Summary

Abstract: Breast cancer accounts for substantial morbidity among women in the United States, with an estimated 230,480 new cases of invasive disease in 2011. Susan G. Komen for the Cure®and its Scientific Advisory Board commissioned a study by the Institute of Medicine (IOM) to assess the current evidence on the contribution of environmental exposures, alone or in combination with genetic factors, to the risk of developing breast cancer; review the challenges in investigating potential environmental contributions; explore evidence-based actions that women might take to reduce the risk of breast cancer; and recommend research directions.

“Environment” was broadly defined to encompass all factors that are not directly inherited through DNA, and a qualitative review examined current evidence on selected factors that illustrate various environmental agents and conditions that may be more amenable to modification. For some of these factors, epidemiologic studies consistently support associations with increased risk for breast cancer (e.g., ionizing radiation, combination hormone therapy, greater postmenopausal weight) or reduced risk (e.g., more physical activity). For many other factors, however, the epidemiologic evidence is more limited, contradictory, or absent. Evidence from animal or mechanistic studies sometimes adds support to the epidemiologic evidence or suggests biologic plausibility when human evidence is lacking for a particular factor.

Knowledge about the complexity of breast cancer and its relation to environmental exposures continues to grow, but researchers face many challenges. To move toward greater opportunities for prevention, more needs to be learned about the biologic significance of the life stages at which



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Summary Abstract: Breast cancer accounts for substantial morbidity among women in the United States, with an estimated 230,480 new cases of invasive disease in 2011. Susan G. Komen for the Cure® and its Scientific Advisory Board commissioned a study by the Institute of Medicine (IOM) to assess the current evidence on the contribution of environmental expo- sures, alone or in combination with genetic factors, to the risk of developing breast cancer; review the challenges in investigating potential environmental contributions; explore evidence-based actions that women might take to reduce the risk of breast cancer; and recommend research directions. “Environment” was broadly defined to encompass all factors that are not directly inherited through DNA, and a qualitative review examined current evidence on selected factors that illustrate various environmental agents and conditions that may be more amenable to modification. For some of these factors, epidemiologic studies consistently support associa- tions with increased risk for breast cancer (e.g., ionizing radiation, combi- nation hormone therapy, greater postmenopausal weight) or reduced risk (e.g., more physical activity). For many other factors, however, the epide- miologic evidence is more limited, contradictory, or absent. Evidence from animal or mechanistic studies sometimes adds support to the epidemiologic evidence or suggests biologic plausibility when human evidence is lacking for a particular factor. Knowledge about the complexity of breast cancer and its relation to environmental exposures continues to grow, but researchers face many challenges. To move toward greater opportunities for prevention, more needs to be learned about the biologic significance of the life stages at which 1

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2 BREAST CANCER AND THE ENVIRONMENT environmental risk factors are encountered; optimal approaches to assess- ing exposures, designing and analyzing epidemiologic studies, and integrat- ing analysis of genetic and environmental influences; the possible combined effects of a multitude of low-level chemical exposures; and interpretation of findings from studies in animals and in vitro systems. Although many questions remain regarding the contributions of envi- ronmental factors to breast cancer risk, evidence suggests that women may have some opportunities to reduce their risk of breast cancer through personal actions: avoiding unnecessary medical radiation throughout life, avoiding use of some forms of postmenopausal hormone therapy, avoiding smoking, limiting alcohol consumption, increasing physical activity, and, for postmenopausal breast cancer, minimizing weight gain. The potential risk reductions for any individual woman will vary and may be modest, but the impact of these actions could be important at a population level. In many cases, however, lack of robust data on environmental agents’ effects on human breast cancer risk, especially during different life stages, and some sense of the trade-offs involved, are major challenges for identifying evidence-based actions that could be taken at the individual or societal level to reduce breast cancer risk. Recommendations for research include applying a life course perspec- tive and a transdisciplinary approach to studies of breast cancer, developing new and better tools for epidemiologic research and carcinogenicity testing of chemicals and other substances, developing effective preventive interven- tions, developing better approaches to modeling breast cancer risks, and improving communication about breast cancer risks to health care provid- ers, policy makers, and the public. B reast cancer has long been the most common invasive noncutaneous cancer among women in the United States, accounting for an esti- mated 230,480 new cases in 2011.1 After lung cancer, it is the sec- ond most common cause of women’s cancer mortality, with about 39,520 deaths expected in 2011. In 2011, there were also approximately 2,140 new cases of breast cancer and 450 breast cancer deaths among men in the United States. Knowledge about the complexity of breast cancer continues to grow: the characterization of multiple tumor subtypes; the likelihood that critical events in the origins of breast cancer can occur very early in life; the variety of pathways through which breast cancer risks may be shaped; the likely contribution to breast cancer of some fundamental biological processes; 1 Approximately 57,650 noninvasive (in situ) breast tumors will also have been diagnosed in 2011.

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3 SUMMARY and the potential significance of the timing and combinations of environ- mental exposures in determining their effect on risks for different types of breast cancer. This growing knowledge is helping to stimulate a transition in breast cancer research, with new ideas influencing the design and analysis of epidemiologic studies, experimental studies in animals, and mechanistic studies of breast cancer biology. As this work elucidates how endogenous and exogenous factors may influence the development of breast cancer, new opportunities for prevention may emerge.2 Susan G. Komen for the Cure and its Scientific Advisory Board requested that the Institute of Medicine (IOM) review the current evidence on environmental risk factors for breast cancer, consider gene–environment interactions in breast cancer, explore evidence-based actions that might reduce the risk of breast cancer, and recommend research in these areas. The Statement of Task for the study appears in Box S-1. The committee interpreted “environment” broadly, to encompass all factors that are not directly inherited through DNA. As a result, this defini- tion includes elements that range from the cellular to the societal: the physi- ologic and developmental course of an individual, by-products of innate metabolic processes that can be modulated by external stressors, diet and other ingested substances, physical activity, microbial agents, physical and chemical agents encountered in any setting, medical treatments and inter- ventions, social factors, and cultural practices. With the potentially vast scope of the study task, the committee focused on areas that it considered to be the most significant and the most pertinent to its charge. In particular, the study focused primarily on breast cancer in women and on the initial occurrence of a tumor, not recurrence. The committee took into account the changes in the breast over a woman’s life and the potential for the timing of exposures to influence risks they may pose for breast cancer. The committee did not address practices in the diagnosis and treatment of breast cancer or policies or practices for breast cancer screening. REVIEWING EVIDENCE ON CERTAIN ENVIRONMENTAL FACTORS The committee explored the available evidence concerning breast can- cer risks associated with a necessarily limited selection of specific factors that illustrate a variety of environmental agents and conditions (see Box S-2 and Chapter 3). The committee drew on evidence reviews by authoritative bodies, especially the International Agency for Research on Cancer (IARC) and the World Cancer Research Fund (WCRF) International, supplemented 2 Theterm “breast cancer” is used in this report to refer to disease in humans, and “mammary cancer” or “mammary tumor” to refer to disease in animals.

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4 BREAST CANCER AND THE ENVIRONMENT B OX S-1 Study Charge In response to a request from Susan G. Komen for the Cure®, the Institute of Medicine will assemble a committee to: 1. Review the evidentiary standards for identifying and measuring cancer risk factors; 2. Review and assess the strength of the science base regarding the relationship between breast cancer and the environment; 3. Consider the potential interaction between genetic and environ- mental risk factors; 4. Consider potential evidence-based actions that women could take to reduce their risk of breast cancer; 5. Review the methodological challenges involved in conducting research on breast cancer and the environment; and 6. Develop recommendations for future research in this area. In addition to reviewing the published literature, the committee will seek input from stakeholders, in part by organizing and conducting a public workshop to examine issues related to the current status of eviden- tiary standards and the science base, research methods, and promising areas of research. The workshop will focus on the challenges involved in the design, conduct, and interpretation of research on breast cancer and the environment. The committee will generate a technical report with conclusions and recommendations, as well as a summary report for the lay public. by reviews and original research reports in the peer-reviewed literature. The committee qualitatively reviewed relevant literature, without a formal systematic review or quantitative analysis (e.g., meta-analysis) or the inten- sive weighing of evidence undertaken by IARC or WCRF. Several familiar topics, such as diet and most dietary components, received less attention because of ongoing systematic review by other groups. Providing a review of a complete set of environmental agents and conditions was not feasible. Of the large number of environmental factors with potential but uncertain impact on breast cancer, the committee reviewed only a selected number that illustrated particular types of challenges in assessment. The aim was to characterize the available evidence on whether the selected environmental factors are associated with breast cancer, and to identify areas of substantial uncertainty. Evidence from epidemiologic stud- ies carried the greatest weight in identifying risk factors. Evidence from experimental studies in animals or in vitro systems, especially in the absence

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5 SUMMARY BOX S-2 E nvironmental Factors Included in the Committee’s Evidence Reviewa Exogenous hormones Consumer products and constituents • ormone therapy: androgens, H • Alkylphenols estrogens, combined • Bisphenol A (BPA) estrogen–progestin • Nail products • Oral contraceptives • Hair dyes • Parabens Body fatness and abdominal fat • Perfluorinated compounds (PFOA, PFOS) Adult weight gain • Phthalates • olybrominated diphenyl ethers P Physical activity (PBDEs; flame retardants) Dietary factors Industrial chemicals • Alcohol consumption • Benzene • ietary supplements and D • 1,3-Butadiene vitamins • PCBs • Zeranol and zearalenone • Ethylene oxide • Vinyl chloride Tobacco smoke • Active smoking Pesticides • Passive smoking • DDT/DDE • Dieldrin and aldrin Radiation • Atrazine and S-chloro triazine • onizing (including X-rays I herbicides (atrazine) and gamma rays) • on-ionizing (extremely low N Polycyclic aromatic hydrocarbons frequency electric and (PAHs) magnetic fields [ELF-EMF]) Dioxins Shift work Metals • Aluminum • Arsenic • Cadmium • Iron • Lead • Mercury aThe committee reviewed a selected set of factors for illustration; the chemicals were not chosen to be representative of any class. Some epidemiologic, mechanistic, or animal data relevant to mammary tumorigenesis or breast cancer are available for numerous other chemicals.

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6 BREAST CANCER AND THE ENVIRONMENT of human data, was the basis for noting that some factors may present a hazard, and thus potentially contribute to breast cancer risk, alone or in combination with other factors, depending on the nature of an exposure (e.g., amount, timing). A hazard has the potential to cause an adverse effect under certain conditions of exposure; a risk is the probability that the adverse effect will occur in a person or a population as a result of an exposure to a hazard. Among the environmental factors reviewed, those most clearly associ- ated with increased breast cancer risk in epidemiologic studies are use of combination hormone therapy products, current use of oral contracep- tives, exposure to ionizing radiation, overweight and obesity among post- menopausal women, and alcohol consumption. Greater physical activity is associated with decreased risk. Some major reviews have concluded that the evidence on active smoking is consistent with a causal association with breast cancer, and other large-scale reviews describe the evidence as limited. For several other factors reviewed by the committee, the available epide- miologic evidence is less strong but suggests a possible association with increased risk: passive smoking, shift work involving night work, benzene, 1,3-butadiene, and ethylene oxide. For some of the reviewed factors (e.g., bisphenol A or BPA), animal or mechanistic data suggest biological plau- sibility as a hazard. A few factors, such as non-ionizing radiation and per- sonal use of hair dyes, have not been associated with breast cancer risk in multiple, well-designed human studies. For several other factors, evidence was too limited or inconsistent to reach a conclusion (e.g., nail products, phthalates). In all cases, these conclusions are based on assessments of the currently available evidence; it is always possible for new evidence to point to different conclusions. As the committee considered the current state of knowledge, it sees a need for research on the etiology of breast cancer to do more to incorpo- rate new understanding of breast development over the life course, recent advances in elucidating the molecular biology of tumorigenesis, and the challenges of assessing the potential impact of a multitude of low-level chemical exposures. A more integrative approach to breast cancer research may accelerate progress in understanding the role that environmental fac- tors may have in breast cancer. CHALLENGES IN STUDYING BREAST CANCER AND THE ENVIRONMENT Trying to determine which environmental exposures may influence rates of breast cancer poses substantial challenges. The biology of breast development and the origins and progression of breast cancer are not fully understood, and much research in the past lacked tools to differentiate

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7 SUMMARY among types of breast cancer. Also, a focus primarily on exposures during adulthood, as in past research, may miss critical windows during early life in which some environmental exposures may influence risk for breast cancer later in life. Tracing multiple and potentially interacting causes of breast cancer will be difficult. Some risk factors may have very weak effects or effects in only a small portion of the population, making their contribution to risk hard to detect. People are exposed to a complex and changing mix of environmental agents over the course of a lifetime; discerning the effects of an individual agent, or knowing whether the components of the mixture may interact to influence the development of disease, is not straightforward. Moreover, many of these agents have never been studied in ways that could indicate whether they might be relevant to breast cancer. Several challenges appear especially formidable. Assessing Human Exposure It can be difficult to identify and measure exposures because few tools and opportunities are available for doing so directly, especially if relevant exposures occurred well in the past or the timing of such exposures is unclear. Many studies must base estimates of exposure on error-prone indicators such as self-reports of past product use or proxies for exposure, such as holding a particular type of job or living in a particular location at a particular time. Even when it is possible to detect evidence of exposure from biological samples (e.g., blood or urine), single measurements are rarely suf- ficient to establish the duration and levels of past exposure, and few studies have the benefit of multiple samples from the same study participant for comparisons over time. Determining the number of samples needed and interpreting comparisons among them requires a good understanding of the biological processes that influence variation in the production and retention of these biomarkers of exposure. Conducting Epidemiologic Studies Experimental studies in humans (i.e., controlled clinical trials), in which host factors and exposures can be carefully controlled, would provide the strongest evidence of causal associations, but they are rarely an option in studying causes of breast cancer because study participants should not be exposed to substances suspected of causing harm. As a result, researchers must generally rely on observational studies that depend on either collecting retrospective information about critical exposures and life events or con- ducting large prospective studies of extended duration. A few large cohorts of adult women have provided a valuable base for investigating breast

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8 BREAST CANCER AND THE ENVIRONMENT cancer risk factors. But because it is likely that breast cancer diagnosed in older adult women is influenced by exposures at various stages of life, ideal prospective investigations would follow a study population throughout life. Such studies are very costly and logistically difficult to implement. Reliable predictors of increased risk for breast cancer that could be assessed at much younger ages (e.g., during adolescence) would greatly aid investigation of the influence of early-life exposures, but current understanding is limited to risk factors such as age at menarche and at first full-term pregnancy. An additional complication is that for some environmental pollutants, low- level exposures are so widespread and co-occur with low levels of numer- ous other possible contributors that it is difficult to identify an unexposed comparison group or adequately control for other exposures. Identifying Genetic Influences Only a few genetic markers of substantially increased risk are well established (e.g., BRCA1 and BRCA2 mutations), and these are rare in the general population. Studies suggest that other, more common mutations and polymorphisms may also be associated with breast cancer, but have a much smaller influence on risk. The multitude of potential associations and the relatively small differences in risk mean that studies must be very large to detect statistically significant effects, and efforts to replicate findings are often not successful because false positive rates are high in small studies. Gene–environment interactions for breast cancer risk have been shown in several epidemiologic studies for high alcohol intake combined with poly- morphisms in enzymes involved in alcohol metabolism. For most chemicals, however, exposures are generally low, and efforts to study interactions between genetics and environmental factors are also hampered by lack of data on environmental exposures of interest in most datasets currently used for genomic studies. Interpreting Findings from Studies in Animals and In Vitro Systems Experimental studies in whole animals and in vitro systems are an essential component of research on breast cancer and of regulatory risk assessment to limit exposure to carcinogens, but the results remain approxi- mations of human experience. In vitro systems are used to explore mecha- nisms by which environmental agents alter cellular and tissue behavior and to identify chemicals that cause genetic damage (genotoxic substances) in regulatory safety testing. Such systems currently do not fully account for the multiplicity of biological processes (e.g., pharmacokinetics, cell interac- tions) that occur in response to an exposure in a whole organism, and the degree to which they detect nongenotoxic carcinogens is uncertain. Even

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9 SUMMARY studies in human cell lines, though they may provide useful mechanistic insights, are ill equipped to capture the full complexity of intact humans. In testing with whole animals (i.e., in vivo animal models), the small numbers of test animals make it statistically impossible to detect small increases in risk. It may also be difficult to interpret results from studies that use doses or routes of exposure that do not correspond to typical human exposures. Adding to the complexity of interpreting in vivo animal studies are differ- ences in responses among the commonly used rat and mouse strains and assessing the significance of underlying differences in anatomy and physiol- ogy between humans and rodents. EMPHASIZING THE LIFE COURSE IN STUDYING RISK FACTORS AND BREAST CANCER MECHANISMS As in most types of adult cancer, breast cancer is thought to develop as a result of accumulated damage induced by both internal and external triggers resulting in initial carcinogenic events. The affected cells and tis- sues then progress through multiple stages, with accompanying alterations in surrounding tissue likely playing a role in permitting or potentiating the cancer process. These events contributing to subsequent cancers may occur spontaneously as a by-product of errors in normal processes, such as DNA replication, or through effects of environmental exposures, such as damage from exposure to sunlight or tobacco carcinogens; or they can be sustained and furthered by physiologic conditions, such as obesity. The breast undergoes substantial changes from the time it begins devel- oping in the fetus through old age, especially in response to hormonal changes during puberty, pregnancy, lactation, and menopause. The tim- ing of a variety of environmental exposures may be important in directly increasing or reducing breast cancer risks or in acting indirectly by influenc- ing the developmental events. There may be critical windows of suscepti- bility (e.g., periods of rapid cell proliferation or maturation) when specific mechanisms that increase the likelihood of a breast cancer developing may be more likely to come into play. Research is continuing on many fronts to increase understanding of the mechanisms that contribute to breast cancer and the ways they relate to or may be modulated by exposure to environmental factors. Some exposures act principally at early stages of carcinogenesis (activating oncogenes or inactivating tumor suppressor genes within affected cells) whereas others act later (stimulating cell division and proliferation), so that mutations are less likely to be repaired and more likely to have detrimental conse- quences. Others may act to alter susceptibility to exposures later in life. Estrogen produced in the body is critical to normal breast development, but it also appears to play a major role in breast carcinogenesis. It may

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10 BREAST CANCER AND THE ENVIRONMENT do this by promoting proliferation of cells (mitogenesis) and possibly via mutagenic activity of its metabolites. Some environmental factors can have estrogenic properties, but the implications for breast cancer are not entirely clear. Environmental exposures might cause damage (mutations) to DNA; they may also act through epigenetic reprogramming, which alters gene expression without altering DNA. Factors that modify the functioning of the immune system may also contribute to carcinogenic processes. Also important may be disruption of the stromal component of the breast that normally functions to maintain the structural and functional integrity of the breast tissues through regulatory and homeostatic mechanisms. OPPORTUNITIES FOR EVIDENCE-BASED ACTION TO REDUCE RISK OF BREAST CANCER On average, girls born in the United States today have approximately a 12 percent risk of developing invasive breast cancer that will be diagnosed at some point in their lifetime. Among 50-year-olds, 2.4 percent of white women (or 24 out of 1,000) are likely to be diagnosed with invasive breast cancer over the next 10 years, compared with 2.2 percent of black women, 2.0 percent of Asian women, and 1.7 percent of Hispanic women. Within average values such as these, groups of women have characteristics that give them a higher or lower 10-year risk, and of course, larger risks if followed through the remainder of their lives. Research findings that certain factors are associated with increased or decreased risk of breast cancer are typically reported in terms of measures that compare the risk in exposed and unexposed populations (i.e., rela- tive risks, odds ratios, hazard ratios, or risk differences). In general, the environmental factors reviewed by the committee were associated with less than a doubling of risk. These findings become more meaningful when they are linked back to the actual rates of illness. Thus, a doubling of risk might mean that the 10-year risk of breast cancer is 5 percent for a group of women who have a risk factor rather than 2.5 percent for those who do not. Finding ways to reduce risk and avert cases of breast cancer is a high priority, but at present, the evidence-based options are limited (see Chap- ter 6). Many of the well-known risk factors for breast cancer—older age, being female, and older age at menopause—appear to offer little or no opportunity to intervene. For a limited set of other risk factors, women have a greater opportunity to act in ways that may have the potential to reduce risk for breast cancer while carrying limited risks of increasing other adverse health outcomes (Table S-1). Some of these actions may have health benefits beyond any contribution they may make to reducing risk of breast cancer.

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11 SUMMARY The potentially risk-reducing—but not necessarily easily accomplished— actions identified by the committee include eliminating exposure to unnec- essary medical radiation throughout life; avoiding use of combination estrogen–progestin menopausal hormone therapy, unless it is considered medically appropriate and the benefits are expected to outweigh the risks; avoiding active and passive smoking; limiting alcohol consumption; increas- ing physical activity; and minimizing overweight and weight gain to reduce risk of postmenopausal breast cancer. Chemoprevention using tamoxifen or raloxifene may be an appropri- ate choice for some women at high risk of breast cancer, but use of these medications also raises the risk of serious adverse events such as stroke and endometrial cancer. Women who qualify for use of chemoprevention should receive appropriate counseling on its benefits and risks to be able to make an informed choice. For some of the chemicals reviewed by the committee, it may be pru- dent to avoid or minimize exposure because the available evidence suggests biological plausibility for exposure to be associated with an increased risk of breast cancer, or there is suggestive evidence from epidemiology, or both. The evidence is clearest for benzene, 1,3-butadiene, and ethylene oxide because there is suggestive evidence from both epidemiologic and nonhu- man data. Occupational exposures to these chemicals can occur in industrial settings, and the general public is exposed through transportation-related air pollution, industrial emissions, and tobacco smoke. For cosmetics and dietary supplements, the Food and Drug Administration (FDA) can remove from the market products found to be hazardous or adulterated, but it generally lacks authority to test the safety of these products before they are sold. The committee urges efforts to better inform consumers and health professionals about the limits of FDA’s role, to encourage manufacturers to identify hormonally active ingredients in cosmetics and dietary supple- ments, and to ensure that FDA has effective tools to identify contaminants or ingredients that are potential contributors to increased risk of breast cancer. Similarly for chemicals in consumer products, interested organiza- tions can help inform the public about the current provisions for testing chemicals and encourage manufacturers to improve testing and make exist- ing information on their products more readily available. The limited set of opportunities for individual action noted by the com- mittee reflects the scientific community’s still incomplete understanding of which exposures might best be avoided and when, of the actions following exposure that might have a long-term benefit in reducing risk for breast cancer, and, in some cases, of the potential for unintended consequences of interventions. Few intervention studies have investigated whether factors associated with increased postmenopausal risk, such as overweight or alco- hol consumption, should be avoided completely, or whether reducing or

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14 BREAST CANCER AND THE ENVIRONMENT eliminating the exposure later in adulthood will reduce the risk that might have accrued from exposure at younger ages. It is also difficult to judge what any individual woman’s change in risk might be. Moreover, much of the evidence on breast cancer risk factors has come from studies of post- menopausal breast cancer in white women, and it has pointed to a greater potential to reduce risk for estrogen receptor–positive (ER+) cancers than other types. A much better basis is needed for guidance for risk reduction for younger women and women of other races and ethnicities. Nevertheless, many of the suggested actions are likely to not only reduce breast cancer risk, but also reduce risks for other major health conditions. DIRECTIONS FOR FUTURE RESEARCH The research needed to better understand the relation between breast cancer risks and environmental factors ranges from further examination of elements of the biology of breast development and carcinogenesis to tests of potential interventions to reduce risk. Important components of the work recommended here are support for the research necessary to develop better tools for assessing the carcinogenicity of chemicals and pharmaceuticals as well as tools needed to strengthen epidemiologic research. The importance of a life course perspective runs throughout the recommendations. Applying a Life Course Perspective to Studies of Breast Cancer Progress has been made in understanding the biology of breast devel- opment and many aspects of breast cancer, but important gaps remain in understanding its causes and the extent of environmental influences on its development. Future research should increasingly focus on the influence of exposure to a variety of environmental factors during potential windows of susceptibility over the full life course, from the prenatal experience throughout adult life. 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. These 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 investiga- tion of windows of susceptibility. Long-term follow-up of cohorts is

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15 SUMMARY critical because new, unexpected evidence frequently arises with longer follow-up. Topics warranting attention include (but are not limited to) the biol- ogy 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 effects of exposures 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 biological 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 (e.g., indicators of breast development, peak height growth velocity) are valid and predictive biomarkers of differences in risk for breast cancer; • investigating the role that environmental factors may have in the origins of the different types of breast cancer to better understand disparities in incidence 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 the capacity of these cohorts to capture information about environmental exposures over the life course. Targeting Specific Concerns From its examination of evidence on a selection of environmental fac- tors, 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

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16 BREAST CANCER AND THE ENVIRONMENT 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: The biological processes and pathways through which shift work and circadian rhythm disruption relate to breast cancer; more detailed and standardized approaches to exposure assessment. • Endocrine activity: Interactions between chemicals, such as BPA, polybrominated diphenyl ethers (PBDEs), zearalenone, and certain dioxins and dioxin-like compounds, and timing of exposure, diet, and other factors that may influence the relationship of these types of compounds to breast cancer risk. • Genotoxicity: 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 spe- cific life stages, contribute to breast cancer risk at current levels of exposure. • Epigenetic activity: Fundamental research on the role of epigenetic modifications in breast cancer risk, and the potential importance of epigenetic modifications by environmental chemicals such as BPA. • Gene–environment interactions: Continued research to identify genes relevant to breast cancer that modify risk from discrete envi- ronmental exposures. Epidemiologic Research Studies of Occupational Cohorts and Other Highly Exposed Populations Many known human carcinogens were first identified through studies in occupational settings where workers had chemical and physical expo- sures that were higher than those of the general population. With many more women in the workforce, occupational studies may now be a means to identify some exposures that increase risk for breast cancer. Other identifiable groups of women with long-term or event-related high-dose exposures may also be promising study populations. 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-

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17 SUMMARY port for these studies should include resources for the development of improved exposure assessment methods to quantify chemical and other environmental exposures potentially associated with the development of breast cancer. New Exposure Assessment Tools A life course perspective on breast cancer suggests that critical peri- ods of vulnerability may exist during in utero development, in childhood, adolescence, and early adulthood, and at older ages. Exposure assessment becomes particularly challenging over such extended intervals. 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; • 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, 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 life stage, body weight, nutrition, comorbidity, or other factors; • developing other biomarkers of exposure through early biologic effects (DNA adducts, methylation, tissue changes, gene expres- sion, 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.

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18 BREAST CANCER AND THE ENVIRONMENT Research to Advance Preventive Actions Minimizing Exposure to Ionizing Radiation Some of the strongest evidence reviewed by the committee supports a causal association between breast cancer and exposure to ionizing radia- tion. However, population exposures to ionizing radiation in medical imag- ing are increasing. Standards exist to ensure that mammography minimizes radiation exposures, but more needs to be learned to determine how to minimize exposures from other medical procedures. 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 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 Interventions to Prevent Breast Cancer Some breast cancer risk factors appear to be modifiable, but it is impor- tant to determine what modifications 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 postmeno- pausal 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;

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19 SUMMARY • 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—Medications to Reduce Breast Cancer Risk Tamoxifen and raloxifene have been shown to substantially reduce risk of ER+ breast cancer in women who have not been diagnosed with the disease, and they are approved by the FDA for this use by women at increased risk of breast cancer. Other medications (e.g., aromatase inhibi- tors, bisphosphonates, metformin) are being studied to assess their effec- tiveness for reducing the risk of either ER+ or estrogen receptor–negative (ER–) breast cancer. However, tamoxifen and raloxifene increase the risk of other poten- tially serious events (e.g., endometrial cancer [tamoxifen], stroke) and are not widely used. Additional research is needed to identify other drugs that can reduce risk of all forms of breast cancer with minimal risk of other adverse health effects. 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. 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 current analyses. Testing to Identify Potential Breast Carcinogens In Vivo Testing for Carcinogenicity Current whole-animal (rodent) protocols for carcinogenicity testing may not be ideally suited to screening for possible human breast car- cinogens because they typically do not address changing sensitivity during the life course, such as during in utero and early postnatal periods, to

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20 BREAST CANCER AND THE ENVIRONMENT carcinogens or to exposures that may alter susceptibility to later carcino- genic exposures. Because of study power constraints, these tests are not usually structured to assess the low-dose exposures to mixtures that are characteristic of human experience, and interpretation of findings (positive or negative) may be complicated by the test animal strains’ characteristic susceptibility (or lack of susceptibility) to mammary tumors. 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 include consideration of the appropriateness of the rodent species and strains used for testing; the utility of genetically engineered mouse models to address specific mechanisms; the frequency, magnitude, and route of dosing that may be most relevant for predicting human risk; potential differences in sensitivity in different life stages; and standard practices for conducting studies and reporting results. New Approaches to Toxicity Testing New toxicity testing approaches are being developed to more rapidly and accurately screen chemicals and minimize in vivo testing. Because breast cancer is a major contributor to women’s morbidity, these tests should be relevant to the basic mechanisms of breast cancer—for example, mutagenesis, estrogen receptor signaling, epigenetic programming, modula- tion of immune functioning, and alterations at the whole-organ level—and to human exposures (low doses and mixtures). 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. The tests should be able to account for changes in susceptibility through the life course and mechanisms charac- teristic of hormonally active agents. The test development 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 gland devel- opment and related intermediate outcomes observed in some

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21 SUMMARY 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 exposures 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. New Approaches to Testing Hormonally Active Candidate Pharmaceuticals Given the evidence for hormonal influences on the development of breast cancer, the committee is concerned that testing required to gain marketing approval for various hormonally active pharmaceuticals, includ- ing oral contraceptives and menopausal hormone therapies, does not ade- quately address the potential for increased risk for breast cancer. 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. If such tests can be developed and validated, FDA should require submission of the results as part of the process for approv- ing the introduction of new hormonal preparations for prescription or over-the-counter use. These tests may also prove useful in testing environmental chemicals. Postmarketing Studies of Hormonally Active Drugs With the demonstration that use of certain hormonally active prescrip- tion drugs is associated with an increased risk of breast cancer and other adverse health effects, it is important to investigate whether use of other hormonally active drugs is also associated with increased risk. Recommendation 11: FDA should use its authority under the Food and Drug Administration 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.

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22 BREAST CANCER AND THE ENVIRONMENT The studies should be adequately powered to quantitatively explore the possible contribution of the products to breast cancer risk. Products that represent a substantial change in pharmacologic composition or dosage schedule from products currently on the market should be a particular focus of attention. 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 Systematic modeling approaches are needed to refine estimates of the proportion of breast cancer in the United States and other countries that can be attributed to established risk factors (individually and in combina- tion), especially those that can be modified. Additionally, better data are needed on the prevalence of these risk factors. Improved estimates of risk associated with established factors should help in determining the scale of residual risk, which may be associated with other environmental exposures. A collaborative approach, such as that used by the Cancer Intervention and Surveillance Modeling Network (CISNET) consortium, may be a cost- effective way to pursue this work. Recommendation 12: Breast cancer researchers and research funders should pursue 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 Accurate and effective communication of breast cancer risks is chal- lenging, and developing better approaches should be a research target. Uncertainty is inherent in risk prediction, but it is important to inform a broad range of stakeholders and constituencies on both those exposures

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23 SUMMARY that are associated with increased risk and those that have no evident asso- ciation with breast cancer. 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. This work should include identifying ways to improve translation of research results into messages that can effectively convey the impli- cations for women in different risk categories, women from diverse racial and ethnic groups, health care providers, and public health deci- sion makers. It also should include ways to convey information about chemicals for which there is suggestive evidence of risk from experi- mental 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 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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