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1 Introduction T he prospect of developing breast cancer is a source of anxiety for many women. Breast cancer remains the most common invasive can- cer among women (aside from nonmelanoma skin cancers), account- ing in 2011 for an estimated 230,480 new cases among women in the United States and another 2,140 new cases among men (ACS, 2011). After lung cancer, it is the second most common cause of mortality from cancer for women, with about 39,520 deaths expected in the United States in 2011. Another 450 breast cancer deaths are expected among men in 2011 (ACS, 2011). Since the mid-1970s, when the National Cancer Institute (NCI) began compiling continuous cancer statistics, the annual incidence of invasive breast cancer rose from 105 cases per 100,000 women to 142 per 100,000 women in 1999 (NCI, 2011). Since then, however, the incidence has declined. In 2008, the incidence of breast cancer was 129 cases per 100,000 women. Further reduction of the incidence of breast cancer is a high priority, but finding ways to achieve this is a challenge. As in most types of adult cancer, breast cancer is thought to develop as a result of accumulated dam- age induced by both internal and external triggers resulting in initial carci- nogenic events. The affected cells and tissues then progress through multiple stages, with accompanying alterations in the surrounding tissue likely play- ing a role in whether the damage leads to a cancer. These events contrib- uting to subsequent cancers may occur spontaneously as a by-product of errors in normal processes, such as DNA replication, or potentially through effects of environmental exposures. The early procarcinogenic events from endogenous and exogenous processes may be sustained and 25
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26 BREAST CANCER AND THE ENVIRONMENT furthered by physiologic conditions such as obesity. It is likely that many such procarcinogenic events may never be entirely preventable because, although potentially modifiable, they are consequences of basic biologic processes, such as oxidative damage to DNA from endogenous metabo- lism, or stimulation of cell growth through normal hormonal processes.1 Although such biological “background” mutagenesis is unavoidable, highly efficient protective pathways, such as DNA repair and immune surveillance, are effective at reducing the impacts of procarcinongenic events (Loeb and Nishimura, 2010; Bissell and Hines, 2011). Although more needs to be learned about both the mechanisms by which breast cancers arise and the array of factors that influence risk for them, much has been established. Among the factors generally accepted as increasing women’s risk are older age, having a first child at an older age or never having a child, exposure to ionizing radiation, and use of certain forms of postmenopausal hormone therapy (HT). Inherited mutations in the BRCA1 and BRCA2 genes also markedly increase risk for breast can- cer (and other cancers as well), but these mutations are rare in the general population and account for only 5 to 10 percent of cases (ACS, 2011). Even though aging, genetics, and patterns of childbearing account for some of the risk for breast cancer, they are not promising targets for preven- tive measures. More helpful would be identifying modifiable risk factors. For example, the publication of findings from the Women’s Health Initiative (Writing Group for the Women’s Health Initiative Investigators, 2002) con- firming earlier indications that estrogen–progestin HT was contributing to an increase in the risk of postmenopausal breast cancer was followed by a rapid reduction in use of HT and in the incidence of invasive breast cancer. As reflected in NCI data, the incidence in 2002 was 136 cases per 100,000 women, compared with 127 in 2003 (NCI, 2011). A portion of the decline in breast cancer incidence since 1999 is attributed to this reduced use of HT (e.g., Ravdin et al., 2007; Farhat et al., 2010). But there are long-standing and still unresolved concerns that aspects of diet, ambient chemicals, or other potentially modifiable environmental exposures may be contributing to high rates of breast cancer. At present, a large but incomplete body of evidence is available on the relationship between breast cancer and the wide variety of external factors that can be said to comprise the environment. Information on interactions between genetic susceptibility and environmental factors is particularly sparse. In contrast, knowledge of the complexity of breast cancer is grow- ing, with the characterization of multiple tumor subtypes; the possibility 1 Loeb and Nishimura (2010, p. 4270) note that each normal cell in a person’s body may be exposed to as many as 50,000 DNA-damaging events each day, and that oxygen free radicals are a major source of DNA damage.
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27 INTRODUCTION 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; and the potential significance of both the timing of exposures and the way combinations of factors determine the effect on risks for different types of breast cancer. This growing knowledge has stimulated a transition in breast cancer research. The new perspectives on breast cancer highlight the limitations of the current understanding of the disease, and innovative ideas are beginning to influence the design and analysis of epidemiologic studies, experimental studies in animals, and mechanistic studies of breast cancer biology, all directed toward elucidating how external factors may influence the etiology of breast cancer. This report presents the results of a study commissioned to 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. STUDY CHARGE AND COMMITTEE ACTIVITIES This study resulted from a request to the Institute of Medicine (IOM) by Susan G. Komen for the Cure and its Scientific Advisory Board. Komen for the Cure funds research on prevention, diagnosis, and treatment of breast cancer, and also provides educational information and support ser- vices for the public and health care providers. The Statement of Task for the IOM study appears in Box 1-1. The members of the study committee were selected to contribute expertise in epidemiology, toxicology, risk assessment, biostatistics, molec- ular carcinogenesis, gene–environment interactions, communication of health messages, environmental health science, exposure assessment, and health care. The committee includes a member from the patient advocacy community. The committee met in person five times from April 2010 through February 2011 and conducted additional deliberations by conference call. During these meetings and calls, the committee reviewed and discussed the existing research literature on the topics central to its charge and developed and revised this report. At three of its meetings, the committee held public sessions during which it heard presentations by researchers, representatives of advocacy organizations, and members of the public. The committee also commissioned work on two topics. One project was a review of data available to assess temporal changes in the potential for exposure to a selected set of chemicals and other environmental agents. The agents included in this paper have been discussed in the research lit- erature and the popular press as possible contributors to increased risk for
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28 BREAST CANCER AND THE ENVIRONMENT B OX 1-1 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. breast cancer. This work served as an information resource for the com- mittee and helped to identify some data presented in Chapter 4. The other project resulted in a paper examining temporal changes in the United States in exposure to ionizing radiation, with a particular focus on exposure from medical imaging (see Appendix F, available electronically at http://www.nap. edu/catalog.php?record_id=13263). APPROACH TO THE STUDY The committee began its work with recognition of the potentially vast scope of the study task and the need to develop a perspective and approach that could lead to a useful and timely report. The committee sought to focus its attention in areas that it considered to be the most significant and the most pertinent to the charge placed before it. For purposes of this report, the committee interpreted “environment” broadly, to encompass all factors that are not directly inherited through
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29 INTRODUCTION DNA. As a result, this definition includes elements that range from the cellular to the societal: the physiologic and developmental course of an individual, diet and other ingested substances, physical activity, microbial agents, physical and chemical agents encountered at home or at work, medical treatments and interventions, social factors, and cultural practices. This perspective was a foundation for the committee’s work; application of it in its broadest sense is something that the committee hopes will expand the scope of future research. For some readers, this interpretation will differ from their association of the phrase “environmental risk factors” primar- ily with pollutants and other products of industrial processes (Baralt and McCormick, 2010). Furthermore, throughout the report the term “breast cancer” is used to refer to disease in humans and “mammary cancer” or “mammary tumor” to refer to disease in animals. The committee explored the available evidence concerning breast can- cer risks associated with a varied but limited collection of specific sub- stances and factors (Chapter 3), and it also reviewed the many challenges that researchers have had to contend with in studying breast cancer, includ- ing those pertaining to gene–environment interactions (Chapter 4). But in its examination of the relation between breast cancer and the environment, the committee chose to highlight an approach that emphasizes the biologic mechanisms through which environmental factors may be operating and the importance of the changing picture over the life course (Chapter 5). This perspective played a major role in shaping the committee’s conclusions and recommendations. A Life Course Perspective Breast cancer is primarily (but far from exclusively) a disease of adult women who are approaching or have reached menopause. In 2009, approx- imately 90 percent of new cases in U.S. women were diagnosed at age 45 or older (ACS, 2009). But the breast undergoes substantial changes from the time it begins developing in the fetus through old age, especially in response to hormonal changes during puberty, pregnancy, lactation, and menopause. With the timing of these developmental events related to risk for some types of breast cancer, there has been growing interest in exploring whether the timing of a variety of environmental exposures also is important in under- standing what influences breast cancer risks. In Chapter 5, the committee has sought to link its examination of the mechanisms of carcinogenesis with a life course perspective on when and how those pathologic pathways may be particularly relevant in relation to when and how environmental expo- sures occur. Attention was paid to growing evidence for critical windows of susceptibility (e.g., periods with rapid cell proliferation or maturation)
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30 BREAST CANCER AND THE ENVIRONMENT when specific mechanisms that increase the likelihood of a breast cancer developing may be more likely to be activated. Identifying Environmental Risks for Breast Cancer Trying to determine which environmental exposures may be influenc- ing rates of breast cancer poses substantial challenges, many of which are discussed in Chapter 4. Cancer is a complex disease, and its “causes” are generally harder to trace than the bacteria and viruses that cause infectious diseases. People who are never exposed to the measles virus will never get measles. But the impact of removing a particular environmental exposure associated with breast cancer is less clear because many other factors can still contribute to the development of breast cancer. The role of underlying susceptibility from inherited genes appears to involve both rare variants and common ones, but it is still not well characterized. Moreover, people are exposed to a complex and changing mix of environmental agents over the course of a lifetime, so discerning the effects of an individual agent, or knowing which components of the mixture may influence the development of disease or how the mixture’s components may interact with each other or with genes, is not straightforward. Observational epidemiologic studies are a critical tool for learning about elevated risks, but they can be difficult to do well. They typically are the basis for demonstrating correlations between risk factors and outcomes, but establishing a causal inference is much more difficult. The challenges in establishing causality in such studies include difficulties with exposure measurement and accounting for undetected or poorly measured differences that may exist between the groups designated as exposed and unexposed. Furthermore, the timing and duration of observational studies may affect whether sufficient time has elapsed to detect differences in the incidence of a cancer that may not appear until many years after an exposure. Random- ized controlled trials, which assign participants to a specific exposure or a comparison condition, are easier to interpret. However, for ethical and methodological reasons, such studies are rarely possible, especially when the goal is to determine whether the exposure is associated with an adverse event. Experimental studies in animal models and in vitro systems offer an important opportunity to study the effects of well-defined exposures and to explore mechanisms of carcinogenicity in ways that are not possible in epi- demiologic studies. They can signal potential hazards to human health that cannot be identified in other ways, but their results have to be interpreted with an understanding of differences across species and the comparability of an experimental exposure to the conditions encountered in the human population.
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31 INTRODUCTION Reviewing Evidence on Specific Risk Factors The literature on risk factors for cancer in general and breast cancer in particular is large and varied. In the United States, the Environmental Protection Agency (EPA) and the National Toxicology Program (NTP) in the National Institute of Environmental Health Sciences have programs to review the evidence on the carcinogenicity of various substances.2 The International Agency for Research on Cancer (IARC), which is part of the World Health Organization, is a focal point for major international col- laboration in such reviews.3 In addition, a collaborative project between the World Cancer Research Fund International and the American Institute for Cancer Research has an ongoing program to review evidence on diet, physi- cal activity, and cancer (WCRF/AICR, 2007).4 All of these review programs consider evidence concerning breast cancer (or mammary cancers in animal studies) when it is available, but it is not their focus. Reviews specifically concerning breast cancer have also been conducted. These reviews include one conducted by the California Breast Cancer Research Program (2007) and a review sponsored by Komen for the Cure and conducted by the Silent Spring Institute (e.g., Brody et al., 2007; Rudel et al., 2007). Assembling a comprehensive review of evidence on the relation between a complete set of environmental factors and breast cancer was not feasible for this study. Instead, the committee chose to focus on a limited selection of various types of environmental factors and potential routes of exposure. These factors are discussed in Chapter 3. The committee’s aim was to characterize the available evidence and identify where substantial areas of uncertainty exist. Observations About Risk One component of the committee’s task was to comment on actions that can be taken to reduce the risk of breast cancer. Opportunities for action are discussed in Chapter 6, but it is important to emphasize from the outset the challenge of interpreting evidence regarding risk and risk reduc- tion. The widely quoted estimate that women in the United States have a 1-in-8 chance of being diagnosed with breast cancer during their lifetimes 2Information on the EPA and NTP review programs is available at http://www.epa.gov/ ebtpages/pollcarcinogens.html and http://ntp.niehs.nih.gov/?objectid=7 2016262-BDB7-CEBA- FA60E922B18C2540. 3 Information on IARC reviews is available at http://www.iarc.fr/ and http://monographs. iarc.fr/index.php. 4 Information on the review by the World Cancer Research Fund International and the American Institute for Cancer Research is available at http://www.wcrf.org/cancer_research/ expert_report/index.php.
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32 BREAST CANCER AND THE ENVIRONMENT can be restated as approximately a 12 percent lifetime risk of developing invasive breast cancer (NCI, 2010). The risk can also be presented for shorter, more comprehensible intervals. For example, among white women who are 50 years old, 2.4 percent are likely to be diagnosed with invasive breast cancer over the next 10 years (NCI, 2010). This 10-year risk is 2.2 percent for 50-year-old black women, 2.0 percent for Asian women, and 1.7 percent for Hispanic women. For 70-year-olds, the 10-year risks are 3.9 percent for white women, 3.2 percent for black women, and 2.4 percent for both Asian and Hispanic women. Estimates for longer follow-up periods (e.g., 20 or 30 years) will only increase those risks. Within average values such as these, there are always groups of women whose particular charac- teristics give them a higher or lower 10-year risk. These estimates of risk are a critical reference point for understanding the implications of findings from epidemiologic studies on factors associ- ated with increased or decreased risk of breast cancer. These findings are typically reported in terms of relative risk, which reflects a comparison between the risk in a population exposed to a particular factor and that in a similar population that is not exposed. Thus, a relative risk of 2.0 (a doubling of risk) might mean that for women with that risk factor, the 10-year risk of breast cancer is 5 percent rather than 2.5 percent. Similarly, a relative risk of 0.5 for a protective factor means that women with that characteristic may have a 10-year risk of 1.3 percent rather than 2.5 per- cent. These examples are offered to illustrate the scale of the change in risk implied by typical epidemiologic findings; they are not a formal analysis. From a public health perspective, another important piece of informa- tion is the prevalence of the risk factor in the population. Finding that an environmental factor is associated with a large relative risk may still mean that it accounts for few cases of disease if the disease or the exposure is rare in that population. Alternatively, an environmental exposure that is associated with only a small increase in risk may be contributing to a large number of cases if the exposure is very common in the population. How- ever, if the exposure is so common that there is little variability across the population (virtually everyone is exposed), it can be extremely difficult to identify the contribution from that exposure. Virtually all of the epidemiologic evidence regarding breast cancer risk is drawn from population-level analyses. As a result, the conclusions reached on the basis of that evidence apply to an exposed population. With current knowledge, it is not possible to apply those conclusions to predict which individuals within that population are most likely to develop breast cancer. Nevertheless, an understanding of population-based estimates of risk can help people make personal choices that may lead to better health outcomes.
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33 INTRODUCTION TOPICS BEYOND THE SCOPE OF THE STUDY Several topics were defined as falling beyond the scope of the study. With the focus on environmental risk factors for breast cancer, the commit- tee chose to devote little attention to the established associations between increased risk for breast cancer and reproductive events such as younger age at menarche, older age at first birth, lack of lactation, and older age at menopause. The committee also chose not to evaluate the established asso- ciations between breast cancer risk and higher birth weight and attained stature. Although some of them might fall under the committee’s very broad definition of environmental factors, they were not the focus of its review. Background is provided on many of these other factors in Chapter 2, and the possibility that some environmental exposures may have an indirect influence on risk for breast cancer because they may affect the timing of these reproductive events is discussed in Chapter 5. The committee also agreed that the nature and effectiveness of breast cancer screening, diagnosis, and treatment were generally beyond the scope of the study. It noted but did not analyze the impact of increased mammog- raphy and changes in screening practices since the 1970s on the observed incidence of breast cancer. The paper commissioned by the committee on medical sources of exposure to ionizing radiation took into account the contribution of mammography. The committee did not examine the appro- priateness of screening recommendations or practices. The committee decided as well that its charge called for a focus on risk for the initial occurrence of breast cancer and not on recurrence or factors that might be associated with the risk of recurrence. Although envi- ronmental exposures may well influence the risk of recurrence, that risk is also influenced by characteristics of tumors at the time of diagnosis and subsequent treatment and follow-up practices. Consideration of clinical practice in the treatment of women (and men) with diagnosed breast can- cers is substantially different from the study’s primary focus on prevention of breast cancer through improved understanding of and response to envi- ronmental risks. Similarly, the committee concluded that its charge called for a focus on the incidence of breast cancer and not mortality. Influences on breast cancer mortality patterns include factors that affect diagnosis and treatment that are separate from the effects of environmental exposures on the incidence of the disease. The committee did not explicitly assess environmental risk factors for male breast cancer, beyond the general assumption that some of the risk factors identified through studies in women may also be relevant to the development of breast cancer in men.
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34 BREAST CANCER AND THE ENVIRONMENT THE COMMITTEE’S REPORT This report reviews the current evidence on the biology of breast cancer, examines the challenges of studying environmental risk factors, and pres- ents the committee’s findings and research recommendations from its review of evidence on environmental risk factors. Specifically, Chapter 2 provides important background for evaluating factors influencing breast cancer risk with a brief review of the biology of breast cancer and trends in incidence in the United States, along with discussion of the kinds of studies used to investigate breast cancer and environmental exposures. Chapter 3 presents the committee’s review of evidence on selected environmental risk factors. Chapter 4 discusses the variety of challenges that complicate the study of environmental risk factors for breast cancer, as well as gene–environment interactions. Chapter 5 examines mechanisms of carcinogenesis and links them to a life course perspective on breast development and the potential for environmental factors to influence risk for breast cancer. In Chap- ter 6, the committee examines opportunities for evidence-based action to reduce risks for breast cancer and also considers the challenges of avoid- ing the unintentional introduction of new risks. Chapter 7 concludes the report with the committee’s recommendations for future research efforts. Included as appendixes are agendas for the committee’s public sessions (Appendix A), biographical sketches of committee members (Appendix B), a summary of weight-of-evidence categories used by major organizations that evaluate cancer risks (Appendix C), a table summarizing reports of population attributable risks for breast cancer (Appendix D), a glossary (Appendix E), and the paper commissioned on exposure to ionizing radia- tion (Appendix F). REFERENCES ACS (American Cancer Society). 2009. Breast cancer facts and figures 2009–2010. Atlanta, GA: ACS. http://www.cancer.org/Research/CancerFactsFigures/BreastCancerFactsFigures/ index (accessed November 17, 2010). ACS. 2011. Breast Cancer facts and figures 2011–2012. Atlanta, GA: ACS. http://www.cancer. org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-030975. pdf (accessed November 15, 2011). Baralt, L. B., and S. McCormick. 2010. A review of advocate–scientist collaboration in fed- erally funded environmental breast cancer research centers. Environ Health Perspect 118(12):1668–1675. Bissell, M. J., and W. C. Hines. 2011. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17(3):320–329. Brody, J. G., K. B. Moysich, O. Humblet, K. R. Attfield, G. P. Beehler, and R. A. Rudel. 2007. Environmental pollutants and breast cancer: Epidemiologic studies. Cancer 109(12 Suppl):2667–2711.
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35 INTRODUCTION California Breast Cancer Research Program. 2007. Identifying gaps in breast cancer research: Addressing disparities and the roles of the physical and social environment. http://cbcrp. org/sri/reports/ identifyingGaps/index.php (accessed October 25, 2011). Farhat, G. N., R. Walker, D. S. Buist, T. Onega, and K. Kerlikowske. 2010. Changes in inva- sive breast cancer and ductal carcinoma in situ rates in relation to the decline in hormone therapy use. J Clin Oncol 28(35):5140–5146. Loeb, L. A., and S. Nishimura. 2010. Princess Takamatsu Symposium on DNA repair and human cancers. Cancer Res 70(11):4269–4273. NCI (National Cancer Institute). 2010. SEER cancer statistics review, 1975–2007. Edited by S. F. Altekruse, C. L. Kosary, M. Krapcho, N. Neyman, R. Aminou, W. Waldron, J. Ruhl, N. Howlader, Z. Tatalovich, H. Cho, A. Mariotto, M. P. Eisner, D. R. Lewis, K. Cronin, H. S. Chen, E. J. Feuer, D. G. Stinchcomb, and B. K. Edwards. Bethesda, MD: NCI. http://seer.cancer.gov/csr/1975_2007/ (accessed January 6, 2011). NCI. 2011. SEER cancer statistics review, 1975–2008. Edited by N. Howlader, A. M. Noone, M. Krapcho, N. Neyman, R. Aminou, W. Waldron, S. F. Altekruse, C. L. Kosary, J. Ruhl, Z. Tatalovich, H. Cho, A. Mariotto, M. P. Eisner, D. R. Lewis, H. S. Chen, E. J. Feuer, K. A. Cronin, and B. K. Edwards. Bethesda, MD: NCI. (Based on November 2010 SEER data submission, posted to the SEER website, 2011.) http://seer.cancer.gov/ csr/1975_2008/ (accessed June 1, 2011). Ravdin, P. M., K. A. Cronin, N. Howlader, C. D. Berg, R. T. Chlebowski, E. J. Feuer, B. K. Edwards, and D. A. Berry. 2007. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 356(16):1670–1674. Rudel, R. A., K. R. Attfield, J. N. Schifano, and J. G. Brody. 2007. Chemicals causing mam- mary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention. Cancer 109(12 Suppl):2635–2666. WCRF/AICR (World Cancer Research Fund/American Institute for Cancer Research). 2007. Food, nutrition, physical activity, and the prevention of cancer: A global perspective. Washington, DC: AICR. Writing Group for the Women’s Health Initiative Investigators. 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333.
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