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4 Understanding Breast Cancer Risk
Pages 123-154

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From page 123...
... 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)
From page 124...
... . 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.
From page 125...
... 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.
From page 126...
... with atypia detected 2.5 Proliferation No abnormality without atypia* detected Other 17.3 Ductal carcinoma No abnormality histologic in situ detected findings 16.4 Lobular carcinoma No abnormality in situ detected Positive 11 Hyperplasia with No hyperplasia, breast biopsy atypia and negative family positive family history history 5.3 Hyperplasia with No hyperplasia atypia 1.9 Hyperplasia No hyperplasia without atypia Past history 6.8 Invasive breast No history of invasive of breast carcinoma breast carcinoma cancer Current age 5.8 65 or older Less than 65 Radiation 5.2 Radiation therapy No exposure exposure for Hodgkin's disease 1.6 Repeated fluoroscopy No exposure
From page 127...
... ? 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
From page 128...
... 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)
From page 129...
... , 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)
From page 130...
... .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.
From page 131...
... . 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)
From page 132...
... 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.
From page 133...
... Low penetrant cancer susceptibility genes: Proto-oncogenes HRAS1 Protein product is a Moderately associated with 2.04 protein kinase that increased risk. CI 1.73-2.41 transmits signals from growth factor receptors.
From page 134...
... Low penetrant cancer susceptibility genes: Metabolic pathways NAT1/NAT2 Protein product is an No association found. 1.13 enzyme that can CI 0.91-1.39 bioactivate several known carcinogens through acetylation.
From page 135...
... CI 0.97-1.45 metabolism of commonly prescribed drugs including codeine. Low penetrant cancer susceptibility genes: Estrogen pathway genes CYP17 Protein product is an No association found in 0.99 enzyme that mediates analysis of several studies.
From page 136...
... HSP70-2: No association 1.74 found. CI 0.55-5.52 Low penetrant cancer susceptibility genes: Iron metabolism genes HFE/HH Mutation of this gene can Do not play major roles in N/A cause iron accumulation increased risk.
From page 137...
... Mammography screening guidelines already take into account two of the most significant risk factors, gender and age. But we could do much
From page 138...
... Screening should only be reduced in cases where it has been demonstrated definitively that less frequent screening will not increase mortality, and it is important that women and their physicians not be misled into underestimating risk. FIGURE 4-1 Breast cancer screening based on stratified risk assessments.
From page 139...
... With the exception of BRCA1 mutations and other gender-specific factors such as me narche and childbirth, breast cancer risk factors for men are similar to those in women, with older age and history of cancer being the predominant factors. How ever, the absolute risk of breast cancer is so low that screening mammography is not warranted in men.
From page 140...
... But the Gail model has some limitations. It has predictive value only for women over age 35 who have not previously been diagnosed with breast cancer,67 and it does not incorporate specific genetic risk factors.
From page 141...
... . In theory, assessment of individuals' breast cancer risk could foster more accurate and less costly early breast cancer detection by determining screening strategies that are tailored to individual risks.
From page 142...
... But the comparison remains impressive -- and suggests that some women over 60 might have a lower risk of breast cancer than average-risk 40-year-old women. It has been known for some time that the risk of developing breast cancer drops with declining levels of serum estradiol, which is the most active type of estrogen,37 but this study used a highly sensitive test to measure estradiol that allowed greater resolution of low estrogen levels than is possible in standard tests.
From page 143...
... A 1996 study in which more than 900 women were interviewed found a striking disparity between Gail model objective risk factors and the accuracy of women's beliefs about their own risk and adherence to mammography screening guidelines.20 The observation that participation in screening mammography programs declines with age reflects this discordance between belief and behavior (Figure 4-2)
From page 144...
... . 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.
From page 145...
... 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.
From page 146...
... 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.
From page 147...
... . 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
From page 148...
... 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.
From page 149...
... 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.
From page 150...
... 2004. Risk factors for breast cancer according to estrogen and progesterone receptor status.
From page 151...
... 1996. Gail model breast cancer risk components are poor predictors of risk perception and screening behavior.
From page 152...
... 2003. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
From page 153...
... model of breast cancer risk prediction and implications for chemopreven tion. J Natl Cancer Inst 93(5)
From page 154...
... 1998. Breast cancer risk and measured mammographic density.


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