Original Article
Effect of Family History, Body-Fat Distribution, and Reproductive Factors on the Risk of Postmenopausal Breast Cancer
N Engl J Med 1992; 326:1323-1329May 14, 1992
- Abstract
- Abstract
Background.
A family history of breast cancer reflects shared cultural factors, genetic predisposition, or both. There is evidence that the estimated risk associated with a family history of breast cancer increases multiplicatively in combination with other risk factors. We examined the combined effect of family history and anthropometric and reproductive factors on the risk of breast cancer in postmenopausal women.
Methods.
Using data from a prospective cohort study, we studied 37,105 women 55 to 69 years of age to determine whether known risk factors for breast cancer are modified by a reported family history at the time of entry into the study.
Results.
During the first four years of follow-up, 493 new breast cancers were diagnosed. The association of the waist-to-hip ratio (the circumference of the waist divided by that of the hips) with the risk of breast cancer was limited predominantly to women with a family history of breast cancer; the age-adjusted relative risk of breast cancer for the women above the fourth quintile for waist-to-hip ratio as compared with those below the first quintile was 3.2 in women with a family history of breast cancer and 1.2 for women without such a family history. An interaction was observed between a family history of breast cancer and the number of live-born children; the protective effect of higher parity was observed primarily among women with a family history of breast cancer. Similarly, the age-adjusted relative risk of breast cancer associated with a late age at first pregnancy (i.e., ≥30 years) was 5.8 for women with a family history of breast cancer and 2.0 for women without such a family history.
Conclusions.
The increase in the risk of breast cancer associated with a high waist-to-hip ratio, low parity, or greater age at first pregnancy is more pronounced among women with a family history of breast cancer. These findings suggest etiologic differences between familial breast cancer and the sporadic form. (N Engl J Med 1992;326: 1323–9.)
Media in This Article
Figure 1
Adjusted Relative Risk of Breast Cancer In Postmenopausal Women According to Family History of Breast Cancer and Waist-to-Hip Ratio.Figure 2
Adjusted Relative Risk of Breast Cancer in Postmenopausal Women According to Family History of Breast Cancer and Number of Live-Born Children.Article Activity
- Article
ONE of the strongest predictors of a woman's risk of breast cancer is the presence of the disease in her immediate family, especially if the relative had bilateral breast cancer1 2 3 or had the disease early in life.3 4 5 6 7 8 9 The association of family history with an increased risk of the disease cannot be explained by other characteristics, such as age at menopause, age at menarche, parity, or the number of years of menstruation.4 , 6 7 8 Rather, the evidence suggests that family history modifies the effects of other known risk factors; the decreased risk associated with a late age at menarche may be limited to women without a family history of breast cancer,4 , 6 , 10 whereas the effects of a greater age at first pregnancy, greater age at menopause, or menstruation for more than 35 years may be more deleterious among women with a family history of breast cancer.6 , 10 11 12
Interest in genetic factors in breast cancer was heightened by recent reports of linkage of susceptibility genes in selected high-risk families. The Li—Fraumeni syndrome, of which breast cancer is an integral feature, has been attributed to inherited mutations in the p53 gene.13 , 14 This association has not been demonstrated, however, in families with aggregation of breast cancer alone.15 The linkage to anonymous markers on chromosome 17q reported by Hall et al.16 was limited predominantly to families with premenopausal breast cancer. This finding has recently been confirmed in three large families with early-onset breast and ovarian cancer.17 No convincing evidence of the existence of a breast cancer—susceptibility gene for postmenopausal breast cancer has accumulated,18 19 20 21 22 although there are suggestive data linking the estrogen-receptor gene locus to increased risk in one family.23 Breast cancer is likely to be genetically heterogeneous; the classification of families according to epidemiologic risk factors may define genetically homogeneous subgroups and enhance efforts to identify breast cancer—susceptibility genes.
Epidemiologic, experimental, and clinical studies have implicated estrogens in the pathogenesis of breast cancer.24 , 25 Consequently, a number of studies have been conducted to determine whether the levels of endogenous or exogenous estrogens and their metabolism might explain the high risk of breast cancer in some families.26 27 28 29 30 31 32 If reproductive and anthropometric variables increase the risk of breast cancer through an effect on hormone levels or hormone metabolism, examining the interactions of these variables with family history may contribute to our understanding of the pathogenesis of breast cancer and permit us to identify women at greater risk for the disease.33 , 34 In the present study, we used data from a large prospective cohort study of postmenopausal women to investigate this hypothesis.
Methods
The Iowa Women's Health Study Cohort
In 1986 a mailed questionnaire was completed by 41,837 women between 55 and 69 years of age who had valid Iowa driver's licenses in 1985.35 Information on new cases of breast cancer and current residence was collected from these women by means of two follow-up questionnaires. The status of women who did not respond to the follow-up surveys was determined through the National Change of Address Service of the U.S. Postal Service (to identify women who had moved out of state) and the National Death Index of the National Center for Health Statistics (to identify out-of-state deaths). Using both these data sources permitted us to determine the vital status of all but 197 women (0.5 percent), each of whom was identified as not currently living in Iowa. The cohort of women considered to be at risk for incident breast cancer excluded those who reported on the original questionnaire that they were premenopausal (n = 569) or that they had had a previous mastectomy (n = 1764), partial removal of a breast (n = 106), or cancer other than skin cancer (n = 2293). After these women were excluded, 37,105 remained in the cohort and were included in our analyses.
Data Collection
Among other items reported on the 1986 base-line questionnaire were sociodemographic variables (including race, occupation, education level, and residence), gynecologic history, and medical conditions or diseases. The prevalence of cancer was determined by asking whether the woman had ever been told by a doctor that she had any form of cancer except nonmelanoma skin cancer. Participants reported their current height and weight, maximal adult weight, weight one year before the survey, and weight at 18, 30, 40, and 50 years of age. A paper tape measure and written instructions were enclosed so that a friend could measure the circumference of the waist (one inch above the umbilicus) and hips (maximal protrusion). The measurements obtained by this method have been shown to be valid (intraclass correlation with measurements made by a trained technician, ≥0.84) and reliable (intraclass correlation of measures made at two diflerent times, ≥0.85).36 Anthropometric measures were used to derive the body-mass index, defined as the weight in kilograms divided by the square of the height in meters; the body-mass index at age 18 (based on the current height); and the ratio of the waist circumference to that of the hips (waist-to-hip ratio).
Data on the history of breast cancer among mothers, grandmothers, aunts, sisters, and daughters of the respondents were also collected in the base-line questionnaire. No questions were asked about family size, age at onset of breast cancer, or cancer in male relatives, nor was an attempt made to validate reports of cancer in family members.
Identification of Cases of Breast Cancer
Follow-up for the occurrence of cancer in the cohort was performed with use of data from the State Health Registry of Iowa, which is part of the National Cancer Institute's Surveillance, Epidemiology, and End-Results Program. New cases of breast cancer (defined according to code 174 of the International Classification of Diseases) were identified through a computer program that matched cases listed in the registry from 1986 through 1989 and study participants by name, ZIP Code, birth date, and social security number.
Statistical Analysis
For the anthropometric variables, the women were assigned to one of five groups according to quintiles for the reported values of the entire cohort (excluding those who were premenopausal or not at risk for breast cancer) at study entry. Data on reproductive and menstrual history, such as age at menarche and age at first pregnancy, were stratified into four or five categories. Since the reliability of data on second-degree relatives is low,37 in our analyses of the effect of a family history of breast cancer we used only data on the status of mothers, sisters, and daughters (first-degree female relatives). The presence of breast cancer in one or more first-degree relatives was considered a positive family history.
Length of follow-up for each woman was designated as the length of time from the completion of the base-line questionnaire to one of the following events, listed in descending order of priority: the date of diagnosis of breast cancer, the date of death (if death occurred in Iowa), the date the woman moved out of Iowa (if known), the midpoint of the interval between the last follow-up contact and December 31, 1989 (if the date of the woman's departure from Iowa was unknown), or the midpoint of the interval between the date of the last contact and the date of death (for deaths in women who had moved from Iowa). Women for whom these criteria did not apply were assumed to be still living in Iowa, and they contributed follow-up data until December 31, 1989.
Person-years in each exposure category were accumulated for the entire cohort at risk, and separately for those with a family history of breast cancer and those with no such family history. Incidence was calculated by dividing the corresponding number of new cases of breast cancer by the number of person-years of follow-up. Age-adjusted rates were calculated with the MantelHaenszel procedure38 for three five-year categories of age at base line: 55 through 59, 60 through 64, and 65 through 69 years. Relative risks were calculated by dividing the incidence in a particular exposure category by the incidence in the comparison category (which was always the group with no family history of breast cancer). Analyses to control other known risk factors for breast cancer were conducted with proportional-hazards models, with use of the SAS program PHREG.39 The assumption of proportional hazards for the exposures of interest was tested and found not to be violated. Interactions were evaluated by entering cross-product terms between family history (as an indicator variable) and other risk factors for breast cancer (as continuous variables). All tests of interactions involving family history were conducted by proportional-hazards methods. For all relative risks, 95 percent confidence intervals were estimated. Differences in risk-factor levels between women with a family history of breast cancer and women without such a family history were assessed by means of contingency-table analyses or two-sided t-tests.
Results
The age distribution of the cohort at risk is shown (according to family history) in Table 1Table 1
Age Distribution of the Study Subjects According to Family History of Breast Cancer.*. The 31,551 women (87.8 percent) who reported a family history of breast cancer at base line were, on average, six months older than the 4368 women (12.2 percent) with no family history of breast cancer (P<0.001). Of the 493 women with new cases of breast cancer identified through December 31, 1989, 83 (16.8 percent) had a positive family history and 386 (78.3 percent) had a negative family history; an additional 24 women (4.9 percent) could not be classified because of missing data. The age-adjusted relative risk of breast cancer associated with a family history of breast cancer was 1.53 (95 percent confidence interval, 1.21 to 1.94).The age-adjusted relative risks of breast cancer according to selected anthropometric measures and family history are presented in Table 2Table 2
Age-Adjusted Relative Risk of Postmenopausal Breast Cancer in Relation to Anthropometric Factors, According to Family History of Breast Cancer.*. There was a slight trend toward increased risk with increased height among the women as a group (P = 0.029), but only among women with a family history of breast cancer did any of the individual point estimates of relative risk achieve statistical significance. The risk of breast cancer also increased significantly with increasing base-line measures of body weight and body-mass index in the entire sample (P for trend <0.001 in both cases). When the sample was stratified according to family history, the greatest relative risks were observed for the women with a family history of breast cancer who had body-weight and body-mass-index values above the fourth quintile. A high body-mass index at 18 years of age was inversely associated with postmenopausal breast cancer among all the women (P for trend = 0.0019), primarily because of the decreased risk among the women with no family history of breast cancer in the upper quintile group. A striking interaction was observed between the waist-to-hip ratio and family history. For the total cohort, the relative risk of breast cancer for the highest as compared with the lowest quintile group for waist-to-hip ratio was 1.50 (95 percent confidence interval, 1.13 to 2.00; P for trend = 0.0049). In the group with no family history of breast cancer the risk was increased a nonsignificant 20 percent, but among the women with a family history of breast cancer the risk was increased significantly for those with waist-to-hip ratios above the fourth quintile. When women were classified according to both body-mass index and waist-to-hip ratio (median splits), the relative risk of breast cancer associated with a high body-mass index and a high waist-to-hip ratio was 1.35 among women with no family history of breast cancer (95 percent confidence interval, 1.06 to 1.72) but 2.42 among women with such a family history (95 percent confidence interval, 1.66 to 3.51).The age-adjusted relative risks associated with selected reproductive and menstrual-history factors are presented according to family history in Table 3Table 3
Age-Adjusted Relative Risk of Postmenopausal Breast Cancer in Relation to Reproductive and Menstrual-History Factors, According to Family History of Breast Cancer.*. The known inverse association between an older age at menarche and the incidence of breast cancer was evident in this study; menarche after the age of 15 years was associated, overall, with a relative risk of breast cancer of 0.54 (95 percent confidence interval, 0.38 to 0.78) as compared with menarche before the age of 12. However, the effect was confined largely to women without a family history of breast cancer. The risk of breast cancer according to age at menopause was analyzed both for women who reported a natural menopause and for those in whom menopause was the result of surgery or medical therapy. There was no indication of significantly reduced risk among women with early natural or medical menopause, regardless of family history. Although the risks associated with a later age at first pregnancy were evident in the entire cohort (P for trend = 0.0026), the association was much stronger among women with a family history of breast cancer; first pregnancy at or after 30 years of age was associated with a doubling of risk for women without a family history of breast cancer but with a 5.75-fold increase in risk for women with a family history of the disease. Having borne children (parity, >0) was not associated with a lower risk among women without a family history of breast cancer. Compared with nulliparous women with no family history of breast cancer, nulliparous women with a positive family history had a 2.24-fold increase in risk, but the relative risk decreased with the increasing number of live births to a low of 0.57 for women with five or more live-born children.To determine whether the apparent interactions between the waist-to-hip ratio, age at first pregnancy, number of live births, and family history could be accounted for by other risk factors for breast cancer, we performed multivariate analyses with Cox proportional-hazards models. The model included age, the square of the age, body-mass index, body-mass index at 18 years of age, waist-to-hip ratio, number of live births, age at first pregnancy, age at menarche, oral-contraceptive use, and education level (high-school graduation or higher vs. less than high-school graduation). Three cross-product terms were created to represent the interactions of family history (treated as a dichotomous variable) with waist-to-hip ratio, age at first pregnancy, and number of live births (all three treated as continuous variables). When all three family-history interactions were included in the model, only the interaction with the waist-to-hip ratio (P = 0.027) and the number of live births (P<0.005) remained statistically significant; the interaction with age at first pregnancy did not remain significant (P = 0.22).
Two additional proportional-hazards models were then fitted to determine the nature of the two significant interactions. In the first model, nine indicator variables were created to represent the 10 cross-classifications of the quintile groups for family history and waist-to-hip ratio; in this analysis the lowest quintile group of women without a family history of breast cancer served as the reference category. Included as covariates were all the previously specified variables with the exception of age at first pregnancy, which was represented by indicator variables for the following categories: <20, 20 through 24, 25 through 29, and ≥30 years and no pregnancies (nulliparous). Although the only significant elevation in risk associated with a high waist-to-hip ratio was observed for the upper quintile group of women with a family history of breast cancer (relative risk = 2.4; 95 percent confidence interval, 1.5 to 3.8) (Fig. 1Figure 1
Adjusted Relative Risk of Breast Cancer In Postmenopausal Women According to Family History of Breast Cancer and Waist-to-Hip Ratio.), the test for a linear dose–response relation across the five levels showed only borderline significance (P = 0.052). No such trend was observed among the women without a family history of breast cancer (P = 0.89).The second proportional-hazards model was designed to test the interaction between family history and the number of live births; it included age, the square of the age, body-mass index, body-mass index at 18 years of age, waist-to-hip ratio, age at menarche, oral-contraceptive use, education level, and indicator variables for four categories of age at first pregnancy (<20, 20 through 24, 25 through 29, and ≥30 years). Three indicator variables were created to represent the following categories among the women with no family history of breast cancer: one or two, three or four, and five or more live births. The women with no live births served as the reference group. Four additional indicator variables were used to represent these same four categories for the number of live births among the women with a family history of breast cancer. Although nulliparity and low parity (one or two live-born children) were associated with an increased risk of breast cancer among the women with a family history of breast cancer (Fig. 2Figure 2
Adjusted Relative Risk of Breast Cancer in Postmenopausal Women According to Family History of Breast Cancer and Number of Live-Born Children.), a significant trend of decreasing risk with increasing parity was observed (P for trend = 0.0021). The association was less apparent among women without a family history of breast cancer (P for trend = 0.089).Discussion
It is fairly well established that obesity influences the risk of postmenopausal breast cancer,40 but several recent studies suggest that the pattern of body-fat distribution also influences that risk.41 42 43 The mechanisms behind this association are not clear, but both body weight and waist-to-hip ratio are correlated positively with androgen levels.44 , 45 In postmenopausal women, the peripheral conversion of androgens, chiefly androstenedione, in adipose tissue is the chief source of estrogens.46 This indirect mechanism has been cited as the most likely explanation for the association of obesity with increased risk of breast cancer.47 However, androgens may also increase risk directly by increasing cell proliferation after binding to androgen receptors.48 Adipose tissue synthesizes substantial amounts of Type I insulin-like growth factors (IGF-I), and stromal cells within primary breast tumors express IGF-I receptors.49 The level of IGF receptors is positively correlated with the levels of estrogen and progesterone receptors,50 , 51 and the proliferation of breast-cancer cell lines by estrogen may be mediated through these IGF-I receptors.52 Finally, the body-mass index is also positively associated with increased concentrations of free and albumin-bound estradiol.53 It is the elevation in the non—protein-bound and albumin-bound fractions that appears to increase the risk of disease.54 55 56 The level of sex hormone—binding globulin is associated with the waist-to-hip ratio,57 and the data from the small study by Ingram et al.53 suggest decreased levels of sex hormone—binding globulin in women with a family history of breast cancer, above and beyond the decrease associated with obesity. Although an interaction of waist-to-hip ratio and family history in causing non-insulin-dependent diabetes has been suggested,58 a relation between these factors and the risk of breast cancer has apparently not been reported previously.
A number of studies have shown that obesity59 60 61 and body-fat distribution61 , 62 are influenced by genetic factors. The study by Stunkard and colleagues,60 for example, showed that the heritability of body-mass index in female twins reared apart may approach 70 percent. One tenable hypothesis raised by our data is that the familial aggregation of breast cancer in postmenopausal women and familial patterns of abdominal fat deposition are part of a common mechanistic pathway. At least one study has demonstrated that siblings of women with breast cancer are more obese than age-matched controls.32 In an earlier report based on two years of follow-up of this cohort,43 the elevation in the risk of breast cancer associated with a high waist-to-hip ratio appeared to be limited to older women with a high body-mass index. In the present analysis, interactions of the waist-to-hip ratio with body-mass index or age were not significant once the interaction of family history and waist-to-hip ratio was entered into the model, providing further support for the interpretation that these factors may be part of a common mechanistic pathway.63 However, these results should be considered preliminary until they are corroborated by other investigators.
Data from this study suggest that women with breast cancer who have a family history of the disease are more likely than those with no family history of breast cancer to be older at first pregnancy and to have fewer children. This observation has been supported by some earlier studies,4 , 11 but not by others.10 , 12 In our data set, these two risk factors were not independent: 79 percent of the women with breast cancer who had a family history of the disease and a first pregnancy at or after 30 years of age also had fewer than three live-born children, whereas only 43 percent of those with a family history of breast cancer and a first pregnancy before the age of 30 had fewer than three live-born children (P<0.05). In multivariate modeling, the interaction between family history and age at first pregnancy was no longer statistically significant once the interaction between family history and the number of live births was included. We were unable to determine in this study whether this risk profile reflects cultural inheritance or difficulty in becoming pregnant. The fact that age at first pregnancy and number of live births are highly inversely correlated further complicates efforts to disentangle their separate effects.
An older age at menarche was associated with a decreased risk of breast cancer only among women with no family history of the disease, but the power of this study to detect this association was lower for women with a family history of breast cancer. These data are consistent with the findings in previous reports.4 , 6 Early menopause, whether natural or medical, was not associated with a decreased risk of breast cancer in either family-history category. This finding is in direct contrast to that reported by Byrne et al.,12 who found a significant increase in risk with older age at natural menopause among women with a family history of breast cancer. Additional study is needed to clarify this inconsistency.
Methodologic limitations of this study warrant consideration. Data on family history of breast cancer were obtained from the women themselves; we did not attempt to verify reports of disease among relatives. However, the accuracy of reports of breast cancer among mothers and sisters is excellent.64 Furthermore, since information on family history was collected at base line, before the detection of disease, we avoided the recall bias inherent in case–control studies that examine family history.65 Since breast cancer develops in approximately one in nine women at some point in their lifetimes, a family history of the disease, as we have defined it, necessarily includes cases in which familial clustering has occurred by chance or as a result of common environmental exposure as well as those with a genetic or hereditary cause. These errors of misclassification would result in the underestimation of the true association between patterns of body-fat distribution and familial clustering of breast cancer. Furthermore, the limited data on family history do not enable us to determine the importance of the age at onset of breast cancer among the affected relatives (i.e., premenopausal vs. postmenopausal disease) on the observed associations.
Despite our rather broad definition of family history, this study indicates that a high waist-to-hip ratio and low parity are more important risk factors for breast cancer among women with a family history of the disease than among those without such a history. In addition, there is no evidence that the waist-to-hip ratio is correlated with low parity or an older age at first pregnancy; case patients with a family history of breast cancer who had waist-to-hip ratios above the fourth quintile were not more likely than those in the lower four quintile groups to have fewer than three live-born children (P>0.75) nor to be 30 years of age or older at first pregnancy (P>0.65). These results suggest etiologic differences between familial breast cancer and sporadic cases of the disease that may direct research into the underlying biologic mechanisms. They also suggest that postmenopausal women with a family history of breast cancer should be monitored particularly carefully if they also have a high waist-to-hip ratio, low parity, or both.
Supported by a grant (ROI CA39742) from the National Institutes of Health. Dr. Kaye's work was supported by a National Institutes of Health training grant (T32 CA099607).
Source Information
From the Division of Epidemiology, School of Public Health (T.A.S., L.H.K., J.D.P., S.A.K., C.L.N., P.G.M., A.R.F.), and the Institute of Human Genetics (T.A.S.), University of Minnesota, Minneapolis. Address reprint requests to Dr. Sellers at the Division of Epidemiology, 1300 S. Second St., Suite 300, Minneapolis, MN 55454.
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