Understanding the risk factors for breast cancer permits us to identify women at increased risk, and intervene to modify that risk, either individually or societally. Incidence — In 2007, approximately 178,480 American women will be diagnosed with breast cancer, and 40,460 women will die from the disease. The lifetime probability of developing breast cancer is one in six overall, and one in eight for invasive breast cancer. In the early 1980s, breast cancer rates rose steeply by 3.7 percent per year over the baseline incidence. This was most likely the result of increasing use of screening mammography, since the incidence of ductal carcinoma in situ (DCIS) and stage I carcinomas increased, while that of higher stages either decreased or remained stable. Since 1987, incidence rates have leveled off, and there was actually a decrease in incidence of 4.1 percent per year from 2001 to 2003. Data collected by the SEER program between 1992 and 1998 suggested that the incidence of estrogen (ER) and/or progesterone (PR) receptor-negative breast cancer was declining while that of hormone receptor-positive disease was increasing. At least some of this increase might be attributable to the use of hormone replacement therapy (HRT) in the 1980s and 1990s, since HRT may preferentially increase the risk of hormone receptor-positive tumors over hormone receptor-negative cancers. It is encouraging that breast cancer incidence rates (particularly those of hormone receptor-positive tumors) appear to have declined in 2003 but with little additional decrease in 2004. The causes of the decrease are not yet known, but discontinuation of HRT due to the data from the Women's Health Initiative (WHI) linking HRT and breast cancer as well as saturation/leveling off of mammography levels may be contributory. Discontinuation of HRT has probably had a greater effect Other SEER data have identified a twofold higher proportion of lobular cancers over the period between 1987 and 1999 (contrasting with stable rates of invasive ductal cancers over this same time period). This finding is particularly interesting in view of studies that link HRT to lobular cancers. Global variation — Globally, breast cancer incidence rates are highest in North America and northern Europe, and lowest in Asia and Africa. Incidence rates in Japan and urban China have been rising in recent years. These international differences are thought to be related to societal changes occurring during industrialization (eg, changes in fat intake, body weight, age at menarche, and/or lactation, and reproductive patterns such as fewer pregnancies and later age at first birth). Studies of migration patterns to the United States are consistent with the importance of cultural and/or environmental changes. In general, incidence rates of breast cancer are greater in second-generation migrants, and increase further in third- and fourth- generation migrants. Even within a country like the United States, the breast cancer risk varies substantially among regions. Mortality — Overall breast cancer mortality rates have declined since 1975, attributable to the increased use of screening mammography and the aggressive use of adjuvant therapies. However, this trend has not been equally seen in all subgroups:
RISK FACTORS — Many risk factors have been associated with breast cancer. These include:
Each of these risk factors and others will be discussed in the remainder of this topic. AGE/GENDER — Both age and gender are among the strongest risk factors for breast cancer development. Breast cancer occurs 100 times more frequently in women than in men. In the United States, there are an estimated 178,480 invasive breast cancers diagnosed annually among women, and 2030 among men Incidence rates rise sharply with age until about the age of 45 to 50 when the rise is less steep. The change in slope probably reflects the impact of hormonal change (menopause) that occurs about this time, although alternative hypotheses have been proposed. At age 75 to 80, the curve flattens and decreases only slightly thereafter. RACE/ETHNICITY — In the United States, breast cancer is the most common cancer among women of every major ethnic group, although there are interracial differences. As an example, in data from the American Cancer Society, the highest rates occur in whites (141 cases per 100,000 women). The rates are lower in blacks (119 per 100,000), Asian Americans/Pacific Islanders (97 per 100,000), Hispanic/Latina women (90 per 100,000), and American Indians/Alaska natives (55 per 100,000). Much of these ethnic differences are attributable to factors associated with lifestyle and socioeconomic status (eg, access to diagnosis and treatment), which also appear to explain at least some of the disparities in survival that are often attributed solely to race. Genetic and/or biologic factors also may contribute As an example, the following observations have been noted in black women:
BENIGN BREAST DISEASE — Benign breast conditions include a wide spectrum of pathologic entities. Nonproliferative lesions (fibrocystic change, solitary papilloma, simple fibroadenoma) are not associated with an increased risk for breast cancer. The important precursors of noninvasive or invasive breast cancer are proliferative lesions, particularly those with cytologic atypia. The risk of invasive breast cancer is slightly increased (relative risk 1.3 to 2) for proliferative lesions without atypia (complex fibroadenoma, moderate or florid hyperplasia, sclerosing adenosis, intraductal papillomas). It is higher (relative risk 4 to 6) for proliferative lesions with atypia (atypical lobular hyperplasia, atypical ductal hyperplasia), and higher still (10-fold) when the atypia is multiofocal PERSONAL HISTORY OF BREAST CANCER — A personal history of either invasive or in situ breast cancer increases the risk of developing an invasive breast cancer in the contralateral breast. With in situ lesions, the 10-year risk of developing an invasive breast cancer in the contralateral breast is 5 percent. In women with invasive breast cancer, the risk of developing contralateral breast cancer is 1 and 0.5 percent per year for premenopausal and postmenopausal women, respectively. Socioeconomic status — Women of higher socioeconomic status are at greater risk for breast cancer, with as much as a twofold increase in incidence from lowest to the highest strata. However, it does not appear that socioeconomic status is an independent risk factor. Instead, the influence of socioeconomic status (educational, occupational, and economic level) is thought to reflect differing reproductive patterns with respect to parity, age at first birth, age at menarche, and utilization of screening mammography Geographic residence — As mentioned above, there are marked variations in breast cancer incidence and mortality among countries. In addition, incidence and mortality rates vary within a country. In the United States, for example:
Most likely, these clusters are due to differences in know breast cancer risk factors such as reproductive hormonal factors including age at first birth or menarche, age at first birth, and breastfeeding ( Weight — Weight and body mass index (BMI) have opposite influences on postmenopausal as compared to premenopausal breast cancer.
- In a pooled analysis of seven prospective studies in the United States, women who weighed at least 80 kg (176 lbs) had a 25 percent higher risk of breast cancer as compared to those weighing less than 60 kg (132 lbs), after adjusting for height. Expressed in terms of BMI, women with a BMI >33 kg/m2 had a 27 percent increased breast cancer risk compared to those with a BMI <21 kg/m2. - In the Nurses' Health Study, among women who did not use HRT, women who gained 10 kg or more since menopause had an 18 percent higher risk of breast cancer as compared with women who maintained their weight . By comparison, women who did not use postmenopausal HRT and who lost and kept off more than 10 kg had a 57 percent lower risk compared to women who maintained their weight after menopause. These relationships are most likely due to higher circulating levels of estrogens in heavier women who have more adipose tissue, leading to an increased peripheral conversion of estrogen precursors to estrogen. As an example, among a sample of postmenopausal women from the Nurses' Health Study, the mean serum estradiol concentration was 4.7 pg/mL among women with a BMI less than 21 but 10.0 pg/mL among women with a BMI greater than or equal to 29 kg/m2 Obesity is also associated with a higher risk of dying from breast cancer [
The biologic mechanisms underlying the association between premenopausal obesity and a reduction in breast cancer are unclear. High BMI can be associated with irregular or long menstrual cycles, or with polycystic ovary syndrome, and it has been suggested that anovulation, which is associated with these characteristics, and with decreased levels of estradiol and progesterone, may explain the lower risk of breast cancer in these women However, the data are conflicting. Although anovulatory fertility was associated with a decreased risk of breast cancer in the Nurses' Health Study, adjustment for menstrual patterns and ovulatory infertility in the statistical models did not significantly influence the inverse association between premenopausal BMI and breast cancer. Thus, it is likely that other mechanisms besides ovulation underlie the BMI/breast cancer relationship in premenopausal women. Height — In the majority of studies, increased height has been associated with a higher risk of both premenopausal and postmenopausal breast cancer. This was illustrated in the previously described pooled analysis of seven prospective cohort studies: women who were at least 175 cm (69 inches) tall were 20 percent more likely to develop breast cancer than those less than 160 cm (63 inches) tall The exact mechanism underlying this association is not known, but may include prenatal as well as childhood exposures, such as birth weight and diet/energy balance, or the components of the Insulin-like growth factor (IGF) axis. Physical activity — Regular physical exercise appears to provide modest protection against breast cancer , but the relationship is complex, particularly in premenopausal women. Although some studies have shown a decreased risk of premenopausal breast cancer in women who exercise more, others have shown no difference. These discrepant findings may reflect counterbalancing effects on risk factors. In premenopausal women, even moderate levels of physical activity can be associated with anovulatory cycles, which are associated with decreased risk. On the other hand, thinner premenopausal women have a higher risk of breast cancer than do heavier women. ( Among postmenopausal women, the data are more consistent for a protective effect of regular strenuous activity on the incidence of breast cancer. As an example, in the Women's Health Initiative Observational study, the benefit of physical activity was most pronounced in women who performed strenuous exercise at age 35 compared to a younger (age 18) or older (age 55) age, and in women who currently engaged in the equivalent of 10 hours or more per week of brisk walking, particularly if they were in the lowest tertile of BMI (RR 0.63 for the combination) The reduction in breast cancer risk in women who exercise may be mediated in part through weight control However, some studies have failed to show an influence of BMI on the relationship between physical activity and breast cancer risk. Other data support the possibility that increased physical activity might reduce breast cancer risk through reduction in serum estrogens, at least in postmenopausal women Dietary factors — With the exception of alcohol intake, which can be measured fairly accurately by questionnaires, there are methodologic issues to measuring nutritional intake and analyzing its relationship to cancer that complicate the interpretation of the studies. Alcohol intake is the dietary factor with the strongest evidence of an association with breast cancer incidence. Alcohol — Moderate alcohol intake is associated with an increased risk of hormone receptor-positive breast cancer, and the effect appears to be additive with hormone replacement therapy. Several mechanisms have been postulated to explain this effect. This topic is discussed in detail elsewhere. Fat intake — Animal and ecologic studies have shown a positive correlation between fat consumption and increased breast cancer risk. However, the results of case-control and prospective cohort studies have been mixed, possibly because of the limited range of dietary fat in the typical American diet, and an interaction between reproductive variables, menopausal status, and fat intake. The following represents the range of findings:
An intake of 20 percent of calories from fat is very low, particularly for Americans whose average fat consumption is 30 percent of caloric intake or higher. In the Nurses' Health Study (described below), fewer than 5 percent of women consumed <20 percent of calories from fat.
An alternative diet hypothesis suggests that the influence of high fat diets may be more important during prepubertal years, particularly in influencing the early onset of menarche. In summary, despite intense interest in dietary fat as a risk factor for breast cancer, the studies have been inconsistent, and for those that show a positive association, the effect has been modest. In contrast, the data linking postmenopausal BMI and weight gain with a higher risk of breast cancer have been consistent, and demonstrate a stronger association. Intake of red meat — An association between higher intake of red meat (> 5 servings per week) and hormone receptor-positive premenopausal breast cancer was also observed in the Nurses' Health Study II and in the UK Women's Cohort Study. A similar association had been previously described in the meta-analysis cited above. Calcium/Vitamin D — Several studies suggest that intake of low-fat dairy products may protect against breast cancer, mainly in premenopausal women. In the largest prospective cohort study of over 88,000 women in the Nurses' Health Study, there was an inverse association between breast cancer risk and the intake of low-fat dairy products, calcium (mainly dairy intake), and vitamin D (mainly non-dairy intake) in premenopausal but not postmenopausal women. The Women's Health Study confirmed these findings, showing a lower risk of premenopausal but not postmenopausal breast cancer with higher calcium/vitamin D intake Similarly, a large pooled analysis of eight prospective studies that mainly comprised postmenopausal women did not find a strong association between dairy intake and breast cancer risk. And, a preliminary report of a WHI randomized trial of calcium plus vitamin D in postmenopausal women did not report any significant influence of supplementation on breast cancer risk. Phytoestrogens — Phytoestrogens are naturally occurring plant substances with a chemical structure that is similar to 17-beta estradiol. They consist mainly of isoflavones (found in high concentrations in soy beans and other legumes), and lignans (found in a variety of fruits, vegetables, and cereal products). Although tofu is the main source of soy in Asian diets, soy intake mainly comes from soy additives to non-soy foods in Western diets. Isoflavones (genistein and daidzein) are an important component of soy; they are weak estrogens compared to estradiol. The high soy intake and low rates of breast cancer in Asian populations have led to the hypothesis that soy consumption might decrease breast cancer risk by displacing estradiol and functioning as a relative antiestrogen. The evidence linking soy to breast cancer risk is summarized by the following observations:
The relationship between intake of non-soy phytoestrogens (ie, lignans) and breast cancer risk has not been well-studied. However, at least one prospective cohort study suggests a modest but significant association between high dietary intake of plant lignans and exposure to enterolignans (as measured by a self-administered diet history questionnaire) and a reduced risk of hormone receptor-positive breast cancer among Western women who do not consume a diet rich in soy. Concerns have been raised as to a possible adverse impact of phytoestrogens on breast cancer risk if started after menopause. In vitro and in vivo studies show that some phytoestrogens have weak estrogenic properties (promote breast cancer cell growth) in a low-estrogen environment, and antiestrogenic properties in a high-estrogen environment . If true, use of phytoestrogens could increase, not decrease breast cancer risk in postmenopausal women. In summary, the data linking soy intake and breast cancer are inconsistent, and there is no strong evidence to promote soy-rich diets to prevent breast cancer. However, given the fact that none of the studies has shown harm, it is probably safe for patients to consume soy in amounts common to American or Asian diets. Micronutrients — There is no strong evidence for an effect of intake of either vitamin E or C and breast cancer risk. The data linking vitamin A intake to breast cancer risk are conflicting. Some studies on selenium suggest that the lowest levels may be associated with an increased risk, but higher levels are not protective. Others have suggested that alterations in selenium concentration are a consequence rather than a cause of cancer Caffeine — A number of studies have failed to show any association between caffeine intake and breast cancer risk . Smoking — The relationship between cigarette smoking and breast cancer is controversial, and complicated by the interaction of smoking with both alcohol and the endogenous hormonal influences that alter the risk of breast cancer. Studies have shown widely varying results, with many showing modestly increased risk, others decreased risk, and some, no effect. A relationship between exposure to secondhand smoke and breast cancer risk in premenopausal women was suggested in a review conducted by the California Environmental Protection Agency.* However, the case sizes in the included studies were small, and the analysis did not control for standard breast cancer risk factors. One case-control study reported a relationship between breast cancer risk and high urinary cadmium levels (for which the predominant source of exposure in smokers is cigarette smoke, although it is also found in foods), although a cause-effect relationship has not yet been proven REPRODUCTIVE/HORMONAL RISK FACTORS — Prolonged exposure to and higher concentrations of endogenous estrogen increases the risk of breast cancer. The production of estrogen subtypes (estradiol, estriol, estrone) is modulated by ovarian function: menarche, pregnancy, and menopause. After menopause, the main source of estrogen is dehydroepiandrosterone (DHEA), which is produced in the adrenal gland and metabolized in peripheral fat tissue to estradiol and estrone. The roles of progestins, prolactin, and insulin-like growth factor are less clearly established. The key reproductive factors that influence breast cancer risk are age at menarche, age at first live birth, age at menopause, and possibly parity and breast-feeding Age at menarche and menopause — Younger age at menarche is associated with a higher risk of breast cancer. In one study, for every two-year delay in the onset of menarche, there was a 10 percent reduction in cancer risk. Age at menarche may influence the biology of breast cancer, with one case control study of disease-concordant monozygotic twin pairs observing that the twin with earlier onset of menses was five times more likely to be diagnosed with breast cancer before the other. In contrast, other hormonal factors (ie, later first pregnancy, lower parity, later menopause) did not predict an earlier diagnosis when both twins were affected. The explanation for this protection is that late onset of regular menstrual cycles are associated with later, and thereby less total lifetime exposure to hormones. Consistent with the importance of cumulative estrogen exposure are the following observations:
Menstrual patterns/infertility — As noted above, epidemiologic studies have consistently found an association between menarche, menopause, and the risk of breast cancer. These events affect the number of lifetime ovulatory cycles, and influence a woman's cumulative exposure to ovarian hormones. In fact, ovulatory abnormalities have been offered as one potential explanation for the inverse association between obesity and breast cancer risk in premenopausal women. Although several epidemiologic studies suggest a link between infertility due to anovulatory disorders and a decreased risk of breast cancer, the results are inconsistent across studies. Others, adjusting for parity and age at first birth, have observed either no association or a slight increase in breast cancer risk associated with infertility Parity — Nulliparous women are at increased risk for breast cancer compared with parous women; the relative risk ranges from 1.2 to 1.7. The protective effect of pregnancy is not seen until after 10 years following delivery. Enigmatically, breast cancer risk increases transiently after a full-term pregnancy. The postulated mechanism by which pregnancy is protective is discussed elsewhere. Whether multiparity confers protection against breast cancer has been a matter of controversy; the majority of studies suggest a decreased risk with increasing number of pregnancies [114]. Age at first birth — The younger a woman is at her first full-term pregnancy, the lower her breast cancer risk
The explanation for the effect of early first live birth is that full cellular differentiation, which occurs in the gland during and after pregnancy, protects the breast from breast cancer development. A later age at first birth is hypothesized to confer a greater risk than nulliparity because of the additional proliferative stimulation placed on breast cells that have already become initiated and are at a later stage in development and perhaps more prone to cell damage. Abortion — Since abortion disrupts the maturation process of the breast, it has been hypothesized to increase breast cancer risk. Research in this area has been difficult to perform because of concerns about underreporting of abortions, particularly in the United States. As a result, the best data come from registry studies from Europe, where abortions are performed through the national health service. Both a large pooled analysis and population-based cohort studies do not support an association between abortion and breast cancer risk. In March 2003, the National Cancer Institute convened a workshop evaluating the link between early reproductive events and breast cancer, which concluded that induced abortion is not associated with an increase in breast cancer risk (available at www.cancer.gov/cancerinfo/ere). Breastfeeding — A protective effect of breastfeeding has been shown in multiple case-control and cohort studies, the magnitude of which is dependent on the duration of breastfeeding, and on the confounding factor of parity. The following findings were noted in the largest pooled analysis that included individual data from 47 epidemiologic studies including 50,302 women with invasive breast cancer and 96,973 controls:
The protective effect of breastfeeding may be stronger for the development of breast cancer during the premenopausal years. A postulated mechanism for the protective effect of breastfeeding is that it may delay the reestablishment of ovulatory cycles. Other mechanisms may be the increase in prolactin secretion and the concomitant decrease in estrogen production. Endogenous hormone levels — Reproductive risk factors such as parity, age of menopause, and age of menarche influence breast cancer risk. The main theory regarding the association between reproductive factors and breast cancer risk is that hormone type, blood/tissue level, timing, and interactions are responsible for the relationships observed. Hormones promote breast cancers in animals, and various studies have manipulated hormones to demonstrate this point. Estrogen levels — Obese postmenopausal women have higher estrogen levels, due to the conversion of adrenal androgens to estrogens in fatty tissue; consequently, they have a higher risk of breast cancer than nonobese postmenopausal women ). Furthermore, reducing estrogen levels (by suppressing ovarian function in premenopausal women or use of drugs such as aromatase inhibitors in postmenopausal women) lowers breast cancer risk. These observations suggest that serum estrogen levels are linked to the risk of breast cancer. The available epidemiologic data are more convincing for postmenopausal as compared to premenopausal women.
- A review of nine prospective epidemiologic studies found a positive relationship between serum estradiol concentration and breast cancer risk. - Similar findings were noted in a later study of 7705 postmenopausal women enrolled on the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: women with the highest tertile of serum estradiol levels (>12 pmol/L) had a two-fold higher risk of invasive breast cancer than women with lower levels. Furthermore, women in the highest estradiol tertile tended to have a greater reduction in the risk of breast cancer with raloxifene compared to women in the low estradiol subgroup (79 versus 64 percent). In contrast to these results, a subset analysis of postmenopausal women enrolled in the NSABP's Breast Cancer Prevention Trial did not find a significant association between endogenous sex hormone levels and either breast cancer risk or benefit from tamoxifen. - Data from the Nurses' Health Study suggest that the association is strongest for hormone receptor-positive breast cancers. In this longitudinal study of 121,700 female registered nurses in the United States, endogenous hormone levels were measured in 322 women who developed breast cancer and in 643 age-matched controls without breast cancer. When the highest and lowest quartiles of serum hormone concentration were compared, there was a significant direct association between breast cancer risk and levels of both estrogens and androgens. However, the association was strongest when the analysis was restricted to ER and PR-positive tumors, and in situ tumors.
Taken together, the results of most prospective case-control and cohort studies and a pooled analysis of five of the reports suggest that, although women who developed breast cancer had somewhat higher prediagnostic blood levels of estradiol than women who did not get breast cancer, the difference was not statistically significant in any of the studies. On the other hand, a significant association between serum estrogen levels during the follicular phase of the menstrual cycle and breast cancer risk was shown in a case control study nested within the Nurses' Health Study. Women in the highest (versus lowest) quartiles of follicular phase total and free estradiol had significantly higher rates of breast cancer (relative risk [RR] 2.1 and 2.4, respectively). The association was stronger for invasive breast cancer (RR 2.7) and for hormone receptor-positive tumors (RR 2.7 and 2.8 for total and free estradiol, respectively). In contrast, there was no significant association between breast cancer risk and luteal phase hormone levels. Serum concentrations of androgens may also be associated with breast cancer risk. Bone density — Because bone contains estrogen receptors and is highly sensitive to circulating estrogen levels, bone mineral density (BMD) may be a surrogate marker for long-term exposure to endogenous estrogen. In multiple studies, women with higher bone density had a higher breast cancer risk. In one study, for example, incidence rates of breast cancer per 1000 person-years increased from 2.0 among women in the lowest age-specific quartile for metacarpal bone mass, to 2.6, 2.7, and 7.0 among those in the second, third, and highest quartiles, respectively Other hormones — Postmenopausal women with higher testosterone levels may have an increased risk of breast cancer in most but not all studies Although the data in premenopausal women are more limited, two large, nested case-control studies suggest a similar relationship between blood levels of androgens and elevated breast cancer risk. In one study, there was an approximately 1.5-fold greater risk for the highest versus lowest quartile of serum testosterone, androstenedione, and dehydroepiandrosterone]. In the Nurses' Health Study, an association between androgen/testosterone levels and higher breast cancer risk was seen only for hormone receptor-positive cancers Studies of other hormones (progesterone, prolactin, insulin, and insulin growth factor) are few. The available data suggest a possible increased risk of breast cancer with higher serum levels of prolactin, and with higher serum levels of insulin-like growth factor I (IGF 1), as well as its main binding protein IGFBP-3 in premenopausal but not postmenopausal women Although some studies suggest a slightly increased risk of breast cancer in postmenopausal women with type 2 diabetes, others do not. Diabetes is not generally considered a significant breast cancer risk factor Breast density — The extent of dense tissue within the breast is variable within the population. Although largely an inherited trait, there appears to be a potentially modifiable component. Hormone replacement therapy increases breast density while tamoxifen decreases it.
Besides increasing the difficulty of mammographic detection, the presence
of dense breast tissue is also independently associated with an increased
risk of breast cancer. In multiple independent epidemiologic
studies, the risk of breast cancer is four to five times greater in women
with mammographically dense breasts (usually defined as
Published guidelines for mammogram interpretation recommend that breast density be routinely reported, though this has not been widely incorporated into general practice. There is little agreement as to the best method to quantify breast density. Little is known about why increased breast density is associated with higher rates of breast cancer, but at least some data suggest that it appears to be independent of estrogen-mediated effects, as evidenced by the following:
Growth factors other than estrogen (eg, insulin-like growth factor-1) may be the mechanism for the noted association. Exogenous hormone factors — Until the Women's Health Initiative was begun in the 1990s, no large prospective randomized controlled study had examined the relationship between exogenous hormones and breast cancer. Otherwise, the bulk of the available data are based upon observational studies, which are more likely to contain biases. Oral contraceptives — Many epidemiologic studies have not demonstrated an association between oral contraceptive use and the risk of breast cancer. However, a large pooled analysis calculated a small but significant increase in relative risk of breast cancer (RR =1.24) in current oral contraceptive users. Concerns have been raised about this analysis because a low percentage of women had ever used oral contraceptives (40 percent), and it lacked the follow-up necessary to determine whether there were long-term effects of oral contraceptive use. There are now reassuring data from two studies that oral contraceptives do not increase breast cancer risk later in life Hormone replacement therapy — The bulk of the currently available evidence supports a causal relationship between the use of postmenopausal hormone replacement therapy (HRT) and breast cancer, predominantly hormone receptor-positive breast cancer. The risk is modest but consistently demonstrated. As an example, in the Women's Health Initiative trial, the relative risk of breast cancer was increased 1.24-fold (95% CI 1.01-1.54) when women taking combined estrogen/progesterone for an average of 5.2 years were compared to those receiving placebo In contrast, a trend towards a slightly lower breast cancer risk was seen in women taking unopposed estrogen (HR 0.77 for unopposed estrogen versus placebo, 95% CI 0.59-1.01). This comparison narrowly missed statistical significance (p = 0.06). Long-term use of HRT is associated with the highest risk. In contrast, short-term HRT appears not to increase the risk of breast cancer significantly, although it may make mammographic detection more difficult. Concurrent progestin use appears to further increase risk above that with estrogen alone. T Infertility treatment — Whether ovulation induction for the treatment of infertility increases the risk of breast cancer is a matter of debate. This topic is discussed in detail elsewhere. FAMILY HISTORY AND GENETIC RISK FACTORS — Family history is an important risk factor for breast cancer. However, a positive family history is only reported by 15 to 20 percent of women with breast cancer. The risk associated with having an affected first or second degree maternal or paternal relative is modulated by the age of both the case patient and the family member at diagnosis, and the number of female first-degree relatives with and without cancer. As an example, in a pooled analysis using data from over 50,000 women with breast cancer and 100,000 controls, the risk of breast cancer for a woman with one affected first-degree relative was increased 1.80 fold. With two affected first-degree relatives, the risk is increased 2.93 fold. The risk ratios were highest for women with young affected relatives. Thus, the risk was increased 2.9 fold for a woman whose relative was diagnosed before age 30, but only 1.5 fold increased if the affected relative was diagnosed after age 60. Similarly, the risk of breast cancer before age 40 was increased 5.7-fold if one relative had breast cancer before age 40. Genetic mutations — Studies in twins suggest that the majority of familial aggregation of breast cancer results from inherited susceptibility. However, specific genetic mutations that predispose to breast cancer are rare; only 5 to 6 percent of all breast cancers are directly attributable to inheritance of a breast cancer susceptibility gene such as BRCA1, BRCA2, p53, ATM, and PTEN In affected families, it is not known to what extent the influence of a shared environment or a shared lifestyle contributes to the development of breast cancer. Inherited genes with a low penetrance may be difficult to identify. Such genes may account for a familial-specific metabolism of DNA toxins, which in turn initiates or promotes breast cancer. The expression of these weak genes may be influenced significantly by differences in the environment. In contrast, BRCA1 and BRCA2 are strong genetic mutations with little respect for environmental differences. Quantifying risk — The assessment of breast cancer risk for a woman with a family history of breast cancer depends upon the likelihood of her having a true hereditary predisposition. When the history is not suggestive of true hereditary breast cancer, empiric models are available (eg, the Gail model to estimate the breast cancer risk. Newer models have been developed that also incorporate other risk factors such as mammographic breast density. Other adjustments to the Gail model reflecting African-American ancestry have also been proposed In contrast, if the patient's family history is suggestive of a hereditary breast cancer syndrome, risk assessment is based upon probabilistic estimates of finding a gene mutation, the chance that the individual is a gene carrier based upon Mendelian analysis, and the risk of cancer based upon estimates of gene penetrance. EXPOSURE TO IONIZING RADIATION — Exposure to ionizing radiation of the chest at a young age, as occurs with treatment of Hodgkin lymphoma or in survivors of atomic bomb or nuclear plant accidents, is associated with an increased risk of breast cancer. The most vulnerable ages appear to be between 10 to 14 (the prepubertal years), but excess risk is seen in women exposed as late as 45 years of age. After age 45, there does not appear to be any increased risk. Whether there is a link between breast cancer and low levels of irradiation, such as those in diagnostic imaging tests (eg, mammography, chest radiographs, diagnostic spine imaging, CT scans), is controversial. At least for women without an inherited predisposition to breast cancer, the impact of radiation-associated breast cancer from routine diagnostic imaging is thought to be small to nonexistent. Data surrounding this issue in women with a genetic predisposition to breast cancer are discussed elsewhere. ENVIRONMENTAL EXPOSURES — Organochlorines include polychlorinated biphenyls (PCB's), dioxins, and organochlorine pesticides such as DDT. These compounds are weak estrogens, highly lipophilic, and capable of persisting in body tissues for years. However, most large studies have failed to find an association Cosmetic breast implants, electromagnetic fields, electric blankets, and hair dyes also have not increased risk in most studies Nocturnal light exposure — At least three studies and a meta-analysis support an association between exposure to light at night and the risk of breast cancer. However, the strength of the association has been variable. A meta-analysis exploring the relationship between night work and breast cancer risk included 13 reported studies of airline cabin attendants and nighttime shift workers. The aggregate estimate of the relative risk for all studies combined was 1.48 (95% CI 1.36 to 1.61) and was of a similar magnitude for female airline cabin crew (standardized incidence rate [SIR] 1.44, 95% CI 1.26 to 1.65) and female night workers (relative risk 1.51, 95% CI 1.36 to 1.68). It is postulated that exposure to light at night suppresses the normal nocturnal production of melatonin by the pineal gland, which in turn, could increase the release of estrogen by the ovaries. In one of the above studies, the risk of developing breast cancer was significantly higher in women who did not typically sleep between 1 AM and 2 AM, the nighttime period when melatonin levels are at their highest (OR 1.14) NSAID use — Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit the formation of both benign and malignant tumors in the colon. However, the data regarding a possible protective effect of NSAID ingestion on breast cancer risk are mixed. Several epidemiologic studies (including data from the Women's Health Initiative Observational Study) suggest a modest benefit (average 15 to 20 percent reduction in risk) for regular, long-term NSAID use. However, other studies, including four large population-based studies (the Nurses' Health study, the California Teachers study, the Women's Health Study, and the American Cancer Society Cancer Prevention Study II Nutrition Cohort) fail to show a significant protective effect of regular NSAID or aspirin use (low-dose or regular strength) on breast cancer risk Thus, the relationship between long-term intake of aspirin or other NSAIDs and breast cancer risk remains uncertain.
Antibiotic use — An association
between antibiotic use and breast cancer was first suggested in a case
control study which compared 2266 women with invasive breast cancer and
7953 randomly selected, age-matched controls who were enrolled in the same
health plan . As expected, this report stimulated other investigations, none of which observed any association between antibiotic use and breast cancer risk. Given the lack of biologic plausibility, and unresolved questions regarding association as well as causality, these data do not justify avoidance of clinically indicated antibiotic usage. However, taken together with the increasing problem of widespread antibiotic resistance, they underscore the importance of carefully considering the use of antibiotics in the absence of a clear indication. RISK FACTORS FOR MALE BREAST CANCER — Men are more than one hundred times less likely to get breast cancer than women. Risk factors for male breast cancer include Klinefelter's syndrome, testicular and liver pathology, a family history of breast cancer, and BRCA2 mutations. RISK MODIFICATION — There are several approaches that women can take to decrease their risk of breast cancer. Lifestyle changes — A number of lifestyle changes may reduce breast cancer risk:
Medication — For women who are already at higher than average risk, their risk of developing breast cancer can be reduced by at least 50 percent or more by taking tamoxifen or raloxifene for five years. Tamoxifen is the only drug approved by the United States Food and Drug Administration (FDA) for the prevention of breast cancer. The common side effects of tamoxifen are not serious (eg, hot flashes, menstrual irregularities, vaginal discharge), but the uncommon ones (eg, blood clots, pulmonary embolus, stroke and uterine cancer) can be life threatening and are predominantly seen in women over 50 years of age. Raloxifene is associated with a lower risk of thromboembolic events, and probably uterine cancer as well, but is not yet approved as a chemopreventive agent. These topics are discussed in detail elsewhere. Early detection — Even if breast cancer incidence cannot be substantially reduced for some women who are at high risk for developing the disease, the risk of death from breast cancer can be reduced by regular mammography screening. |
75
percent density) compared to women of similar age with less or no dense
tissue. Furthermore, others have shown a significant association between
longitudinal increases or decreases in breast density on serial screening
mammography and an increased or decreased risk of breast cancer,
respectively