2

Background, Definitions, Concepts

The committee’s examination of breast cancer and the environment required considerations at the intersection of diverse fields, including the biology and epidemiology of breast cancer, the identification of carcinogens and cancer-promoting agents, exposure assessment, toxicity and carcinogenicity testing, and the design and interpretation of research studies. This chapter provides some brief, fundamental background on these topics as a basis for the discussions in subsequent chapters.

AN INTRODUCTION TO BREAST CANCER

The breast begins forming during the prenatal period and undergoes substantial changes during adolescence and adulthood. Breast cancer arises when abnormal cellular growth occurs in certain structures and types of cells within the breast.

Although breast cancer is often spoken of as if it were a single disease, evolving techniques of analysis of the molecular characteristics of tumors are pointing to a variety of types of potentially differing origins. Gaining a better understanding of the nature of the heterogeneity of breast cancer will be critical in helping researchers improve the design and interpretation of studies of possible risk factors, and it may influence approaches to prevention.

Described here are the basics of the anatomy of the breast and breast development, types of breast cancer, and levels and trends in the incidence of the disease, focusing primarily on experience in the United States. The mechanisms that appear to result in female breast cancers and the pathways



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2 Background, Definitions, Concepts T he committee’s examination of breast cancer and the environment required considerations at the intersection of diverse fields, including the biology and epidemiology of breast cancer, the identification of carcinogens and cancer-promoting agents, exposure assessment, toxicity and carcinogenicity testing, and the design and interpretation of research studies. This chapter provides some brief, fundamental background on these topics as a basis for the discussions in subsequent chapters. AN INTRODUCTION TO BREAST CANCER The breast begins forming during the prenatal period and undergoes substantial changes during adolescence and adulthood. Breast cancer arises when abnormal cellular growth occurs in certain structures and types of cells within the breast. Although breast cancer is often spoken of as if it were a single disease, evolving techniques of analysis of the molecular characteristics of tumors are pointing to a variety of types of potentially differing origins. Gaining a better understanding of the nature of the heterogeneity of breast cancer will be critical in helping researchers improve the design and interpreta- tion of studies of possible risk factors, and it may influence approaches to prevention. Described here are the basics of the anatomy of the breast and breast development, types of breast cancer, and levels and trends in the incidence of the disease, focusing primarily on experience in the United States. The mechanisms that appear to result in female breast cancers and the pathways 37

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38 BREAST CANCER AND THE ENVIRONMENT BOX 2-1 B reast Cancer in Men Approximately 1 percent of breast cancer cases occur in men, and less than 1 percent of men’s cancer diagnoses are for breast cancer (ACS, 2011b). Because it is rare, breast cancer in men has been difficult to study. Based on what is known, however, it is considered to resemble breast cancer in postmenopausal women (Korde et al., 2010). As in women, men’s breasts respond to changes in sex hormone concentrations (both estrogens and androgens), but under normal cir- cumstances they do not undergo the differentiation and lobular devel- opment that women’s breasts experience with puberty, pregnancy, and lactation (Johansen Taber et al., 2010). Either an excess of estrogens or deficit of androgens appears to increase risk of breast cancer in men (Korde et al., 2010). Beginning after age 20, rates rise steadily with age. Approximately 92 percent of male breast cancers are estrogen receptor positive, compared with approximately 78 percent of breast cancers in women (Anderson et al., 2010). As is the case for women, inherited mu- tations in BRCA1 and especially BRCA2, as well as other mutations, are associated with an increased risk of male breast cancer, but the majority of cases are not associated with a family history of the disease (Korde et al., 2010). along which they operate are one of the main topics in Chapter 5. A brief description of breast cancer in men is provided in Box 2-1. The Breast, Breast Development, and Breast Cancer The development of the human female breast begins during gestation but is not complete at the time of birth. Further development and differen- tiation of breast tissue occurs over time and especially in response to fluctu- ating estrogen and other hormonal signals beginning in puberty, continuing through the reproductive years, during pregnancy and lactation, and at menopause. Monthly ovulatory cycles are accompanied by cyclical changes in the form and behavior of cells and structures in the breast, including progressive differentiation. Pregnancy and lactation trigger maximal dif- ferentiation of the breast. When pregnancy and lactation end, as well as at menopause, breast tissue regresses to a less differentiated state. Within the breast are adipose and connective tissues that surround multiple collections of lobules in which milk is produced during lactation. Milk moves to the nipple through ductal structures. The ducts are lined by luminal epithelial cells and have an outer layer of myoepithelial cells. Popu-

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39 BACKGROUND, DEFINITIONS, CONCEPTS lations of stem cells that can give rise to either luminal or myoepithelial cells are also found in the ductal tissue. The ducts are anchored to a basement membrane, which contributes to both the structure and the function of the ductal tissue. Connective tissue within and between the lobules, known as the stroma, further contributes to the structure of the breast and plays an important role in regulating both normal and abnormal breast cell growth and function (Arendt et al., 2010). Cell types within the stroma include (but are not limited to) fibroblasts, adipocytes, macrophages, and lympho- cytes (Johnson, 2010). These cells and structures in the breast generate and respond to a diverse mix of hormones, especially estrogen, and other regulatory factors. Certain disruptions in the complex processes that govern the structure and function of breast tissue may set the stage for breast cancer. Some carcinogenic events occur spontaneously in the course of normal biological processes and others are triggered by external factors. Although the body has efficient protective responses, such as DNA repair and immune surveil- lance, that can reduce the effect of such events, these protective responses are not always successful. The interval between the earliest “event” and the detection of a cancer may span several decades. Specific mechanisms that may play a role in breast cancer are noted here but discussed further in Chapter 5. The contribution of genetic mutations to cancer is well known. They may be inherited (e.g., germline mutations in the BRCA1 or BRCA2 genes, which normally have a role in DNA repair) or develop in some cells during a person’s lifetime (somatic mutations) as a result of reactive by-products of normal biological processes, or from the effects of external exposures. Other mechanisms include epigenetic changes that can alter gene expression without changes to DNA, promotion of cell growth by estrogen and other hormones or cell-signaling proteins, and eva- sion of the immune system. Types of Breast Cancer Most commonly, breast cancers develop in the ducts, but cancers also develop in the lobules or take other forms. Several systems are used to characterize breast cancers, with the systems developed primarily to provide information on prognosis and treatment decisions. For example, breast tumors may be classified by tumor size, extent of spread beyond the tumor site (localized, regional, distant), the anatomical characteristics of the tumor cells (e.g., ductal or lobular histology), and the molecular features of the tumor cells, such as presence or absence of estrogen and progesterone recep- tors and human epidermal growth factor receptor 2 (HER2/neu). The age at which a woman is diagnosed with breast cancer is associated with tumor characteristics, such as the likelihood that the breast cancer

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40 BREAST CANCER AND THE ENVIRONMENT is estrogen receptor positive or negative (ER+ or ER–). In addition, age or menopausal status also guides treatment decisions. For example, aro- matase inhibitors are part of treatment for postmenopausal women who have ER+ breast cancers, but tamoxifen is used among premenopausal women. Except for reference to menopausal status, breast cancers in men are characterized in similar ways. Differences in patterns of such features as tumor histology, grade, and receptor status may distinguish between a more aggressive form of breast cancer with a generally earlier onset and a more common and less aggressive form that tends to occur at older ages (see Anderson et al., 2006b, 2007; Kravchenko et al., 2011). Another major distinction is between invasive and noninvasive (or in situ) tumors. As the terms suggest, invasive tumors spread beyond the site at which they arise, while in situ tumors remain within the tissue where they originate, such as the epithelial cells lining the breast ducts. About 20 per- cent of reported tumors are noninvasive (ACS, 2011a). Ductal carcinoma in situ (DCIS) is the most common form of abnormal but noninvasive growth in the breast. Although DCIS can, in some cases, progress to an invasive cancer, the natural history of these tumors is poorly understood, and it is not yet possible to identify which ones are likely to progress (Allred, 2010). As a result, most women with in situ tumors receive treatment that is simi- lar to the treatment for early-stage invasive tumors. Estrogen and Progesterone Receptor Status The molecular and genetic characteristics of breast tumors are used to guide treatment and assess prognosis. A feature for which breast tumors are now commonly evaluated is whether the cells express estrogen or progester- one receptors. Tumors that express these receptors are designated ER+ or PR+, and those that do not as ER– or PR–. In the United States, approxi- mately 75 percent of invasive tumors for which receptor status is reported are ER+ and 65 percent are PR+ (Ries and Eisner, 2007; Kravchenko et al., 2011). ER+ and PR+ tumors have a generally better prognosis than tumors that do not express these receptors. These receptor characteristics are cor- related with other tumor markers related to regulation of cell growth and proliferation and appear to reflect important differences in tumor origin (Phipps et al., 2010). Researchers are also finding that they are associated with differences in response to risk factors (e.g., Althuis et al., 2004; Yang et al., 2011). Triple Negative Breast Cancer Tumors lacking not only ER and PR expression but also HER2 are called triple negative breast cancers (TNBCs), and they are considered

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41 BACKGROUND, DEFINITIONS, CONCEPTS closely related to basal-like breast cancers (Carey et al., 2006; Foulkes et al., 2010). Triple negative breast tumors are typically aggressive and are more likely to be diagnosed in women who are younger (below age 50) and are African American. These cancers in African American women tend to be more advanced and of higher grade at the time of diagnosis than tumors in other racial groups (Carey et al., 2006; Stead et al., 2009; Trivers et al., 2009). Triple negative tumors have been associated with BRCA1 and BRCA2 mutations (Armes et al., 1999; Foulkes et al., 2003; Turner et al., 2007; Atchley et al., 2008). Additionally, a large proportion of TNBCs have altered p53 levels (Carey et al., 2006; Kreike et al., 2007; Rakha et al., 2007). Genetic Susceptibility to Breast Cancer Genetic mutations may contribute to breast cancer by altering various critical processes such as those related to DNA repair, hormone synthesis, and metabolism of carcinogens. Two types of genetic mutations are pos- sible. Germline mutations are genetic variants that are passed from parents to offspring and are present in all cells. Genetic changes can also occur in specific cells during a person’s lifetime; these changes, which can persist as cells divide, are called somatic mutations. They can arise by chance, as a by-product of normal processes such as cellular respiration or DNA rep- lication, or from external exposures. Such mutations may lead to that cell becoming a cancer cell. Inherited genetic variation is found across the population. Many of these variations, called polymorphisms, may have little or no impact on the function of a gene, but some of them are associated with increased susceptibility to disease. Common genetic variants are found in 1 percent or more of the population. Every breast cancer contains somatic genetic changes, but only a few inherited mutations are known to convey a high risk of breast cancer in the carrier. The strongest evidence of inherited genetic susceptibility is for germline mutations in the BRCA1 and BRCA2 genes. Research suggests that a larger number of lower-risk germline variants also exist. Hereditary Syndromes A family history of breast cancer is an established breast cancer risk factor. This risk factor represents both inherited genetic risks as well as environmental factors that may cluster in families. Overall an inherited susceptibility to breast cancer contributes to about 10 percent of breast cancer cases, and in about 5 percent of breast cancer cases this inherited susceptibility is attributed to mutation in the BRCA1 or BRCA2 genes.

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42 BREAST CANCER AND THE ENVIRONMENT Mutations in these two genes are associated with increased susceptibility not only for breast cancer, but also for other cancers such as ovarian cancer. BRCA1/2 mutations are high-penetrance mutations, meaning that women with these mutations have a very high lifetime risk of developing breast cancer. This risk is estimated to be at least 40 percent and possibly as high as 85 percent (Oldenburg et al., 2007). However, these mutations are rare, with substantially less than 1 percent of women in most populations carrying them (Narod and Offit, 2005). In addition to increasing the risk of breast cancer for women, they also increase risk for male breast cancer. Families in which such mutations may be present may have multiple cases of breast cancer, occurring at younger ages and in multiple generations, and a family history of ovarian cancer (Narod and Offit, 2005). Other sources of increased familial genetic risk include the Li-Fraumeni syndrome1 from germline mutations in the p53 gene (Malkin et al., 1990) and Cowden disease2 from germline mutations in the PTEN gene (Liaw et al., 1997). Genetic testing is available to identify BRCA1 and BRCA2 mutations. Identification of a familial mutation that carries an increased risk of breast cancer allows women, and men, who carry such a mutation to seek closer monitoring of their health and to consider primary and secondary preventive measures, such as increased screening, bilateral prophylactic mastectomy and, for women, bilateral salpingo-oophorectomy (Walsh et al., 2006). Use of medications that can reduce the risk of breast cancer (i.e., tamoxifen and raloxifene) may also be appropriate for some women (USPSTF, 2002). Breast Cancers in Women Without a Strong Family History Most women diagnosed with breast cancer do not have a strong fam- ily history of the disease and do not carry mutations in highly penetrant cancer-susceptibility genes. They may, however, have other more common genetic variants that affect gene function and that may be responsible for a proportion of the breast cancer cases that develop. These genetic variants are called low-penetrance variants because they are associated with only a small degree of risk for breast cancer. Yet because they are common, they may contribute to the burden of disease. In addition, these variants may interact with environmental exposures such that risk is only expressed in the presence of the environment exposure (gene–environment interaction). Two approaches have been used to identify low-penetrance genetic variants: a candidate gene approach and genome-wide association studies. 1 Li-Fraumeni syndrome is characterized by a predisposition to sarcomas, lung cancer, brain cancer, leukemia, lymphoma, adrenal-cortical carcinoma, and breast cancer. 2 Cowden disease is a syndrome involving mucocutaneous and gastrointestinal lesions and breast cancer.

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43 BACKGROUND, DEFINITIONS, CONCEPTS Studies initially relied on the candidate gene approach, in which poly- morphic variants of genes that plausibly influence breast cancer risk are assessed in epidemiologic studies (i.e., case–control or cohort studies) for their association with breast cancer. For example, the Breast and Prostate Cancer Cohort Consortium has conducted extensive analyses of genetic variation in large numbers of specific genes in biological pathways thought to be most relevant to breast cancer, such as the steroid hormone metabo- lism and insulin-like growth factor pathways (Canzian et al., 2010; Gu et al., 2010). These studies did not find an association with breast cancer risk. In general, the candidate gene approach has had limited success in consis- tently identifying specific variants associated with breast cancer. Genome-wide association studies (GWAS) allow for a comprehen - sive and unbiased search for modest associations across the genome. The approach in these studies is to identify a relatively limited set of readily recognized single nucleotide polymorphisms (SNPs) that are highly cor- related with a larger block of genetic variants and to use the limited set of “tagSNPs” in the analysis (Manolio, 2010). These studies require very large sample sizes (thousands or tens of thousands of cases and controls) because these variants tend to be associated with a small degree of risk. Because these studies make use of large numbers of statistical tests, they require extreme levels of statistical significance to identify true positive results (Hunter et al., 2008). Results from several GWAS of breast cancer in women of European ancestry have been published (Easton et al., 2007; Hunter et al., 2007; Stacey et al., 2007; Turnbull et al., 2010), and one of women of Asian ancestry (Zheng et al., 2009). Out of the many variants studied, approxi- mately 20 risk variants have been robustly associated with breast cancer risk, all having only modest influence on risk (relative risks in the range of 1.05–1.3 per allele). Stronger associations with common variants are unlikely to exist, but they may be possible for rarer variants (e.g., those with minor allele frequencies of <5 percent) that have not been tested with the technologies available to date. Even so, statistical modeling suggests that low-penetrance gene variants may do at least as well in predicting risk as using traditional risk factors such as age at first birth, family history of breast cancer, and history of breast biopsy(ies) (Wacholder et al., 2010). This is a rapidly evolving area of research. BREAST CANCER INCIDENCE IN THE UNITED STATES As noted in Chapter 1, an estimated 230,480 new cases of invasive breast cancer were diagnosed among women in the United States in 2011 and another 2,140 new cases among men (ACS, 2011a). In addition, approximately 57,650 in situ cases were diagnosed in women, of which

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44 BREAST CANCER AND THE ENVIRONMENT B OX 2-2 Data on Breast Cancer For data on patterns and trends in incidence and mortality for all forms of cancer in the United States, researchers generally rely on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. In 1973, SEER began systematic collection of data from cancer registries in sites selected to characterize the diver- sity of the U.S. population. The number of participating registries has increased, and as of 2005 covered approximately a quarter of the U.S. population (NCI, 2005). The SEER Program establishes standards for completeness and quality of the data provided to it, and it works with participating registries to achieve those standards. As practices change, new data elements may be collected. For breast cancer, for example, data on estrogen and progesterone receptor status of tumors were added in 1990 (Ries and Eisner, 2007). Annual reports present data and analysis on cancer incidence, mortality, survival, and trends since 1975. Datasets can also be made available to qualified researchers for inde- pendent analyses. States also have cancer registries, but some of these registries are less than 20 years old (CDC, 2010). Through the National Program of Cancer Registries (NPCR), which was established by federal legislation in 1992 and is administered by the Centers for Disease Control and Preven- tion, states receive assistance to improve the quality and completeness of their cancer registries. The NPCR now produces an annual report that combines data from state registries with data from the SEER program. about 85 percent were DCIS (ACS, 2011a). Sources of surveillance data on breast cancer are described in Box 2-2. Age Patterns and Changes Over Time Breast cancer can occur in women and men of any age, but it is predomi- nantly a disease of middle and older ages. Rates of invasive cancer increase rapidly after age 35 and currently peak at approximately 432 cases per 100,000 women in the age group 75–79 years (NCI, 2011) (see Figure 2-1). Rates of in situ disease rise more slowly and increase as women reach ages at which mammographic screening becomes common. The peak rate is 99 cases per 100,000 women at ages 65–69 (NCI, 2011). Among men, cases of invasive breast cancer are found at young ages, but incidence peaks at ages 85 and older at a rate of approximately 10 cases per 100,000 men (NCI, 2011). The incidence of breast cancer has increased since at least the mid- 1970s but has dropped from its peak in 1999. Figure 2-2 shows the rates

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45 BACKGROUND, DEFINITIONS, CONCEPTS Cases per 100,000 women 500 400 Invasive 300 200 In situ 100 0 <1 5-9 15-19 25-29 35-39 45-49 55-59 65-69 75-79 85+ Age at diagnosis FIGURE 2-1 Age-specific incidence rates for invasive and in situ breast cancer Figure 2-1 Age rates Invasive-InSitu.eps among women in the United States, 2004–2008. SOURCE: NCI (2011). over time for both older (age 50 and older) and younger women (ages 20–49) and for invasive and in situ cases. Among older women, rates of invasive cancer rose during the 1980s and showed a slower increase dur- ing the 1990s. During the 1980s, use of menopausal hormone therapy had increased (Hersh et al., 2004; Glass et al., 2007). The 1980s and 1990s were also a period when use of screening mammography increased (Breen et al., 2001; Anderson et al., 2006a; Glass et al., 2007). In 1987, roughly 23 to 32 percent of women were screened, depending on their age, and by 1997, screening rates were as high as 74 percent among women ages 50–64 (Breen et al., 2001). Increased screening allowed for the earlier detection of tumors and for the detection of tumors that might never have progressed. When more tumors are detected at earlier stages, it will appear as if inci- dence rates are rising even if they are not, or are rising more rapidly than they actually are.

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46 BREAST CANCER AND THE ENVIRONMENT Cases per 100,000 women 500 400 Invasive, ages 50+ 300 200 In situ, ages 50+ In situ, ages < 50 100 Invasive, ages < 50 0 1975 1980 1985 1990 1995 2000 2005 Year of diagnosis FIGURE 2-2 Age-adjusted incidence of invasive and in situ breast cancer in women, Figure 2-2 Annual Rates.eps United States, 1975–2008. SOURCE: NCI (2011). A decline in breast cancer incidence occurred between 1999 and 2003 (Figure 2-2), principally in ER+ tumors in women ages 50–69 (Jemal et al., 2007). The decline is widely attributed to reductions in the use of hor- mone therapy (HT) (Clarke et al., 2006; Ravdin et al., 2007; Robbins and Clarke, 2007). In 1998, the Heart and Estrogen/Progestin Replacement Study (HERS) reported that use of combined estrogen–progestin HT failed to show an anticipated protective effect against coronary heart disease and was associated with an increase in risk for blood clots (Hulley et al., 1998). The subsequent publication of findings from the Women’s Health Initiative confirmed the lack of benefit for heart disease and also showed an increased risk for breast cancer with use of combined estrogen–progestin therapy (Writing Group for the Women’s Health Initiative Investigators, 2002). Reports from these studies were a major factor in the decline in use of HT. As reflected in Figure 2-2, a recent analysis found that for 2003–2007 incidence rates of invasive cancer did not significantly change, although use of HT continued to decline (DeSantis et al., 2011). Use of screening mammography in 2008 remained similar to rates seen in 1997 (Breen et al., 2011). Rates of in situ cancer among older women also rose somewhat

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47 BACKGROUND, DEFINITIONS, CONCEPTS in the 1980s and into the 1990s, but they have remained relatively stable since the late 1990s. Although the perception is widespread that breast cancer is becoming more common among young women, the best data available indicate that invasive breast cancer incidence rates have been almost unchanged since 1975 in women ages 20–49 (Figure 2-2). What has changed is the rate of in situ breast cancer, which has been rising since the introduction of mammog- raphy screening in the 1980s (Breen et al., 2001; Kerlikowske, 2010). The perception that breast cancer is increasing in younger women may come from several factors. First, any cancer diagnosis in a young woman in her prime working and reproductive years is notable, emotionally laden, and an event that will gain attention in many settings. An analysis of vignettes about breast cancer in popular magazines found that nearly half the sto- ries were about women who were diagnosed before age 40 (Burke et al., 2001), a group that accounts for approximately 5 percent of cases (ACS, 2011a). Second, diagnosis of cases of “carcinoma in situ,” especially DCIS, has increased, but its relation to invasive cancer can be unclear to women, at least in part because of the terminology and because of the aggressive treatment that may be recommended (De Morgan et al., 2002; Partridge et al., 2008; Liu et al., 2010). As noted, even within the research and medi- cal communities, the natural history of DCIS is poorly understood, so the proportion of DCIS cases that would become invasive if untreated is unclear (Allred, 2010). Race and Ethnicity Differences can be seen in the age patterns and trends in breast cancer among the country’s racial and ethnic groups. For 2004–2008, the overall incidence of breast cancer was 136 cases per 100,000 among non-Hispanic white women, 120 per 100,000 among African American women, 94 per 100,000 among Asian and Pacific Islander women, and 78 per 100,000 among Hispanic women (who can be of any race) (NCI, 2011).3 For African American women, the lower incidence rates compared with white women are most evident at older ages (Figure 2-3). However, incidence rates are higher among African American women under age 45. At ages 30–34, for example, African American women have an incidence of breast cancer of 31.8 cases per 100,000, compared with a rate of 25.8 for 3 Throughout the report, incidence rates such as these are age-adjusted using the U.S. standard population for 2000. Age adjustment applies each group’s incidence rates at specific ages to a single common population, the U.S. population for 2000 in this case. This process ensures that comparisons of rates are not affected by differences among the groups the age distribution of their populations.

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62 BREAST CANCER AND THE ENVIRONMENT sure play a large role, but inhalation is highly relevant for tobacco smoke and other air pollutants. Sometimes potential routes of exposure can be overlooked. For example, when taking showers, people experience dermal exposure to chemicals in the water supply, but showers also present an opportunity to inhale (typically low levels of) any water contaminants that readily volatilize. The potential effect of an environmental exposure is usually strongly influenced by the magnitude of that exposure—the dose. A higher dose of a hazardous exposure is generally more likely to be associated with adverse health effects than a lower dose is. Factors that influence dose include the duration and frequency of exposure and the biologic processes that gov- ern the absorption, distribution, metabolism, excretion, and storage of a substance in the body. The results of these toxicokinetic processes differ depending on the substance introduced into the body. Some ingested chemi- cals, for example, are poorly absorbed and rapidly excreted, while others may be readily absorbed, transformed by metabolism into new substances, and possibly stored in body tissues such as fat. The route of exposure may influence how the body responds to a substance. Also, differences among individuals in their genetics or exposure to other risk factors can result in differing responses to equal doses of a substance. SOME MEASURES OF DISEASE RISK Estimates of disease risk associated with a factor of interest—such as a personal characteristic (e.g., age), an environmental exposure (e.g., alcohol consumption or radiation exposure), or a medical treatment (e.g., a pre- scribed medication)—can be measured in multiple ways, including absolute risk, relative risk, hazard ratios, odds ratios, attributable risk, population attributable risk, and number needed to treat (NNT) or number needed to harm (NNH). The measure that is used depends on the study design, the available data, and in some cases the purpose for which the information is presented.7 In case–control studies, the prevalence of the factor of interest among cases and controls is compared using an odds ratio: the odds that a case is exposed compared to the odds that a control is exposed. Odds ratios of 1.0 mean that cases and controls were equally likely to have been exposed, and therefore the exposure is not associated with the disease and it is not a risk factor. An odds ratio that is statistically significantly less than 1.0 means that cases were less likely to have been exposed than controls. An odds ratio that is statistically significantly greater than 1.0 indicates that the 7 Additional methodologic information is available from sources such as Rothman (2002) and Jewell (2004).

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63 BACKGROUND, DEFINITIONS, CONCEPTS exposure is more likely to be reported among the case group than among the control group, indicating that the exposure is statistically associated with the disease, and thus is a potential risk factor for the disease. Cohort studies typically use the measure of relative risk or the hazard ratio. Relative risk is a ratio of the absolute risk (incidence) of disease in an exposed group (or groups with different levels of exposure) to the absolute risk (incidence) of disease in an unexposed group (or some other designated comparison group). A hazard ratio incorporates information on the pace at which events (e.g., cases of breast cancer) occur over the course of a study. Clinical trials also use relative risk and hazard ratios. The relative risk is interpreted in much the same way as the odds ratio. A relative risk of 1.0 means the exposure is not associated with development of disease; a ratio that is statistically significantly less than 1.0 means that those who were exposed were less likely to develop the disease than those who were not (indicating that the exposure is protective); and a ratio that is statistically significantly greater than 1.0 means that the exposure is associated with the disease, indicating that it is potentially a risk factor for the disease. Relative risk estimates and odds ratios represent an estimate of the strength of the association of a risk factor with breast cancer, but by themselves they do not provide insight into the underlying incidence of the disease and the absolute impact of a given factor. A relative risk of 2.0 means that a factor is associated with a doubling of the incidence of the health outcome in the exposed group compared to the unexposed. But this can mean an increase to 2 cases per 100,000 people or 200 cases per 100,000 people, depending on whether the underlying incidence is 1 case per 100,000 people or 100 cases per 100,000 people. Measures such as NNT and NNH are other ways of relating estimates of risk to absolute numbers. NNT is the number of people who would have to receive a treat- ment during a given time period for one person to benefit. Other measures that are used to assess the impact of a risk factor include attributable risk (AR) and population attributable risk (PAR). The AR is defined as the percentage of cases that occur in the exposed group that are in excess of the cases in the comparison group. The PAR is a population-based measure of the percentage of excess cases associated with the exposure of interest that also takes into account the distribution of the risk factor within the population. If a risk factor is rare, it may contribute only a small proportion of a population’s disease risk, even if the incidence of the disease is much higher among those who are exposed (which would produce a high relative risk). To adequately estimate the PAR requires high- quality studies in which confounding and overlapping contributions from multiple factors are analyzed appropriately. There are numerous pitfalls in interpreting the PAR (discussed in Chapter 4) (Rockhill et al., 1998). Ide- ally, the PAR provides information on the percentage of disease that can

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64 BREAST CANCER AND THE ENVIRONMENT be eliminated by avoiding the exposure, but the variation in estimates of PAR underscores how difficult it is to separate the effects from multiple risk factors. Because of this problem, and because PARs for individual fac- tors cannot simply be added together, PARs are sometimes calculated for a group of factors rather than single factors. Appendix D shows, for instance, a range of estimated PAR values (see e.g., physical activity or hormone therapy). These ranges may reflect variation in the contribution of a given factor across different populations, or variation in the degree to which the different studies adequately controlled confounding, or a combination of the two. SUMMARY Overall, breast cancer becomes increasingly common as women grow older, but the patterns of the disease vary among women in different racial and ethnic groups. These differences are likely to reflect the influence of a mix of genetic and environmental factors. Although the scope of environ- mental influences can be understood to encompass cultural and societal factors, most of the human, animal, and mechanistic research to date has focused more narrowly on individual exposures and the related biologi- cal processes. In the following chapter, the committee examines evidence regarding a set of environmental factors that illustrate varied types of expo- sures that may occur and the range of evidence available to assess whether exposure is associated with increased risk of breast cancer. REFERENCES ACS (American Cancer Society). 2011a. Breast cancer facts and figures 2011–2012. At- lanta, GA: ACS. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/ documents/document/acspc-030975.pdf (accessed October 24, 2011). ACS. 2011b. Cancer facts and figures 2011. Atlanta, GA: ACS. http://www.cancer.org/ Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2011 (accessed June 22, 2011). Allred, D. C. 2010. Ductal carcinoma in situ: Terminology, classification, and natural history. J Natl Cancer Inst Monogr 2010(41):134–138. Althuis, M. D., J. H. Fergenbaum, M. Garcia-Closas, L. A. Brinton, M. P. Madigan, and M. E. Sherman. 2004. Etiology of hormone receptor-defined breast cancer: A systematic review of the literature. Cancer Epidemiol Biomarkers Prev 13(10):1558–1568. Anderson, L. M., and D. S. May. 1995. Has the use of cervical, breast, and colorectal cancer screening increased in the United States? Am J Public Health 85(6):840–842. Anderson, W. F., I. Jatoi, and S. S. Devesa. 2006a. Assessing the impact of screening mammog- raphy: Breast cancer incidence and mortality rates in Connecticut (1943–2002). Breast Cancer Res Treat 99(3):333–340. Anderson, W. F., R. M. Pfeiffer, G. M. Dores, and M. E. Sherman. 2006b. Comparison of age distribution patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev 15(10):1899–1905.

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