame of the initial study and analyses.
TESTING TO IDENTIFY POTENTIAL BREAST CARCINOGENS
In Vivo Testing for Carcinogenicity
Rationale: Testing in animals is currently an established component
of the evaluation of the carcinogenicity of chemicals in industry and com-
merce, but it is unclear which whole-animal test protocols are best suited
for screening for possible human breast carcinogens. Human sensitivity to
breast cancer has been demonstrated for exposures in utero (e.g., diethylstil-
bestrol [DES]), before and during puberty (e.g., radiation), and postmeno-
pausally (e.g., combination hormone therapy). Studies in animals have also
demonstrated that some exposures early in life that are not themselves car-
cinogenic may alter susceptibility to carcinogens encountered later in life.
But these age windows are typically not included in standard can-
cer bioassays such as those used in conjunction with the registration of
pesticides and pharmaceuticals. The standard protocols commonly begin
exposures when animals are 7 to 8 weeks of age. Thus they miss the rapid
mammary ductal growth and branching during pubertal development, a
period of heightened sensitivity in the rat to adverse effects from chemical
exposures. These protocols also miss gestational exposures and terminate
the experiments at 2 years, which omits the older age period, a time of
increasing incidence of breast cancer in humans.
Interpretation of rodent bioassays for mammary carcinogenicity is
complicated by certain characteristics of the animals typically used for
these studies. The mouse strains appear generally insensitive to hormon-
ally induced mammary tumors. Conversely, a commonly used rat strain is
overly sensitive to the occurrence of constant estrus and early reproductive
senescence. Constant estrus and early reproductive senescence can tend to
increase the incidence of mammary tumors, but this phenomenon may not
be relevant for humans. Thus results of bioassays of hormonally active
agents are confounded when mammary tumors are increased concomitantly
with constant estrus in the treated rats. With the insensitivity of mice, nega-
tive results from tests in mice are not necessarily a reliable indicator of lack
of mammary carcinogenicity.
To increase the ability to detect statistically significant increases in
cancer rates in the limited number of animals that can be used in toxicity
and carcinogenicity testing, chemicals are typically administered at dose
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336 BREAST CANCER AND THE ENVIRONMENT
equivalents that are far higher than the exposures humans would normally
have. Pharmacokinetic and metabolic differences between high- and low-
dose chemical exposures complicate the prediction of risks at lower doses
that would be more comparable to human experience.
Finally, standard bioassay protocols for regulatory testing generally test
individual chemicals. However, humans are generally exposed throughout
life to a myriad of hormonally active and genotoxic chemicals. Some experi-
mental protocols used in cancer research employ mixed exposures (e.g., in
utero exposure to one agent and subsequent high-dose exposure to a geno-
toxic chemical during a period of rapid ductal growth). Other tests look
for abnormal development of the mammary gland following in utero or
early in life exposure, to identify early predisposing events. In reports from
some research studies, it is difficult to assess the level of attention devoted
to important design issues such as randomization, blinded assessment of
endpoints, and standardization of endpoints.
Recommendation 8: The research and testing communities should pur-
sue a concerted and collaborative effort across a range of relevant
disciplines to determine optimal whole-animal bioassay protocols for
detection and evaluation of chemicals that potentially increase the risk
of human breast cancer.
The development of these protocols should address several issues,
including the following:
• potential differences in sensitivity to carcinogenic effects and dur-
ing different life stages;
• the appropriateness and limitations of the rodent strains and spe-
cies used for testing, and potential alternatives;
• the frequency, magnitude, and route of dosing, and the possible
need for alternative protocols that provide improved relevance for
predicting human risk;
• the utility of genetically engineered mouse models, which show
promise for studying breast tumor formation and progression and
the effectiveness of treatments; and
• standard practices for conducting and reporting results of animal
studies.
This work will probably also require targeted mechanistic and phar-
macokinetic studies to assess appropriate dosing levels in test protocols to
better address human exposure circumstances, including the influence of life
stage, genetic variability, and multiple chemical exposures.
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New Approaches to Toxicity Testing
Rationale: Most of the thousands of chemicals used in industry and
commerce have not been tested for their potential to contribute to breast
and other cancers. Screening all chemicals with the standardized approaches
used for pharmaceuticals and pesticides is impracticable because of the
time and resources (including large numbers of test animals) that would be
required (NRC, 2006, 2007). Furthermore, the tests are done chemical-by-
chemical, which does not address the potential consequences of exposures
to mixtures of chemicals or interactions with other ongoing exposures (e.g.,
dietary components). The high doses used in testing also introduce uncer-
tainty and limitations for predicting risks at lower doses that are relevant
to human exposures.
Under the broad umbrella of the Tox21 (EPA, 2011) and National
Toxicology Program initiatives, new toxicity testing approaches are being
developed to more rapidly and accurately screen and identify the toxic-
ity of chemicals encountered in human environmental, occupational, and
product exposures. This effort relies on the elucidation of key toxicity
pathways involved in human disease, and on the development of sen-
sitive, rapid testing approaches to determine a chemical’s potential to
perturb such pathways and at what concentrations. A variety of tests are
being developed and considered: high-throughput in vitro screens that use
cell components and engineered cells; toxicogenomic responses follow-
ing cellular, tissue, and organism exposures; novel animal systems (e.g.,
the roundworm, Caenorhabditis elegans); and limited, targeted testing in
laboratory animals to anchor test results and understand mechanisms, new
chemistries, and pharmacokinetics (Dix et al., 2007; NRC, 2007).
The new approach also calls for the use of pharmacokinetic evalua-
tions, human biomonitoring data, and epidemiologic results to establish
the predictive ability of the tests. Pharmacokinetics will be an important
consideration in understanding test results, in studying uptake and distribu-
tion to target cells, and in examining the biochemical transformations that
make the chemical biologically active or inactive. This aspect of the effort
is currently a significant challenge in the development of high-throughput
and other in vitro tests.
Because breast cancer is a major contributor to morbidity among
women, these tests should address pathways that underlie the basic mecha-
nisms of breast cancer—mutagenesis, estrogen receptor signaling, epigenetic
programming, growth promotion via mitogenic cell signaling, and modu-
lation of immune functioning—with particular attention to cell types and
environments relevant to breast cancer. They should also take into account
alterations at the whole-organ level, and they should be relevant to typical
human exposures, which often occur at low doses and as mixtures.
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338 BREAST CANCER AND THE ENVIRONMENT
Recommendation 9:
a. The research and testing communities should ensure that new testing
approaches developed to serve as alternatives to long-term rodent
carcinogenicity studies include components that are relevant for
breast cancer.
To be relevant for breast cancer, it will be necessary to be able to
assess changes in susceptibility through the life course and mecha-
nisms characteristic of hormonally active agents. The test develop-
ment should also include exploring the predictive value of in vitro
and in vivo experimental testing for site-specific cancer risks for
humans.
b. A research initiative should assess the persistence and consequences
for mammary carcinogenicity of abnormal mammary development
and related intermediate outcomes observed in some toxicological
testing.
As useful predictors of increased mammary cancer risk become
available, intermediate outcomes may aid in identifying chemicals
that may pose increased risk of human breast cancer when expo-
sures occur early in life.
c. Research should be conducted to improve understanding of the
potential cumulative effects of multiple, small environmental expo-
sures on risk for breast cancer and the interaction of these exposures
with other factors that influence risk for breast cancer.
Improved understanding of both mixed and serial low-dose
exposures is critical for the interpretation of in vivo results and
is of heightened importance for understanding the results of the
emerging in vitro tests. Relevant exposures may come from sources
that include food, pharmaceuticals, and the general environment. It
is also critical for the understanding of epidemiologic and in vivo
and in vitro experimental research results on the health effects of
chemical mixtures that are characteristic of human environmental
exposures.
Identifying Breast Cancer Risks Associated with
Hormonally Active Pharmaceutical Products
The committee sees a need to ensure that mechanisms for detection and
assessment of breast cancer risks associated with use of drugs regulated
by FDA are adequate. It also recognizes that enhanced methods to detect
breast cancer risks represent only one specific dimension of a more general
interest in strengthening FDA’s ability to ensure the safety and timely avail-
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ability of prescription and over-the-counter drugs (IOM, 2007a,b) and in
strengthening the science to support FDA’s regulatory work (e.g., IOM,
2011).
Menopausal hormone therapy was originally developed to control
menopausal symptoms. Some health professionals advocated long-term and
substantially expanded use in anticipation that it would reduce age-related
health problems, including cardiovascular disease and memory disorders,
even before clear evidence was in hand. Although these products are effec-
tive in reducing menopausal symptoms and osteoporotic fractures while
women are taking them, evidence from the Women’s Health Initiative
examining multiple health outcomes in a randomized trial design showed
that use of a combination of estrogen and progestin in postmenopausal
hormone preparations increases risk of breast cancer and stroke and does
not provide overall benefits for cardiovascular risk or memory disorders
(Writing Group for the Women’s Health Initiative Investigators, 2002). This
experience is an illustration of the dangers of exposing millions of healthy
women to pharmacological doses of exogenous hormones without sufficient
evidence of net benefit. Decades of study have also confirmed a small excess
risk of breast cancer among current users of oral contraceptives (Collabora-
tive Group on Hormonal Factors in Breast Cancer, 1996; Marchbanks et
al., 2002; Strom et al., 2004; IARC, 2011). Although the increased risk of
breast cancer that is associated with use of combination hormone therapies,
including oral contraceptives, declines after treatment stops, women should
be aware of the full range of potential harms as well as the benefits when
they decide whether to use any form of hormone therapy, including those
touted as safe because they are “bioidentical” or “natural.”
New Approaches to Testing Hormonally Active Candidate
Pharmaceuticals
Rationale: Given the evidence for hormonal influences on the develop-
ment of breast cancer, the committee is concerned that testing required
to gain marketing approval for various hormonally active pharmaceuti-
cals that are already on the market or that are being developed does not
adequately address the potential impact on the risk for breast cancer. For
example, the 2-year rodent carcinogenicity studies done for Prempro, the
combined estrogen–progestin product used in the Women’s Health Initia-
tive, showed a reduction in mammary tumors in rats (Ayerst Laboratories,
2003), and premarketing human safety and efficacy studies are generally
too small and too brief to detect an effect on the incidence of breast cancer.
Given that some hormonal products have been found to increase the risk of
breast cancer, it is important that new postmenopausal hormone prepara-
tions, including those advertised as bioidentical or natural hormones, have
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340 BREAST CANCER AND THE ENVIRONMENT
an adequate evidence base to support any claims that they do not cause
breast cancer. It is also important to have an adequate understanding of the
implications for breast cancer risk of the hormone composition and dos-
ing schedules of new oral contraceptives (e.g., a preparation that causes a
woman to have only four menstrual periods per year).
Identifying hormonally active substances is complex, in that vari-
ous models are used to measure hormonal activity and the activity levels
detected for a substance may differ depending on the model and dose used.
It is important to assess the effectiveness of current testing protocols for
hormonally active products in providing indicators of the potential for
increased risk of breast cancer, and to develop and validate new testing
practices where needed.
Recommendation 10: The pharmaceutical industry and other sponsors
of research on new hormonally active pharmaceutical products should
support the development and validation of better preclinical screening
tests that can be used before such products are brought to market to
help evaluate their potential for increasing the risk of breast cancer.
A suite of in vitro and in vivo tests will likely be needed to address
the different mechanisms of action that may be relevant over the life
course (in utero, early infancy, pre- and postpuberty, pregnancy, and
pre- and postmenopause). If such tests can be developed and validated,
FDA should require submission of the results as part of the process
for approving the introduction of new hormonal preparations for pre-
scription or over-the-counter use. These tests may also prove useful in
testing environmental chemicals.
Postmarketing Studies of Hormonally Active Products
Rationale: With the demonstration that use of certain hormonally
active prescription drugs is associated with an increased risk of breast can-
cer and other adverse health effects, it is important to investigate whether
use of other hormonally active drugs is also associated with increased risk.
The Food and Drug Administration Amendments Act of 2007 gave FDA
the authority to require postmarketing studies or clinical trials for approved
drugs when adverse event reporting would not be sufficient to assess a
known or suspected serious risk (FDA, 2011). Because adverse event report-
ing systems are generally better suited to the detection of adverse events that
occur soon after use of a drug than to events such as breast cancer that take
years to develop, formally conducted studies appear necessary to assess the
potential breast cancer risk.
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Recommendation 11: FDA should use its authority under the Food and
Drug Adminisration Amendments Act of 2007 to engage the pharma-
ceutical industry and scientific community in postmarketing studies or
clinical trials for hormonally active prescription drugs for which the
potential impact on breast cancer risk has not been well characterized.
Study oversight should be designed to mitigate against bias and conflict
of interest of study sponsors. Special attention should be accorded to
those products that represent a substantial change in pharmacologic
composition or dosage schedule from products currently on the market.
The studies should be adequately powered to quantitatively explore the
possible contribution of the products to breast cancer risk, as well as
other risks that have been associated with these classes of drugs (e.g.,
cardiovascular effects).
UNDERSTANDING BREAST CANCER RISKS
Researchers, health care providers, and the public all have an incom-
plete picture of the components of breast cancer risk. Further work is
needed to clarify the contribution of recognized risk factors to differences
and changes in the incidence of breast cancer and to determine the most
effective ways to convey information about breast cancer risk.
Risk Modeling
Rationale: Public health messages about ways to reduce risk should
rest on strong science on the attribution of risks to various causal factors.
Systematic modeling approaches are needed to refine the estimates of the
proportion of breast cancer in the United States and other countries that
can be attributed to known factors, especially modifiable factors. Substan-
tial proportions of the increase in breast cancer incidence rates in the United
States over the past century, and of the differences in rates of breast cancer
between less developed countries and more affluent countries, are prob-
ably due in large part to differences over time and between countries in the
prevalence of established breast cancer risk factors (e.g., age at menarche,
age at first birth, parity, use of menopausal hormone therapy, physical activ-
ity, weight and weight change). Few reliable estimates of these temporal and
international differences in risk factor prevalence exist.
Developing data on changes in the prevalence of known risk factors,
along with changes in breast cancer incidence, should permit statistical
modeling of the size of these proportions associated with individual risk
factors and combinations of these risk factors. This information will also
help in determining the magnitude of risk associated with other unidentified
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342 BREAST CANCER AND THE ENVIRONMENT
factors, which may include other environmental exposures. Of particular
interest are the modifiable risk factors.
Risk modeling on both the individual and population levels will benefit
greatly from improved understanding of the etiology of breast cancer. As
the science improves, risk models can also help guide future research invest-
ments and policy decisions for population-level interventions. A collabora-
tive approach, such as that used by the Cancer Intervention and Surveillance
Modeling Network (CISNET) consortium, may be a cost-effective way to
pursue some of this work.
Recommendation 12: Breast cancer researchers and research funders
should support efforts to (1) develop statistical methodology for the
estimation of risk of breast cancer for given sets of risk factors and that
takes the life course perspective into account, (2) determine the propor-
tion of the total temporal and geographic differences in breast cancer
rates that can be plausibly attributed to established risk factors, and (3)
develop modeling tools that allow for calculation of breast cancer risk,
in both absolute and relative terms, with the goal of assessing potential
risk reduction strategies, at both personal and public health levels.
Communicating About Breast Cancer Risks
Rationale: Accurate and effective communication of breast cancer
risks is important for individuals, the public at large, and policy makers
and public health officials. Individuals need to be able to make informed
choices regarding risk factors, prevention opportunities, and health care
appropriate to their risk circumstances. Research indicates that women
may have a poor understanding of their risk of breast cancer, with both
over- and underestimates of risk observed (Lipkus et al., 2001; Apicella et
al., 2009; Waters et al., 2011). A systematic review under the auspices of
the Cochrane Collaborative found that both health care providers and con-
sumers understood risks of health outcomes better when those risks were
presented as frequencies rather than as probabilities (Akl et al., 2011). Both
thought the risks were lower when presented as absolute risk reduction
than as relative risk reduction, and both were more persuaded by relative
than absolute risks in terms of potential behavioral change. To allow a fair
comparison of risks and benefits, supplementing presentation of relative
measures with absolute ones is useful because other disease endpoints may
be more or less common than breast cancer.
From a public health policy and practice perspective, it is important to
determine where risks lie and the potential for benefit and risk at a popula-
tion level. Uncertainty is inherent in risk prediction, and it can be difficult
or impossible to establish that an exposure is not associated with cancer
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risk. However, moderate or large risks can be ruled out with reasonable
confidence when studies with robust and appropriate research designs and
analyses have been conducted in populations with relevant exposures.
Meaningful differences in risk need to be effectively communicated to the
public, health care providers, and policy makers so that limited funds can
be invested in the most promising research and intervention strategies.
Recommendation 13: Breast cancer researchers and research funders
should pursue research to identify the most effective ways of commu-
nicating accurate breast cancer risk information and statistics to the
general public, health care professionals, and policy makers.
Because people differ in their health literacy, their numeracy (ability
to understand numerical information), and in their preferred modes
of learning, multiple communication strategies, modes, and messaging
tactics will be needed to reach diverse communities and stakeholders.
Among the topics that should receive attention in this research are
• perception and comprehension of different ways to present mes-
sages (numbers, graphs, text), modalities of communication (audio,
video, print, face-to-face, and multiple modalities, etc.), as well as
the content of the messages themselves;
• ways that personal experiences (e.g., family history) affect the abil-
ity to absorb messages;
• determination of the similarities and differences in how individuals
from diverse racial, ethnic, educational, and occupational groups
understand and respond to breast cancer risk information that is
presented various ways;
• comprehension of terms such as relative risks, absolute risks, and
hazards;
• ways to improve translation of research results into messages that
can effectively convey the implications of the results for women
in different risk categories, women from diverse racial and ethnic
groups, health care providers, and public health decision makers;
and
• ways to convey information about chemicals for which there is
suggestive evidence of risk from experimental studies.
CONCLUDING OBSERVATIONS
Breast cancer is a leading cause of cancer morbidity among women
in the United States and many other countries. Major advances have been
made in understanding its biology and diversity, but more needs to be
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344 BREAST CANCER AND THE ENVIRONMENT
learned about the causes of breast cancer and how to prevent it. Familiar
advice about healthful lifestyles appears relevant, but it remains difficult to
discern what contribution a diverse array of other environmental factors
may be making. Important targets for research are the biologic significance
of life stages at which environmental risk factors are encountered, what
steps may counter their effects, when preventive actions can be most effec-
tive, and whether opportunities for prevention can be found for the variety
of forms of breast cancer.
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