3

What We Have Learned from
Current Approaches to Studying
Environmental Risk Factors

As one of its tasks, the committee was asked to review and assess the strength of the science base regarding the relationship between breast cancer and the environment. This body of evidence has evolved over many years through diverse fields of inquiry, including epidemiologic investigations, experimental studies in laboratory animals, and in vitro laboratory research on questions at the molecular, genetic, cellular, and tissue levels. Indeed, since the rise in breast cancer diagnoses that became particularly steep around 30 years ago, tremendous efforts have been made to identify the causes.

In this chapter the committee reviews approaches to assessing evidence concerning risk for breast cancer, summarizes the existing evidence on a selection of factors, and offers its assessment of the implications of the evidence. For many of the environmental risk factors, the results of the committee’s review are far from conclusive. Reasons for the continuing gaps in knowledge are numerous. Chapter 4 discusses some of the challenges to studying causes of breast cancer and why the existing evidence permits few definitive conclusions. In some cases, recent advances using more sensitive tools to examine the pathobiology of breast cancer can be expected to provide new models for research in humans, animals, and in vitro systems.

Although the results of newer approaches to research on risk factors for breast cancer are promising, the extant literature is primarily grounded in older technologies and approaches. In light of this transitional state of the science, the committee nevertheless faced the question, what has been possible to discern from the work done so far? Here the committee outlines the scope of its review, describes evidentiary standards that have been used



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3 What We Have Learned from Current Approaches to Studying Environmental Risk Factors A s one of its tasks, the committee was asked to review and assess the strength of the science base regarding the relationship between breast cancer and the environment. This body of evidence has evolved over many years through diverse fields of inquiry, including epi- demiologic investigations, experimental studies in laboratory animals, and in vitro laboratory research on questions at the molecular, genetic, cellular, and tissue levels. Indeed, since the rise in breast cancer diagnoses that became particularly steep around 30 years ago, tremendous efforts have been made to identify the causes. In this chapter the committee reviews approaches to assessing evidence concerning risk for breast cancer, summarizes the existing evidence on a selection of factors, and offers its assessment of the implications of the evidence. For many of the environmental risk factors, the results of the committee’s review are far from conclusive. Reasons for the continuing gaps in knowledge are numerous. Chapter 4 discusses some of the challenges to studying causes of breast cancer and why the existing evidence permits few definitive conclusions. In some cases, recent advances using more sensitive tools to examine the pathobiology of breast cancer can be expected to provide new models for research in humans, animals, and in vitro systems. Although the results of newer approaches to research on risk factors for breast cancer are promising, the extant literature is primarily grounded in older technologies and approaches. In light of this transitional state of the science, the committee nevertheless faced the question, what has been possible to discern from the work done so far? Here the committee outlines the scope of its review, describes evidentiary standards that have been used 73

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74 BREAST CANCER AND THE ENVIRONMENT by leading authoritative bodies, and reviews the evidence on a selected set of risk factors. SCOPE OF THE REVIEW As discussed in Chapters 1 and 2, the committee adopted a broad definition of “environment” that includes all factors not directly inherited through DNA. In selecting environmental factors for examination, the committee took into account several considerations, including variety in the types of potential risk factors and routes of exposure, availability of evidence for review, and indications of public concern. From the enor- mous list of candidates, the committee selected a limited set of factors in order to illustrate a variety of environmental exposures, and to emphasize the need for new approaches to investigate and increase the knowledge base of potential environmental risks for breast cancer. With an evolving understanding of the mechanisms for cancer development and concern about whether the right questions have yet been asked or asked using appropriate study designs, the committee saw limited value in a full review of evidence for an extensive list of environmental factors that is available from a number of other sources (e.g., International Agency for Research in Cancer [IARC], the World Cancer Research Fund/American Institute for Cancer Research [WCRF/AICR], the U.S. Environmental Protection Agency [EPA], and the National Toxicology Program [NTP]), nor was it feasible for the present study. Of the large number of environmental factors with poten- tial but uncertain impact on breast cancer, the committee reviewed only a selected number that illustrated particular types of challenges in assess- ment. For example, the committee evaluated factors for which extensive epidemiologic evidence and systematic reviews were available (e.g., alcohol consumption), and it also reviewed chemicals for which studies evaluating breast cancer in humans were very limited (e.g., bisphenol A). Little attention was given to several very familiar topics, such as dietary fat and micronutrients, that are receiving ongoing systematic review by other organizations. The committee also chose not to include established reproductive risk factors, such as age at menarche or first full-term preg- nancy, and anthropometric features such as birthweight or attained height in its review of environmental factors. These risk factors have also received considerable attention elsewhere. In Chapter 7 the committee has included recommendations for additional research to confirm the appropriateness of using alterations in such reproductive and anthropometric intermediate endpoints as valid and reliable markers of alterations in risk for breast cancer.

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75 WHAT WE HAVE LEARNED FROM CURRENT APPROACHES Process for the Evidence Review Given the scope and time line of the committee’s study, it was not feasible to carry out formal, systematic reviews of the scale or depth of those carried out by the WCRF/AICR, IARC, or the Cochrane Collabora- tion. Such reviews entail examination of the results of exhaustive literature searches and extensive documentation.1 The committee found that given the changing science and the apparent gaps in the evidence base, it could most fruitfully apply its efforts in reviewing and speaking to a larger picture in the science of breast cancer and the environment. The committee’s process for its review of the evidence was as follows: The committee turned first to the conclusions available from the extensive reviews by authoritative groups (WCRF/AICR, 2007, 2008, 2010; EPA, 2011b; IARC, 2011; NTP, 2011a). Where the results of a systematic review were available for particular risk factors, the committee preferentially drew on these resources. These sources were supplemented by review of addi- tional literature identified by committee members and staff and in targeted searches by an Institute of Medicine (IOM) research librarian. The targeted searches on the committee’s selected risk factors discussed in this chapter used the PubMed and Embase databases in searches of the peer-reviewed, English-language literature published between January 2000 and October 2010, expecting that literature available before 2000 had been extensively reviewed by other authoritative reviews or subsequent publications. The searches were designed to identify literature on breast cancer in humans, mammary neoplasms in animals, and related in vitro and mechanistic stud- ies. The process was supplemented by testimony from advocates, expert scientists, and members of the public. Committee members examined these resources to evaluate the strength of the science base regarding the association of a given risk factor with breast cancer. Hierarchy of Studies Widely used standards of evidence for identifying and evaluating hazards or risks from potential carcinogens share several features. They 1 For example, the WCRF/AICR review released in 2007, Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective, took place over 6 years (WCRF/AICR, 2007, Appendix A, p. 396). It required the work of an expert task force to develop the sys- tematic review methodology, and methods testing at two centers. Next, research teams at nine institutions in Europe and North America carried out systematic literature reviews. Finally, a panel of experts worked to assess the evidence and agree on recommendations. Since then, the Continuous Update Project has been following scientific developments in this field. Its updates capture new evidence since the last systematic literature review to permit review and meta-analysis (WCRF/AICR, 2010).

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76 BREAST CANCER AND THE ENVIRONMENT typically rely only on published and peer-reviewed literature, and they ultimately reach conclusions about factors/agents based on the relevant studies, the strength of the results, and the coherence and plausibility of the evidence base. By virtue of their design, certain study types are given greater weight based on their relevance and freedom from bias. Randomized controlled trials have an experimental design and, when well conducted, are considered the strongest form of epidemiologic study for directly determining causal associations between interventions or expo- sures and health outcomes. As discussed further in Chapter 4, randomiza- tion for many environmental exposures would be unethical or not feasible. In research on suspected environmental hazards, which is the focus of the committee’s work, most epidemiologic studies are observational rather than experimental. Observational studies evaluate the exposures to the factor of interest as they take place in the real world, not based on intervention by any scientist. Thus, the determination of who is and who is not exposed may be related to marketing practices; changes in formulations, regulations, and laws (e.g., for emissions into air, water, or soil, or for chemicals to be used in manufacture of consumer products) at the federal, state, or local level; disposal practices; and personal choices about consumer product use, or behaviors (eating pesticide-free produce or not; leaving windows open to ventilate home). Observational studies can be informative when the comparison populations are appropriately defined and sufficient attention is given to exposure assessment and to confounding.2 Other characteristics of observational studies that influence their validity are discussed in Chapter 4. In addition to experimental (when available) and observational epi- demiologic studies in humans, the committee drew on information from experimental studies in animals and studies carried out in vitro (in cells or tissues, rather than a whole organism) to inform its assessment of risk fac- tors for breast cancer. As discussed in Chapter 4, these studies are powerful tools for exploring possible health effects, mechanisms of action, and the biologic plausibility of a factor’s association with a change in risk for breast cancer. The literature review included reports from experimental studies in animals conducted for regulatory purposes as well as from studies by researchers. Categories of Evidence Several organizations have developed methods and criteria to classify the strength of evidence for the carcinogenicity of an exposure or to con- vey the strength of an association between a risk factor and a particular 2Confounding can occur when an exposure variable and the disease outcome are both related to one or more other variables not being studied. It is discussed further in Chapter 4.

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77 WHAT WE HAVE LEARNED FROM CURRENT APPROACHES health effect. The criteria aim to be explicit about the weight, or relative importance, given to studies in humans and in animals or other experi- mental systems. For example, IARC, EPA, NTP, and the WCRF/AICR each have a set of categories and approaches to applying them that reflect their work to classify potential carcinogens or risk factors. These classification schemes are developed under different mandates and missions with regard to their role in informing decision making. Designations by IARC, NTP, and WCRF/AICR are qualitative and do not attempt to quantify risk in relation to dose, whereas EPA carries out more quantitative evaluations. Various IOM committees have also developed qualitative systems of clas- sification of evidence for their work in evaluating associations between exposures and outcomes (e.g., IOM, 1991, 2001, 2010, 2011). The IARC, EPA, and NTP classification systems focus on identifying substances that may pose a cancer hazard; that is, whether a given sub- stance is “capable of causing cancer under some circumstances” (IARC, 2006b). These systems work first by separately evaluating and rating the three types of evidence—human, animal, and other relevant data, such as from cell cultures—in categories such as “sufficient evidence in animals” or “limited evidence in humans.” Second, the three evidence streams are integrated to reach an overall conclusion about the potential for a substance to be a carcinogen. Terms like “known” or “possible” carcinogen are used for the overall evidence categories. The IOM, WCRF, and Cochrane reviews primarily focus on the human evidence of risk (i.e., that an exposure is asso- ciated with an adverse human health outcome) and do not go through the formal exercise of rating the animal or other relevant evidence to reach con- clusions about possible human carcinogenicity. The various IOM categories are applied to evidence for any relevant health outcome, not just cancers. Strong and consistent positive epidemiologic evidence in rigorously conducted studies is prima facie evidence that the substance is a risk fac- tor: People exposed to the agent were affected in sufficient numbers or the associated risk was sufficiently strong that it was possible to detect the breast cancer effect through epidemiologic study. There is a range of views within the scientific community as to whether strong nonhuman evidence of hazard should be a basis for concluding that a human risk exists. For- mal translation of a hazard conclusion into a risk conclusion could involve quantitative evaluations of a number of factors, including the extent of the population that is exposed to the factor in question; the magnitude of exposure for specific segments of the population; and the extent to which the exposure to the substance accumulates with other exposures to pose risk to the population. But experimental evidence in nonhuman species or in vitro systems can indicate that the substance is a possible, biologically plausible risk factor, given sufficient dose at a relevant time. At present, in

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78 BREAST CANCER AND THE ENVIRONMENT the absence of adequate human data, nonhuman evidence of hazard is used as the basis for regulatory decision making. A critical difference among the categories and approaches used by IARC, EPA, NTP, IOM, and WCRF/AICR is the role that data from experi- mental studies in animals and studies employing in vitro systems using human or other cell lines play in determining the category for a substance. Full descriptions of the classifications used by IARC, EPA, NTP, IOM studies of Gulf War exposures, and WCRF are provided in Appendix C. For each organization, strong and convincing evidence from human epide- miologic studies is a basis for concluding that a substance or risk factor is causally associated with human cancer. WCRF includes in its criteria for “convincing causal relationship” that there be strong experimental evidence from human or animal studies that typical human exposure can lead to rel- evant cancer outcomes.3 In rare circumstances (“exceptionally”) under the EPA, NTP, and IARC schemes, very strong animal and mechanistic evidence (EPA and IARC) or strong human mechanistic evidence (NTP) can lead to a conclusion that a substance causes human cancer when definitive epide- miologic evidence is absent. Also in those schemes, strong experimental evi- dence alone can lead to a finding that a substance is probably or possibly a human carcinogen. In one case (EPA), suggestive animal evidence is treated as suggestive evidence of carcinogenic potential. In contrast, the approach used in several IOM studies focuses on evaluating the strength of human data, using animal and in vitro studies only as supplemental evidence for considering the biologic plausibility of observed epidemiologic associations in making determinations about causality. The classifications used by this committee take elements from systems used by IOM, IARC, and EPA. The committee chose to use terms that more explicitly identify the relative strengths of the epidemiologic data for point- ing out known and probable risk factors being evaluated, along the lines of approaches used by IOM committees. Factors for which epidemiologic evidence shows a consistently positive association with breast cancer that is not explained by bias or confounding and that falls outside the realm of chance are considered as “risk factors” for breast cancer. Thus, because epidemiologic studies by their very nature include consideration of human exposures, they are able to observe “risk,” not just “hazard.” In contrast, mechanistic and animal studies address “hazard” (the potential to cause an effect), but are not observations of human “risk factors.” As noted above, other steps are needed to make judgments about whether substances identi- 3 Experimental evidence must fall into the WCRF/AICR (2007) Class I category, either in vivo data from studies using human volunteers, genetically modified animal models related to human cancer (e.g., gene knockout or transgenic mouse models), or rodent cancer models designed to investigate modifiers of the cancer process.

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79 WHAT WE HAVE LEARNED FROM CURRENT APPROACHES fied experimentally in animals or in vitro as cancer hazards should be con- sidered risk factors. However, analogous to IARC and EPA, the committee indicated in certain instances that it is possible or biologically plausible that certain substances are risk factors for breast cancer. The committee’s criteria thus reflect the important differences between studies that observe risk factors in human populations and those that evaluate hazard potential. The committee chose these criteria in part because of its mandate to consider potential evidence-based actions that women could take to reduce their risk of breast cancer. It was conscious of a wish to note “risk factors” and distinguish them from hazards, as described above. After careful consideration, the committee chose to convey its assess- ments of the literature using broad groupings that reflect very generally the state of the evidence available. For example, for a factor for which compel- ling evidence from studies in humans, often distilled by others’ systematic reviews, shows it to be an established risk factor for breast cancer, the com- mittee used the designation assigned by the systematic reviews. Similarly, the committee noted as “probable” breast cancer risk factors those with strong but not definitive evidence from epidemiologic studies, sometimes with supporting evidence from animal or in vitro models. Factors that did not fall into these categories were reviewed and dis- cussed in terms of the need for additional questions to be answered, and some were flagged as possible, biologically plausible risk factors based on the hazard indicated in animal or in vitro studies or other relevant data. “Biologically plausible” meant consistent positive results for mammary tumors in animal bioassays or multiple, consistent in vitro studies demon- strating that a substance can modify a pathway or processes involved in breast carcinogenesis (e.g., modification of hormonal signaling pathways, mutagenesis of oncogenes or tumor suppressor genes, inhibition of apop- tosis of precancerous breast cells, etc.). In some instances, concerns about the potential later effects of exposures that may occur at specific (earlier or later) times of life are underscored. For other factors, addressing the remaining uncertainty was considered not to be a high priority, given the limited population exposures to the substance. In addition to reviewing the extent and strength of evidence indicat- ing an association between a particular risk factor and breast cancer (and its direction: i.e., whether it is associated with an increase or a decrease in risk), the committee also reported on additional dimensions, when informa- tion was available. For example, quantitative estimates of the size of the effect in terms of relative risk or absolute risk, and accompanying mea- sures of uncertainty in the form of confidence limits, are presented when available. The committee also noted information relevant to consideration of whether the timing of exposure influenced risk, such as the effects or associations pertaining to in utero or early-life exposures as compared with

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80 BREAST CANCER AND THE ENVIRONMENT adult exposures. Similarly, the review notes whether the exposure showed a relationship to a particular tumor type based on hormone receptor status or other molecular markers. DISCUSSION OF SPECIFIC ENVIRONMENTAL FACTORS In the remainder of the chapter the committee presents summaries describing the strength of the evidence regarding the association of its selec- tion of environmental factors with breast cancer. These factors are listed in Box 3-1 and grouped by their initial characteristic uses (e.g., industrial chemicals), route of exposure (e.g., ingestion of diet-related substances), or other features. Some of the substances reviewed by the committee are mixtures or classes of chemicals (e.g., tobacco smoke, polychlorinated biphenyls [PCBs]) and others are single chemicals (e.g., ethylene oxide). In either case, the committee typically focused on the literature on that specific mixture, class, or single chemical. It generally did not attempt to evaluate the evidence on interactions among risk factors but recognized that this is an important area to address in advancing knowledge in the field. These groupings and labels are not definitive; different groupings or group labels may be used when these factors are discussed by others. Also, many additional factors that were not reviewed by the committee could be included in several of these groups; the committee’s assessments concern only the specific factors listed. The committee frequently uses relative risks (RRs) or similar measures in reporting evidence regarding the size of the association or effect for a given risk factor. A relative risk is an estimate of comparative risk derived from a defined population exposed to the factors, compared to an unex- posed group. These measures of association do not convey the absolute risk that may be experienced by any one individual or group of individuals exposed to the factors. Chapters 2 and 6 describe these measures of risk further. Exogenous Hormones As described in Chapter 2, the breast is a hormonally responsive organ, and the majority of breast cancer that occurs responds to hormonal therapy. Thus it is no surprise that hormonal risk factors have been a major focus of breast cancer research. Prospective cohort studies have clearly shown an association between endogenous estrogen levels and development of breast cancer (Key et al., 2002). Because many of the established risk factors, such as age at menarche and age at first birth, are related to changes in the endogenous hormonal milieu, it was plausible to anticipate that exogenous factors that influence endogenous hormone levels may have an impact on

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81 WHAT WE HAVE LEARNED FROM CURRENT APPROACHES BOX 3-1 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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82 BREAST CANCER AND THE ENVIRONMENT breast cancer incidence. Although much of the focus has been on influences specifically of estrogen, prospective studies have also shown an association with androgen concentrations and the risk of breast cancer (Helzlsouer et al., 1992; Key et al., 2002; Tworoger et al., 2006). Many factors are thought to affect breast cancer by influencing endogenous hormone levels. Exogenous hormone use is an obvious factor to consider in relation to breast cancer. Exogenous hormone use by women is fairly common. The oral contra- ceptive pill was the leading method of contraception in the United States in 2006–2008, used by 10.7 million women (Mosher and Jones, 2010). Use of hormone therapy (HT) for relief of menopausal symptoms has also been widespread, but it has changed as findings have emerged about health risks associated with these products (Haas et al., 2004; Hersh et al., 2004). In a 1995 telephone survey of U.S. households (Keating et al., 1999), cur- rent use of menopausal hormone therapy was reported by 37.6 percent of women participating. National Health Interview Survey data from 2008 (DeSantis et al., 2011) report rates of combination HT use for women ages 50 and older of 0.9 to 2.8 percent, depending on race and ethnicity, and of estrogen-only HT from 2.1 to 5.9 percent, depending on race and ethnicity. Evaluating the hormonal effects of exogenous hormone sources, such as oral contraceptives and hormone therapy, is challenging because of the use of a variety of single or combined hormone preparations and a multitude of dosages and delivery schedules. Additionally, hormones have differential effects on hormonally responsive tissue such as the ovaries, endometrium, and breast. Oral contraceptives are mostly combined hormonal prepara- tions of estrogen and progestins and have been classified by IARC (2007) as Group I carcinogens; however, the effects are not consistent across all cancer types. Oral contraceptives modestly increase the risk of breast cancer among current users, as indicated by the Nurses’ Health Study II (multi- variate RR = 1.33, 95% CI, 1.03–1.73) (Hunter et al., 2010), but this risk dissipates 4 years following cessation. On the other hand, oral contracep- tives are associated with a long-term reduced risk of endometrial and ovar- ian cancers. The overall evaluation by IARC reflects this mixed risk profile: “Combined oral estrogen–progestogen contraceptives are carcinogenic to humans (Group 1). There is also convincing evidence in humans that these agents confer a protective effect against cancer of the endometrium and ovary” (IARC, 2007, p. 175). IARC has also classified combined estrogen and progestin postmeno- pausal HT as “carcinogenic to humans” (Group 1). Data from randomized controlled clinical trials (19 trials involving 41,904 women) have shown that combined long-term menopausal hormone therapy with estrogen and progestins is associated with a significantly increased risk of breast cancer (Farquhar et al., 2009). The largest controlled clinical trial of combined

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83 WHAT WE HAVE LEARNED FROM CURRENT APPROACHES postmenopausal HT with estrogen and progestin was the Women’s Health Initiative (WHI), a 5-year randomized trial that was stopped early due to lack of a global health benefit with hormone therapy (Writing Group for the Women’s Health Initiative Investigators, 2002). After a mean of 5 years, the RR of invasive breast cancer among the combined HT group compared with the placebo was 1.26 (95% CI, 1.02–1.56). This risk translates into an absolute excess of 8 cases of invasive breast cancer per 10,000 person- years attributed to estrogen and progestin (Writing Group for the Women’s Health Initiative Investigators, 2002). After stopping combined hormone therapy, the excess risk declined (Chlebowski et al., 2009) in a manner similar to that observed after stopping combined oral contraceptive therapy. A rapid decline in breast cancer rates has been observed in the United States and several other countries following release of the WHI trial results (DeSantis et al., 2011; NCI, 2011) concomitant with declines in prevalence of combination HT use or prescriptions. The effects of estrogen-only postmenopausal hormone therapy on breast cancer risk are not as clear as those of combined estrogen–progestin therapy. While estrogen-only therapy has been associated with a modestly increased risk of breast cancer in prospective cohort studies (Beral et al., 2011), this observation was not supported in the large randomized con- trolled clinical trial of estrogen-only therapy among women who had a hysterectomy (Anderson et al., 2004; LaCroix et al., 2011). The inconsis- tency in the findings between the observational study and the randomized controlled trial may imply some heterogeneity across subgroups in the population. Or, it may be partially due to misclassification of women in the observational study as taking only estrogen when they may have taken combined estrogen–progestin therapy at some point in their treatment. In addition, the timing of therapy with respect to onset of menopause may influence the magnitude of risk. In the Million Women Study, women initiating estrogen-only HT more than 5 years after menopause had little or no increase in risk of breast cancer, while those initiating therapy before or within 5 years of onset of menopause had an excess risk of breast cancer compared to never users of hormones (Beral et al., 2011). In the WHI estrogen-only trial, women taking estrogen-only hormone therapy had a decreased risk of breast cancer that was not statistically significant. The magnitude of risk, after a mean follow-up of 7 years, was an RR of 0.77 (95% CI, 0.59–1.01), which would translate to a reduction of 26–33 breast cancers per 10,000 person- years (Anderson et al., 2004). In subsequent follow-up the decreased risk of breast cancer persisted and, when considering the intervention and follow-up periods, was statistically significant (LaCroix et al., 2011). It is important to note that women in the estrogen-only arm of the WHI did not have a uterus and therefore were not at risk for endometrial cancer, which

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