4
Understanding Breast Cancer Risk

Every woman is at some risk for breast cancer, but the degree ofrisk for individual women ranges from very low to very high. Understanding risk is important because it affects medical decisions—from whether a symptom-free woman should have a mammogram to how intensively to treat existing breast disease to how aggressively to pursue prevention strategies, such as the use of anti-estrogens or prophylactic mastectomy and removal of a woman’s ovaries.

If a screening technology existed that was so simple and so inexpensive that it could be used often enough to detect even fast-growing cancers, so reliable that no supplemental screening or diagnostic tools would be needed, and so convenient and comfortable that every woman would be willing and able to undergo frequent screening, then every woman could be screened and risk assessment would not be necessary. Unfortunately, not a single one of these conditions is met by current screening options for any type of cancer. Nor are there any tools on the horizon that promise to meet these conditions in the near term. Risk assessment is and will almost certainly remain an essential component of early detection of breast cancer.

Risk factors are identified (and new ones continue to be identified) through epidemiologic research studies, which typically measure the relative risk of the factors being studied (see Box 4-1). If a woman has a factor that is associated with a relative risk greater than 1, then—all other things being equal—her risk will be higher than the population average. If she does not have that factor, her risk will be lower.

Risk, or absolute risk, is a measure of the probability of developing cancer over a specified time interval. This is sometimes expressed as the



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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis 4 Understanding Breast Cancer Risk Every woman is at some risk for breast cancer, but the degree ofrisk for individual women ranges from very low to very high. Understanding risk is important because it affects medical decisions—from whether a symptom-free woman should have a mammogram to how intensively to treat existing breast disease to how aggressively to pursue prevention strategies, such as the use of anti-estrogens or prophylactic mastectomy and removal of a woman’s ovaries. If a screening technology existed that was so simple and so inexpensive that it could be used often enough to detect even fast-growing cancers, so reliable that no supplemental screening or diagnostic tools would be needed, and so convenient and comfortable that every woman would be willing and able to undergo frequent screening, then every woman could be screened and risk assessment would not be necessary. Unfortunately, not a single one of these conditions is met by current screening options for any type of cancer. Nor are there any tools on the horizon that promise to meet these conditions in the near term. Risk assessment is and will almost certainly remain an essential component of early detection of breast cancer. Risk factors are identified (and new ones continue to be identified) through epidemiologic research studies, which typically measure the relative risk of the factors being studied (see Box 4-1). If a woman has a factor that is associated with a relative risk greater than 1, then—all other things being equal—her risk will be higher than the population average. If she does not have that factor, her risk will be lower. Risk, or absolute risk, is a measure of the probability of developing cancer over a specified time interval. This is sometimes expressed as the

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis BOX 4-1 Relative Versus Absolute Risk A relative risk compares the risk of disease among people with a particular risk factor to the risk among people without that risk factor. If the relative risk is above 1.0, then risk is higher among those with the risk factor than those without. Relative risks below 1.0 indicate a protective effect, or lower risk, associated with a particular factor. Relative risks are useful for comparisons, but they do not provide information about the absolute amount of additional risk experienced by the group with the risk factor in question. For example, current users of combination estrogen and progestin hormone replacement therapy (HRT) have a relative risk of 1.26, or a 26 percent increased risk. Although this increased risk may seem substantial, it proves to be less so in absolute terms because of the very low risk of breast cancer among young women in general. Among 10,000 women who have been using HRT for 5.2 years, 38 breast cancers would be expected to be diagnosed. Among 10,000 similar women who never used HRT, 30 cases would be expected over the same period. Therefore, the 26 percent increased relative risk results in an absolute risk of only 8 additional breast cancer cases per 10,000 women over a period greater than 5.2 years. Adapted from the American Cancer Society, Breast Cancer Facts and Figures 2003-2004.1 lifetime risk, or the risk to, say, age 70. Or the risk may be expressed as the probability that a woman of a given age will develop cancer in the next 10 years. The statistic that one in eight women who survive to age 85 will develop some form of breast cancer in her lifetime is alarming, but this masks the important influence of age on risk (Table 4-1). Fewer than 5 percent of invasive breast cancers occur in women under age 40, whereas over three-quarters are in women over the age 50. Numerous case-control and cohort studies over the past several decades have identified various factors, some of which have been shown to be consistently associated with risk, such as reproductive hormones, and others that are less consistent, such as dietary factors (Box 4-2, Table 4-2). Risk factors such as body mass index and dietary fat have been associated with specific types of breast cancer whose growth is stimulated by the sex hormones estrogen and progesterone.15 Family history increases risk although not as much as some women believe. Eighty-nine percent of women who develop breast cancer have no family history among their first-degree relatives (mother, daughter, or sister).16 The amount of increased risk depends on how close a relation the affected relative is, the age at which they developed breast cancer, and the number of relatives affected.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE 4-1 Age-Specific Probabilities of Developing Breast Cancer1 If current age is Then the probability of developing breast cancer in the next 10 years is: or 1 in: 20 0.05% 2,152 30 0.40% 251 40 1.45% 69 50 2.78% 36 60 3.81% 26 70 4.31% 23 BOX 4-2 Epidemiological Methods for Discovering Genetic Links to Disease Case-control studies are retrospective observational studies in which investigators identify one group of patients with a specified outcome (cases) and another group without the specified outcome (controls). Investigators then compare the histories of the cases and the controls to determine the extent to which each had the possible risk factor being investigated. Cohort studies are observational studies in which outcomes in a group of patients who possess the possible risk factor being tested (the cohort) are compared with outcomes in a control group of patients who do not possess the possible risk factor. For example, the occurrence of breast cancer would be compared between two groups of women neither of whom have breast cancer at the beginning of the study; one of the groups would possess the possible risk factor and the other group would not. The number of new cases of breast cancer in the two groups would be compared over time. Approximately 70 percent of women who develop breast cancer have the type of cancer called hormone receptor positive, which means that the cancerous tissue contains receptors for estrogen and/or progesterone. This association may, therefore, prove to be more relevant among women with elevated levels of these hormones, for example, premenopausal women or women using hormone replacement therapy.17,40,46 More research into risk profiles of such subtypes of breast cancers may elucidate a clearer connection between risk factors and the development of breast cancers. Although many factors that influence risk have been identified, it is still not possible to determine which women will develop breast cancer and which will not.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE 4-2 Risk Factors for Breast Cancer Risk Factor Relative Risk Category at Risk Comparison Category Germ-line mutation 200? Heterozygous for BRCA1, age <40 Not heterozygous for BRCA1, age <40   15? Heterozygous for BRCA1, ages 60-69 Not heterozygous for BRCA1, ages 60-69 Cytological findings (fine-needle aspiration; nipple aspiration fluid) 18.1 Proliferation with atypia and positive family history No abnormality detected 4.9-5 Proliferation with atypia No abnormality detected   2.5 Proliferation without atypia* No abnormality detected Other histologic findings 17.3 Ductal carcinoma in situ No abnormality detected   16.4 Lobular carcinoma in situ No abnormality detected Positive breast biopsy 11 Hyperplasia with atypia and positive family history No hyperplasia, negative family history   5.3 Hyperplasia with atypia No hyperplasia   1.9 Hyperplasia without atypia No hyperplasia Past history of breast cancer 6.8 Invasive breast carcinoma No history of invasive breast carcinoma Current age 5.8 65 or older Less than 65 Radiation exposure 5.2 Radiation therapy for Hodgkin’s disease No exposure   1.6 Repeated fluoroscopy No exposure

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Risk Factor Relative Risk Category at Risk Comparison Category Breast density 47,72 More than 75% of breast is mammographically dense Less than 25% of breast is mammographically dense Family history 3.6 Two 1st-degree relatives with breast cancer No 1st- or 2nd-degree relative with breast cancer   3.3 1st-degree relative with premenopausal breast cancer No 1st- or 2nd-degree relative with breast cancer   1.8 1st-degree relative 50 years or older with postmenopausal breast cancer No 1st- or 2nd-degree relative with breast cancer   1.5 2nd-degree relative with breast cancer No 1st- or 2nd-degree relative with breast cancer Age at first birth 1.7-1.9 Nulliparous or 1st child after 30 1st child before 20 Late menopause 1.2-1.5 Older than 55 years Younger than 45 Hormone replacement therapy65,≠ 2.70 Current user of estrogen and progestin Never used   1.96 Current user of estrogen only Never used Early menarche 1.3 Younger than 12 years Older than 15 years Alcohol intake 1.2 2 drinks per day Nondrinker Body mass index 1.2 80th percentile 20th percentile *There is controversy over whether pathologic hyperplasia detected in breast biopsy samples is directly equivalent to cytologic hyperplasia detected in samples obtained through fine-needle aspiration or nipple aspiration. ?These relative risks are subject to ascertainment bias and may overestimate the true risk associated with germline mutations in BRCA genes.5 ≠The data for hormone replacement therapy was updated due to the release of a new study after the original risk of hormone replacement was presented by Singletary et al., 2003.64 SOURCE: Adapted from Singletary and colleagues.64

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis BREAST DENSITY Mammographic breast density may be the most undervalued and underused risk factor in studies investigating breast cancer.13,38,73 It is a heritable trait, although the contribution of breast density to increased risk is independent of the risk associated with BRCA1 and BRCA2 mutations.7 Despite the ethnic variation in breast density, breast cancer risk rises with increasing breast density for each of the ethnic groups recently analyzed by Ursin and colleagues; the groups they analyzed included African Americans, Asian Americans, and non-Latino whites.69 A 2002 study reported that the average relative risk of breast cancer for women in the highest category of percentage of dense tissue compared with those in the lowest category is about 4.7 Previous studies reported relative risk estimates ranging from 2 to 6, with the majority of those studies reporting a relative risk of 4 or more (reviewed by Boyd and colleagues, 2002).7 The genetic factors that determine breast density may also play a role in breast cancer.73 GENETIC RISK FACTORS Before a cell becomes cancerous, it must accumulate a “critical mass” of molecular changes that alter key genes or their functions. The end result is a loss of the normal molecular controls on the cell’s growth and differentiation. Some of the cellular changes that make a woman susceptible to developing breast cancer can be inherited. Such germ-line mutations are believed to account for the striking incidence of breast cancer in certain families, especially breast cancer that develops in both a woman’s breasts and/or at a young age. But less than 10 percent of all breast cancer cases are thought to stem from inherited mutations, such as BRCA1 and BRCA2, that individually increase risk by a substantial amount.41 The majority of breast cancer cases are due to an accumulation of cellular (somatic) changes that occur during a patient’s lifetime. This is why age is such a significant factor in most cancers—because the longer a person lives, the more time there is for mutations to accumulate. These changes are not inherited, but rather stem from factors such as exposure to carcinogens in the external environment, or from excessive or untimely exposure to breast cancer-promoting substances within the body, such as circulating hormones, or simply because of random mutations that occur during cell division. Inherited genes can also influence genetic mutations that occur during a person’s lifetime if they increase the susceptibility of other genes to mutation. For example, the ability of a cell to correct mistakes in gene replication that occur during cell division is diminished when the genes that normally support DNA repair have mutated. As a result, mutations accumulate faster than they would otherwise.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis BRCA Genes and the Shortcomings of Genetic Testing Studies of families with an exceptionally large number of members with breast and ovarian cancer led to the discovery of the first two inherited breast cancer susceptibility genes. By searching for genetic markers shared by all affected family members (linkage analysis), researchers in the 1990s were able to pinpoint two breast cancer susceptibility genes, BRCA1 and BRCA2.41 Both genes are rare, but they confer very high risk. Both genes code for proteins that are thought to play a role in the repair of genetic defects, and therefore mutations that decrease their ability to repair or limit the proliferation of cells with genetic defects will increase the susceptibility to breast cancer.41 Initial studies suggested that women who tested positive for either mutation would have nearly a 90 percent chance of developing breast cancer by age 70.29 A recent study found that Ashkenazi Jewish women who carry one of the three BRCA1 and BRCA2 mutations associated with Ashkenazi ancestry and who reach age 80 have an 82 percent risk of developing breast cancer; those who reach age 60 have a 55 percent risk.45 These studies indicate that BRCA1 and BRCA2 tests would be a useful clinical tool to identify women at high risk for breast cancer, but the lifetime probability estimates for developing breast cancer among women who test positive for mutations of BRCA1 or BRCA2 (also called penetrance of the genes) is variable and often overestimated. Lifetime risks of breast cancer in women in the general population who test positive for BRCA1 (that is, women who are not preselected on the basis of a family history of breast cancer) could be as low as 45 percent, and 26 percent in such women who test positive for BRCA2 (reviewed by Begg, 2002).5 Other studies based on women from the general population produced higher penetrance estimates, but none was as high as those seen in women from high-risk families. Overestimates of the penetrance of BRCA1 or BRCA2 result from sampling bias. Studies of women who have breast cancer and are known to have a family history of breast cancer will generate higher estimates of penetrance than studies that start with women in the general population and assess the overall percentage of women who test positive for BRCA mutations and develop breast cancer. Women with BRCA mutations who develop breast cancer usually have several other risk factors that are likely to be shared with their relatives. These relatives could be at somewhat greater than average risk of developing breast cancer, even if they do not test positive for BRCA mutations. Consequently, the percentage of these women who test positive and develop breast cancer is likely to be greater than that of women who test positive in lower-risk populations.5 Evidence shows that environmental factors also play a role in determin-

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis ing the penetrance of BRCA genes. Some studies find that a woman’s reproductive history can modify the penetrance of BRCA1 or BRCA2 (reviewed by Burke and Austin, 2002).10 Other studies find that cancer risk is relatively greater in younger women who test positive for BRCA mutations than in older women.10,45 Birth cohort and physical exercise also have been shown to partially mitigate the influence of BRCA1.45 Ashkenazi Jewish women born with one of the three mutations associated with Ashkenazi ancestry who were born before 1940 have an average lower likelihood of developing breast cancer than similar women born after 1940. In the same study, women with those mutations who had been physically active as teenagers and were not obese as young adults showed an approximate risk reduction of 10 years—that is, a 60-year-old woman who was not obese at age 21 and with a history of physical activity had approximately the same average risk as a 50-year old woman with a history of obesity and no physical activity. Such a change in penetrance over time is likely due to the influence of a changing environment. As Wylie Burke and Melissa Austin summarize in an editorial in the Journal of the National Cancer Institute: The most important implication of penetrance studies should perhaps be to temper our expectations for predictive genetic tests. Without a healthy respect for the many factors that may influence penetrance, we will continue to overestimate the risk conferred by BRCA 1 and BRCA 2 mutations alone and, thus, miss opportunities to develop truly effective prevention strategies for women who are genetically susceptible to breast cancer that are based on a broad understanding of causative factors.10 The wide range of penetrance estimates complicates decisions for preventive interventions like prophylactic mastectomy or tamoxifen chemoprevention, although even the lowest penetrance estimates might be high enough to suggest that women who test positive for BRCA mutations should be screened more aggressively. However, one study found that annual mammograms and biannual physical exams were less sensitive, and detected tumors at later stages in women with BRCA mutations than in women at greater than average risk for breast cancer who lack the mutations.9 Furthermore, studies have found that BRCA2-deficient cells are hypersensitive to the effects of radiation,54 so there is concern (but so far no evidence) that women, especially those with BRCA2 mutations, might be susceptible to radiation-induced genetic defects and cancer. Another problem is that researchers have detected more than 2,000 mutations of BRCA1 or BRCA2,54 but the clinical significance of these is not yet known; some may not influence breast cancer risk. Consequently, more than 1 in 10 BRCA tests yields inconclusive results because the clinical significance of the specific mutations detected by the tests is unknown.2

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Women also may test negative for mutations in BRCA1 or BRCA2 and still harbor a BRCA mutation that increases their risk of breast cancer because this mutation falls outside the range of mutations detected by current BRCA1 or BRCA2 tests.66 There is only one commercially available test for BRCA mutations. It costs about $450, and tests only for the three Ashkenazi mutations. A test for all of the known mutations in BRCA1 and BRCA2 genes would cost nearly $3,000 (Personal communication, W.A. Hockett III, Myriad Genetics, Inc., Vice President of Corporate Communications for Myriad Genetics, Inc., December 2, 2003). Testing negatively for BRCA mutations also does not rule out the possibility that a woman with a strong family history for breast cancer has inherited mutations in other genes that increase her breast cancer risk.63 Perhaps the biggest limitation is that less than one-quarter of 1 percent of women in the general population are believed to harbor BRCA mutations,18,32,57 and mutations in either of the BRCA genes account for only 2 to 3 percent of all breast cancers (reviewed by Wooster and Weber, 2003).71 Because more than 10 percent of women will develop breast cancer in their lifetimes, BRCA tests clearly will be a small piece in the puzzle of identifying individual risk. Many more genetic risk factors have been published than have been verified. A literature review of epidemiological studies that assessed associations between polymorphisms and risk of cancer found that only a small proportion of the published studies were large and population-based.35 Because studies based on small samples sizes are prone to false-positive or false-negative findings, large and well-designed studies of genetic risk are essential. Studies that analyze multiple genes or polymorphisms would be especially useful in improving our understanding of breast cancer. Polymorphisms The search for other genetic markers that determine breast cancer susceptibility is ongoing and has focused on subtle DNA changes, known as polymorphisms, that are shared by many people, and that may affect susceptibility to carcinogens and cancer promoters in the environment or the body, or affect the body’s immune response to cancer cells. Each polymorphism probably increases or decreases breast cancer risk by only a small amount, perhaps a few percentage points. But because these polymorphisms are found in all people, their impact on breast cancer risk may be considerably greater than that of the relatively rare BRCA mutations,22 and the combined impact of several polymorphisms on breast cancer risk could be substantial. A compilation of various polymorphisms might enable the stratification of some women into low- or high-risk breast cancer groups. However,

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis research on genetic polymorphisms that influence breast cancer susceptibility is in its infancy, and many more studies are needed before they are useful in stratifying women into breast cancer risk groups.22 Researchers seeking to discover polymorphisms that boost breast cancer risk have tended to focus their search on the most biologically plausible genes, such as those known to be involved in the metabolism of carcinogens, or the regulation of estrogen levels, or that are the normal variants (proto-oncogenes) of genes known to cause cancer (oncogenes). (Proto-oncogenes are involved in the regulation of normal cell growth and differentiation.) For the most part, reports of polymorphisms that affect susceptibility to breast cancer have been based on relatively small studies. Table 4-3 presents the results of meta-analyses of studies on genetic polymorphisms that have been linked to breast cancer risk. Precise and validated estimations of the genetic risk associated with these polymorphisms will require large case-control studies. Of 35 polymorphisms in 19 different genes described in at least two breast cancer studies, only 13 polymorphisms in 10 genes showed an association with breast cancer. Only TNF-alpha and a variant of the HSP-70 protein show odds ratios higher than 3. Although an odds ratio of 3 or higher is a common benchmark of an important risk factor, this is still much lower than what is needed for screening tests, and would involve high false-positive or -negative rates, or both. Thus, although statistically significant at the population level, such a risk factor would not, by itself, be helpful in predicting individual risk. As of this writing, except for BRCA1 and BRCA2, no single genetic risk factor predicts the development of breast cancer well enough to be used on its own for individual risk stratification. Relatively little research has been performed on combinations of polymorphisms which are addressed in only a few studies in breast cancer patients. Because the products of several genes interact (for example, nearly half of the genes reviewed by de Jong and colleagues play a role in estrogen metabolism), interactions between the genes are likely. Some investigators believe a whole genome screen would be the ideal method to detect new breast cancer susceptibility genes. This method, however, is still too expensive to carry out in large study populations.22 Until this is feasible, it would be useful to collect data on appropriately sized, well-described study populations.22 Analysis of several (or all) of the polymorphisms already known to be associated with breast cancer in the same population may increase our understanding of the etiology of breast cancer and permit better risk assessments (reviewed in 2001 by de Jong).22

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE 4-3 Genes Other Than BRCA1 and BRCA2 Involved in Breast Cancer Susceptibility22 Gene Description Effect on Breast Cancer Risk Odds Ratio* Rare genetic syndromes with increased breast cancer risk Tp53 Mutation of this gene causes Li-Fraumeni syndrome and is characterized by an increased risk of several cancers. Expressed in three different variants. Associated with increased risk, particularly in white populations. Risk not shown in Hispanic, African-American, or Pakistani study participants. 1.08 CI 0.88-1.13 ATM Mutation of this gene causes ataxia telangiectasia, a neurodegenerative disease characterized by lack of coordination, red lesions, and immune defects. Few patients survive to an age at which breast cancer occurs, but a role in increased risk is plausible and has been shown in some small studies. N/A PTEN Mutation of this gene causes Cowden syndrome, characterized by malformations resembling tumors composed of mature tissues, especially of the skin, mucous membranes, breast, and thyroid. Not likely to have an effect in the sense of classical heredity. Unknown if PTEN plays a role in sporadic breast cancer susceptibility. N/A LKB1 Mutation of this gene causes Peutz-Jeghers syndrome and is characterized by freckle-like spots on the lips, mouth and fingers and benign polyps in the intestines. Only likely to play a role in increased risk among those patients with Peutz-Jeghers syndrome. N/A Low penetrant cancer susceptibility genes: Proto-oncogenes HRAS1 Protein product is a protein kinase that transmits signals from growth factor receptors. When mutated can result in abnormal cell cycle control. Moderately associated with increased risk. 2.04 CI 1.73-2.41

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 4-2 Mammography use declines when breast cancer risk is greatest. SOURCE: Data obtained from Medstat (2003)49 and Ries et al. (2003).59 developing breast cancer within 10 years would be, on average, about 1.5 percent (Table 4-1). With her family history that risk is multiplied by 1.8 which gives her a 10-year breast cancer risk of 2.7 percent—higher than average, but still relatively low. Indeed, many women are surprised to learn than almost 90 percent of women who develop breast cancer have no close family history; that is, neither a mother, sister, or daughter with breast cancer. Some women have gone to extreme measures to reduce their risk. For example, one study reported on 75 high-risk Canadian women who underwent bilateral mastectomy to avoid breast cancer, but the researchers found that on average the women had overestimated their lifetime risk of developing breast cancer before surgery three-fold.50 The women in the study with strong or limited family histories of breast cancer estimated their lifetime risk for breast cancer as approximately 75 percent, whereas their calculated risks were only 25 percent (for strong family histories) and 18 percent (for limited family histories). In contrast, the women with BRCA gene mutations estimated their lifetime risk as 80 percent, while the model used to calculated their risk (BRCAPRO) indicated a 65 percent lifetime risk—a difference that was not statistically significant. Of course, there is no way to be sure that the models are accurate for the individual women in this study because of uncertainty about the penetrance of the BRCA mutations in each woman. Distorted risk perception includes perceptions about prognosis as well. Although the prognosis for DCIS is excellent, the prognosis for early inva-

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE 4-4 Percent of Women Who Rated Certain Outcomes “Likely” Was Not Significantly Different for Diagnoses, Despite Significantly Different Prognoses   Perceived Risk Among Women with Different Diagnoses* Possible Event DCIS Early Invasive Breast Cancer Developing a local recurrence 53% 45% Developing a distant recurrence 36% 39% Dying of breast cancer 27% 27% *None of the differences between diagnoses meet statistical significance. sive breast cancer is not. Ten years after a diagnosis of DCIS, 2 percent of women will have died of breast cancer compared to 11 percent of women diagnosed with early invasive breast cancer.28 Despite the different levels of risk, a study of 228 patients with either DCIS or early invasive breast cancer found no significant differences between the two groups in terms of perceived risk for recurrence or death from breast cancer (Table 4-4).58 In addition, both groups of women expressed similar levels of anxiety and depression: 56 percent of women with DCIS and 54 percent of women with early invasive breast cancer reported anxiety; 41 percent of women with DCIS and 48 percent of women with early invasive breast cancer reported depression. Finally, not only do many women have distorted perceptions of their risks of developing breast cancer, but most women misunderstand or overestimate the benefits of mammography.6,24 A survey conduced in 1999 reported that a 57 percent majority of women in the United States believe that mammography affects their risk of developing breast cancer, compared to 37 percent who correctly responded that mammography does not influence breast cancer risk (Table 4-5).24 Women in the United Kingdom and Italy who were surveyed overestimated the benefits of mammography to an even greater extent, 69 and 81 percent, respectively. Likewise, most women in all countries surveyed overestimated the extent to which mammography can reduce mortality due to breast cancer. Decisions and Uncertainty When information is certain, decisions are simple. A 40-year-old woman with an invasive breast tumor that will metastasize within 5 years

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE 4-5 Most Women in the United States Overestimate the Benefits of Mammography   Response Question Prevents the risk of developing Reduces the risk of developing No effect on risk of developing Don’t know Does mammography prevent or reduce the risk of developing breast cancer? 26% 31% 37% 6%   Hardly at all By about a quarter By half or more Don’t know How much does mammography reduce mortality for women over 50 who are screened regularly every 2 years for 10 years? 4% 12% 71% 13% NOTE: Headings in bold and shading indicate the correct or most appropriate answer. unless it is removed does not need a decision aid to take action. In contrast, a 65-year-old woman diagnosed with low-grade DCIS is likely to welcome a decision aid that allows her (and her physician) to integrate what is known about her personal risk factors with the likely benefits of different treatments. Likewise, a 75-year-old woman may want information that would assess her 10-year likelihood of death from other causes against the likelihood of dying from breast cancer in deciding whether to undergo screening. Decision aids are tools that assist in choosing between complex alternatives such as determining optimal breast cancer screening strategies or choosing breast cancer treatment options. Sometimes these aids take the form of complex decision analyses, and sometimes they provide baseline probabilistic data in a variety of forms so that patients can better understand tradeoffs between risks and benefits. In the context of screening, formal decision analyses have been used by policymakers to evaluate the societal implications of varying strategies for a variety of tumors. From the perspective of an individual patient, these models can also be useful. However, information about probabilities at varying points in the screening and management process is sometimes more valuable. In the screening situation such information is useful because no screening test is 100 percent sensitive and specific. For example, a positive test for a BRCA1 or BRCA2 mutation

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis does not mean that it is certain a woman will get breast cancer, and conversely, a negative test does not mean she will not. Emerging data on genomic markers and circulating biomarkers suggest that genetic or chemical analyses may help stratify patients into individualized risk categories, but the results are in continual flux and will be difficult to interpret until appropriate longitudinal large-population studies are done. Thus, there is a need to transfer information as clearly as possible to patients as they face decisions about having one or more screening tests for breast cancer. Effectiveness of Risk Communication and Decision Aids A large body of research has shown that good communication and strong patient-provider relationships are linked to greater patient satisfaction, and positive health outcomes.43,55 Moreover, specific provider behaviors such as soliciting patients’ opinions, checking patient understanding, and encouraging patients to talk have been linked to reduction of malpractice claims.47 Poor communication, conversely, was associated with dissatisfaction, conflict, and worse outcomes. Studies suggested that dissatisfied patients tend to opt out of health plans,21 to change physicians,44,62 to initiate complaints against physicians,47 and to be noncompliant with medical recommendations.31,44 Women are more likely to get involved in decision making once they are given sufficient information about their medical options.30 These findings underscore the importance of educating women about the risks and benefits of various options. Studies show that without help, physicians are not consistently doing this well.8 Although there are some reputable decision aids available on the Internet, as well as risk information provided by the print lay press, there is also an abundance of misinformation to which women are exposed. Messages from direct-to-consumer advertisements about medical tests, procedures, or treatments can also be misleading (see Box 1-3 in Chapter 1). These advertisements tend to overemphasize breast cancer risks to women and the benefits that are likely to accrue if they pursue the medical options the ads publicize.34 The ads also tend to be fraught with misinformation, such as confusion of clinical benefits with laboratory accuracy.34,70 Individualized risk communication tends to improve women’s accuracy about their own risk, although different studies have reported that anywhere from 22 to 50 percent of the women studied still overestimate their risk.12 Edwards and colleagues reviewed 13 studies and concluded that individualized risk communication is also linked to increased participation in mammography screening programs.26,27 However, many studies have been based on the presumption that the goal of risk communication is to increase participation in screening services, whereas the more important

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis goal is to increase the number of women whose breast cancer is detected early enough to be effectively treated. Indeed, Edwards and his colleagues concluded that, based on the available data, increased use of mammography is not necessarily a consequence of more informed decision making.26,27,61 O’Connor and colleagues reviewed 200 decision aids, of which only 30 had been evaluated in methodologically valid clinical studies.56 Based on those 30 studies, they concluded that the decision aids improved subjects’ knowledge about their medical risks—although they did not necessarily influence their medical decisions. For example, the four breast cancer decision aids involved decisions about whether to undergo genetic testing for BRCA mutations. Those decision aids improved the test subjects’ understanding of their personal risk, but did not influence whether or not they intended to pursue genetic testing. Although risk perception is often at odds with actual risk, numerous studies have shown that genetic risk counseling improves people’s understanding of their personal risk (reviewed by Hopwood in 2000).39 A systematic review of studies published from 1980 to 2001 on the effects of genetic counseling and testing for familial breast cancer on women’s perception of risk indicated that, overall, genetic counseling and testing appear to produce psychological benefits and to improve accuracy of risk perception, although 22 to 50 percent of the women in the studies reviewed continued to overestimate their risk.12 Even straightforward and accurate communication of risk can lead to unintended outcomes. For example, if people are asked to choose between an option that carries a 20 percent risk of dying versus an option that carries an 80 percent chance of survival, the overwhelming majority will opt for the survival option—even though the probable outcomes are identical. The differences in how the options are presented, or framed, are referred to as “loss framing” or “gain framing.” Women’s responses to information about the value of mammography are similarly affected by how the risks and benefits of mammography are framed.25 Communication of risk must ensure that women do not mistakenly identify themselves as being at such low risk that they make choices, such as foregoing mammograms entirely, that increase their risks of a preventable death from breast cancer. SUMMARY The ultimate purpose of this Institute of Medicine report is to identify better ways to reduce the burden of breast cancer through improving early detection and diagnosis. Because there is so much individual variation in susceptibility to breast cancer, it makes sense to develop more refined screening strategies that provide the greatest possible benefit for individual

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis women. Current screening strategies rely most heavily on age, followed by a history of breast disease. However, the development and progression of breast cancer is driven by biological factors such as genetic inheritance and mutations accumulated during a woman’s lifetime. Although much has been learned, research on the genetic risk factors for breast cancer is still in its infancy, but should, in time, increasingly yield the knowledge for individualized risk stratification. The goal of improved risk assessment is not to increase the use of screening mammography, but rather to identify optimal strategies. For some women, that might mean fewer mammograms. For others, it might mean staying the course and getting annual mammograms after age 50. For still others, it might mean more frequent mammograms or the use of supplemental imaging technologies, such as magnetic resonance imaging or ultrasound, or eventually molecular imaging. The primary goal of national screening programs has been to maximize the number of women who receive regular mammograms, yet it is clear that not all women will benefit equally. Risk assessment, however, is only the first step. The goal of revising screening strategies necessarily includes revising screening behaviors. Risk must be communicated to individual women (and understood by their physicians) in such a way that they can make informed decisions about screening and their lifestyle. Numerous studies have indicated that a physician’s or other provider’s referral is the single most important predictor of whether a woman will receive a mammogram. But as discussed earlier, this is correlated with a variety of other factors that influence access to mammography. One example is whether a women who receives a referral is already receiving regular health care and, in most cases, has health insurance, which is itself a major determinant of which women will receive regular mammograms (see section Equal Access in Chapter 3). To date, the impact of risk communication on informed medical decision making is limited. Even for mammography, which has been the subject of much research on communicating risk, few data show that women are making informed decisions—even within programs to communicate individualized risk.27 This education is particularly relevant in enabling women to make appropriate decisions about their breast cancer screening because, as discussed earlier, a woman’s perception of her breast cancer risk often does not match her actual risk. Risk communication might increase participation in screening mammography for several reasons that are, in fact, contradictory to informed decisions. For example, a woman might be motivated to follow mammography guidelines, because she overestimates her personal risk, or because she overestimates the potential of mammography to reduce her risk. Many women’s health and breast cancer advocates argue that women

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis must be enabled to make informed choices about screening,4,53,68 but that is not enough. Women and their physicians need better tools for assessing risk. Finally, communicators—physicians, professional societies, national health organizations, breast cancer advocates, and journalists—need a better understanding of how risk should be communicated. REFERENCES 1. American Cancer Society. 2003. Breast Cancer Facts and Figures 2003-2004. Atlanta, GA: American Cancer Society. 2. American Medical Association, CME program publication. 2001. Identifying and Managing Hereditary Risk for Breast and Ovarian Cancer. 3. Aro AR, de Koning HJ, Absetz P, Schreck M. 1999. Psychosocial predictors of first attendance for organised mammography screening. J Med Screen 6(2):82-88. 4. Baines CJ. 2003. Mammography screening: are women really giving informed consent? J Natl Cancer Inst 95(20):1508-1511. 5. Begg CB. 2002. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 94(16):1221-1226. 6. Black WC, Nease RF Jr, Tosteson AN. 1995. Perceptions of breast cancer risk and screening effectiveness in women younger than 50 years of age. J Natl Cancer Inst 87(10):720-731. 7. Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, Giles GG, Tritchler D, Chiarelli A, Yaffe MJ, Hopper JL. 2002. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347(12):886-894. 8. Braddock CH 3rd, Edwards KA, Hasenberg NM, Laidley TL, Levinson W. 1999. Informed decision making in outpatient practice: time to get back to basics. JAMA 282(24):2313-2320. 9. Brekelmans CT, Seynaeve C, Bartels CC, Tilanus-Linthorst MM, Meijers-Heijboer EJ, Crepin CM, van Geel AA, Menke M, Verhoog LC, van den Ouweland A, Obdeijn IM, Klijn JG. 2001. Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19(4):924-930. 10. Burke W, Austin MA. 2002. Genetic risk in context: calculating the penetrance of BRCA1 and BRCA2 mutations. J Natl Cancer Inst 94(16):1185-1187. 11. Burke W, Olsen AH, Pinsky LE, Reynolds SE, Press NA. 2001. Misleading presentation of breast cancer in popular magazines. Eff Clin Pract 4(2):58-64. 12. Butow PN, Lobb EA, Meiser B, Barratt A, Tucker KM. 2003. Psychological outcomes and risk perception after genetic testing and counselling in breast cancer: a systematic review. Med J Aust 178(2):77-81. 13. Carney PA, Miglioretti DL, Yankaskas BC, Kerlikowske K, Rosenberg R, Rutter CM, Geller BM, Abraham LA, Taplin SH, Dignan M, Cutter G, Ballard-Barbash R. 2003. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med 138(3):168-175. 14. Cockburn J, Sutherland M, Cappiello M, Hevern M. 1997. Predictors of attendance at a relocatable mammography service for rural women. Aust N Z J Public Health 21(7):739-742. 15. Colditz GA, Rosner BA, Chen WY, Holmes MD, Hankinson SE. 2004. Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst 96(3):218-228.

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