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Recent evidence suggests that adequate dietary folate may attenuate the risk of breast cancer associated with intake of alcohol. However, patients with breast cancer have been commonly treated with antifolate chemotherapies. The present analysis was performed to test the hypothesis that high folate intake may diminish the effectiveness of chemotherapy and, therefore, adversely influence survival. Women at risk of postmenopausal breast cancer (n = 37,105) participated in the Iowa Women's Health Study. Total folate intake (diet + supplements) was estimated from a food frequency questionnaire administered at baseline in 1986 and categorized into tertiles. From all incident breast cancer cases ascertained in the cohort, we selected those with a diagnosis between 1986 and 1994, chemotherapy as first course of treatment, and adequate diet assessment. Mortality was determined through the State Health Registry of Iowa and the National Death Index. Cox regression was used to estimate survival while adjusting for important covariates. Through 14 yr of follow-up, 80 deaths occurred among the 177 breast cancer cases treated with chemotherapy. Among these patients, high folate intake was not associated with worse survival. After adjustment for age, extent of disease, total calories, alcohol, and estrogen receptor status, women with total folate intake in the highest tertile had a mortality risk ratio of 0.88 (95% confidence interval = 0.44-1.76) compared with cases in the lowest tertile of folate. These findings, although preliminary, afford some reassurance that folate supplementation is unlikely to have a significant adverse effect on survival after chemotherapy for breast cancer. [ABSTRACT FROM AUTHOR]

Background: Several recent studies suggest that adequate dietary folate may attenuate the risk of breast cancer associated with intake of alcohol. We examined whether the putative benefit extends to women with a family history (FH) of breast cancer using a cohort of 33,552 postmenopausal women aged 55-69 years in 1986., Method: Folate and alcohol intake was estimated from a food frequency questionnaire completed at baseline. Folate was categorized as upper 50th, 31st-50th, 11th-30th, and <10th percentiles. Alcohol use was initially classified into three levels; never drinkers, less than the median and greater than the median. Subsequent models collapsed levels of intake to any versus none. Occurrence of breast cancer was determined through linkage to the Iowa SEER registry. Multivariate-adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated through Cox proportional hazards regression, stratified on FH using non-drinkers with high folate and no FH as the referent group., Results: Through 14 years, 1823 incident cases were identified, 308 among FH+ women. Among FH- women, low folate was not a risk factor among non-drinkers (RR = 0.96, CI = 0.73-1.26), but was among drinkers (RR = 1.40, CI = 1.05-1.86). Drinkers with high folate were not at elevated risk (RR = 1.03, CI = 0.89-1.19). Among FH+ women, low folate was a risk factor among drinkers (RR = 2.21, CI = 1.43-3.41) and non-drinkers (RR = 2.39, CI = 1.36-4.20). Further, drinkers with high folate remained at increased risk (RR = 1.67, CI= 1.30-2.14). However, FH+ women with high folate who did not drink alcohol had no elevated risk., Conclusion: These results suggest that folate may attenuate the risks of postmenopausal breast cancer associated with family history, but only if alcohol use is avoided or minimized.

Objective: To determine whether the association of adolescent anthropometric characteristics with breast cancer is modified by a family history of the disease., Methods: These interactions were evaluated in a historical cohort of 426 families of breast cancer probands diagnosed between 1944 and 1952 at the University of Minnesota. The occurrence of breast cancer and the measurement of risk factors in sisters, daughters, granddaughters, nieces and marry-ins was determined through telephone interviews and mailed questionnaires conducted from 1991-1996. Cox proportional hazards regression, accounting for age, birth cohort, adult body mass index (BMI), and clustering within families, was used to estimate relative risks (RR) and 95% confidence intervals (CIs) of breast cancer., Results: Among 4632 women from 426 families available for analysis, there were 175 breast cancers. There was a strong interaction between degree of relationship to proband and relative weight at age 12 on breast cancer risk ( p < 0.001). Among sisters and daughters of the probands, risk of breast cancer was slightly increased in those with below average weight at age 12 (RR = 1.55; 95% CI = 0.66-3.64), and strongly increased in those with above average weight (RR = 4.25; 95% CI = 1.71-10.5), compared to those with average weight. In contrast, among marry-ins, there was a weak positive association for those with below average weight at age 12 (RR = 1.61; 95% CI = 0.91-2.83), while there was an inverse association for above average weight (RR = 0.75; 95% CI = 0.26-2.16), compared to those with average weight. There were no significant interactions between degree of relationship to proband and height ( p = 0.55), weight at age 18 ( p = 0.22) and BMI at age 18 ( p = 0.63) on breast cancer risk., Conclusions: Family history appears to modify the effect of obesity in early adolescence on subsequent breast cancer risk, and may identify differing etiologic pathways.

Few studies examining familial clustering of breast and prostate cancer (PC) have focused on a clearly defined high-risk population with epidemiologic risk factors. We conducted a cohort study of prostate cancer among a subset of 426 families ascertained through female breast cancer probands. Three groups of males were included: 804 relatives in 60 families with four or more breast or ovarian cancers, 536 marry-ins in these high-risk families, and 484 relatives in 81 families where only the proband had breast cancer. A total of 118 prostate cancers were reported. The rate of prostate cancer among blood relatives in high-risk families was significantly lower than among marry-ins (RR = 0.6, 95% C.I.: 0.4-0.9). The rate of prostate cancer among blood relatives in low-risk families was not significantly different from the rate among marry-ins (RR = 0.8, 95% C.I.: 0.5-1.2). These results provide little evidence that male relatives in high-risk breast cancer families are at increased risk of prostate cancer., (Copyright 2002 International Society for Preventive Oncology)

Objective: Women with a strong family history of breast cancer are at significantly increased risk of developing the disease. There is emerging evidence that certain reproductive factors may further elevate risk in these women. We examined whether a family history of breast cancer modifies the association between correlates of endogenous hormonal exposures and breast cancer in a study of 426 families ascertained through breast cancer probands., Methods: Analyses of reproductive factors and breast cancer were performed on 395 sisters and daughters of probands, 3014 nieces and granddaughters. and 2768 marry-ins., Results: Through 226,266 person-years of follow-up since 1952, 240 women developed breast cancer. No statistically significant interactions were observed between relationship to proband and age at menarche, age at menopause, other characteristics of the menstrual cycle, parity, age at first and last birth, infertility, and total ovulatory years., Conclusions: Our findings suggest that most reproductive factors influence breast cancer risk similarly in women with and without a family history of breast cancer. Further studies are needed on individuals who are more homogeneous with regard to hereditary background. However, other options for prevention, such as prophylactic surgery or chemoprevention, may be necessary to have a substantial impact on risk reduction in women at high genetic risk.

Abdominal fat has been shown to be an important risk factor for many chronic conditions, including diabetes, heart disease, and breast cancer. The objective of this study was to provide evidence for a major gene influence on the ratio of waist to hip circumference (WHR), a measurement commonly used in large scale studies to indicate the presence of abdominal fat. Segregation analysis was conducted on three subsets of families from the Minnesota Breast Cancer Family Study. One analysis was conducted among families with WHR measurements on all women. Two additional analyses were conducted on subsets of women stratified on menopausal status. Multiple regression analysis was used to identify factors associated with WHR expressed as a continuous trait. Complex segregation analyses were performed on the continuous trait of WHR and the covariates identified in the regression analysis. In the analysis of all women, all hypotheses were rejected. Among premenopausal women, the environmental hypothesis with no heterogeneity between generations fit the data best (P = 0.85). However, among postmenopausal women, the requirements for conclusion of the presence of a major gene were met. All non-Mendelian hypotheses were rejected (P < 0.0001), but the additive hypothesis was not rejected (P = 0.19) and provided the best fit to the data. The putative major gene identified by this model accounted for 42% of total phenotypic variance in WHR among these postmenopausal women. The allele for high WHR had a frequency of 27%. These findings support the hypothesis that the distribution of abdominal fat in postmenopausal women is under genetic control., (Copyright 2001 Wiley-Liss, Inc.)

Most epidemiological studies of cigarette smoking and breast cancer have failed to demonstrate a strong association. Only one study has been performed on women at high genetic risk, and smoking was reported to be a protective factor. To further explore this observation, we examined the association of cigarette smoking with the risk of breast cancer in a historical cohort study of high-risk breast cancer families. A total of 426 families ascertained through a consecutive series of breast cancer patients (probands) between 1944 and 1952 were followed through 1996. Occurrence of breast cancer and detailed smoking histories for sisters, daughters, granddaughters, nieces, and marry-ins were obtained through telephone interviews between 1991 and 1996. Cox proportional hazards regression, accounting for age, birth cohort, and other risk factors, was used to calculate relative risks and 95% confidence intervals (CIs) of breast cancer. All of the models were constructed within strata defined by relationship to the index case (proband), with nonsmokers designated as the referent group. Of the 426 families in the cohort, 132 had at least three incident breast and/or ovarian cancers in the biological relatives at the end of the follow-up period. Among sisters and daughters in these 132 high-risk families, those who ever smoked were at 2.4-fold increased risk of breast cancer (95% CI, 1.2-5.1) relative to never-smokers. No association between breast cancer and smoking was observed among nieces and granddaughters of probands or among marry-ins. When the analysis was restricted to 35 families at highest genetic risk (each containing five breast and/or ovarian cancers), smoking became an even stronger risk factor. Among sisters and daughters, ever-smokers were at 5.8-fold greater risk than nonsmokers (95% CI, 1.4-23.9). Among nieces and granddaughters, the risk of breast cancer associated with smoking was increased 60% (95% CI, 0.8-3.2). These results suggest that smoking may increase risk for breast cancer in families with multiple cases of breast or ovarian cancer, especially those with the strongest apparent familial predisposition.

Context: Oral contraceptive (OC) use is weakly associated with breast cancer risk in the general population, but the association among women with a familial predisposition to breast cancer is less clear., Objective: To determine whether the association between OC use and risk of breast cancer is influenced by family history of the disease., Design and Setting: Historical cohort study of 426 families of breast cancer probands diagnosed between 1944 and 1952 at the Tumor Clinic of the University of Minnesota Hospital. Follow-up data on families were collected by telephone interview between 1991 and 1996., Participants: A total of 394 sisters and daughters of the probands, 3002 granddaughters and nieces, and 2754 women who married into the families., Main Outcome Measure: Relative risk (RR) of breast cancer associated with history of OC use by relationship to proband., Results: After accounting for age and birth cohort, ever having used OCs was associated with significantly increased risk of breast cancer among sisters and daughters of the probands (RR, 3.3; 95% confidence interval [CI], 1.6-6.7), but not among granddaughters and nieces of the probands (RR, 1.2; 95% CI, 0.8-2.0) or among marry-ins (RR, 1.2; 95% CI, 0.8-1.9). Results were essentially unchanged after adjustment for parity, age at first birth, age at menarche, age at menopause, oophorectomy, smoking, and education. The elevated risk among women with a first-degree family history of breast cancer was most evident for OC use during or prior to 1975, when formulations were likely to contain higher dosages of estrogen and progestins (RR, 3.3; 95% CI, 1.5-7.2). A small number of breast cancer cases (n = 2) limited the statistical power to detect risk among women with a first-degree relative with breast cancer and OC use after 1975., Conclusions: These results suggest that women who have ever used earlier formulations of OCs and who also have a first-degree relative with breast cancer may be at particularly high risk for breast cancer. Further studies of women with a strong family history who have used more recent lower-dosage formulations of OCs are needed to determine how women with a familial predisposition to breast cancer should be advised regarding OC use today. JAMA. 2000;284:1791-1798.

A family history of breast cancer is well established as a risk factor for the disease. Because family history is a dynamic rather than a static characteristic, longitudinal studies of entire families can be very instructive in quantifying the significance of risk classification. The Minnesota Breast Cancer Family Study is a historical cohort study of relatives of a consecutive series of 426 breast cancer cases (probands) identified between 1944 and 1952. The incidence of cancer and the measurement of risk factors in sisters, daughters, granddaughters, nieces, and marry-ins was determined through telephone interviews and mailed questionnaires. Ninety-eight percent of eligible families were recruited, and 93% of members participated. A total of 9073 at-risk women were studied: 56% were biological relatives of the case probands, whereas the others were related through marriage. Through 1996, 564 breast cancers were identified in nonprobands. Compared to the rate of breast cancer among marry-ins (188 cases), sisters and daughters of the probands were at a 1.9-fold greater age-adjusted risk (128 cases; 95% confidence interval, 1.4-2.4); granddaughters and nieces were at a 1.5-fold greater risk (248 cases, 95% confidence interval, 1.2-1.8). The breast cancer risk since 1952 was not distributed equally across families: although all biological relatives had a family history of breast cancer, 166 families (39%) experienced no additional cases. Most of the cases occurred among a subset of families: 21 families had 5 breast or ovarian cancers, 8 had 6, 2 had 7, and 4 had > or =8. There was no evidence of significantly increased risk for cancer at other sites, including the ovaries, cervix, uterus, colon, pancreas, stomach, or lymphatic tissue, although there was some evidence that stomach cancer in previous generations may help define the susceptible subset. These families contain four to five generations of validated occurrences of cancer, thus minimizing the uncertainty of genetic risk inherent in a disease with a late and variable age at onset. The patterns of breast cancer in these multigeneration families is consistent with the influence of autosomal dominant susceptibility in a subset, low penetrance genes in another, and purely environmental influences in the remainder.

In a cohort of 27,578 postmenopausal Iowa women, we examined whether the risk with a family history of breast cancer differs by self-reported ethnicity. A total of 1042 breast cancer cases occurred over 10 years of follow-up. Using a phylogenetic tree, ethnicities were combined into five groups: Scandinavian; English, Scottish, Welsh, and Dutch (ESWD); Irish; German; and Other European. The incidence of breast cancer did not differ significantly by ethnicity, although the highest rates were observed among Scandinavian women (488 per 100,000 per year) and the lowest among Irish women (353 per 100,000 per year). The prevalence of a family history of breast cancer was not significantly associated with ethnicity when only first-degree relatives were considered (P = 0.17), but inclusion of data on second-degree relatives increased the statistical significance of the association (P = 0.003). Differences in mean levels of breast cancer risk factors between ethnicities were generally small but statistically significant. Proportional hazards regression was performed to evaluate potential interactions of family history with ethnicity on breast cancer incidence. A family history of breast cancer was associated with increased relative risks among ESWD, Germans, and Other Europeans but not among Irish and Scandinavians. Relative risk estimates were not attenuated upon addition of known breast cancer risk factors to the model, implying that the distribution of these risk factors by ethnicity is unlikely to explain some of the observed ethnic-specific differences between family history and risk of breast cancer. Results of this study could have implications for studies of common genetic polymorphisms and cancer risk.

Although many segregation analyses of breast cancer have been published, few have included risk factor covariates. Maximum likelihood segregation analyses examining age-at-onset (model 1) and susceptibility (model 2) models of breast cancer were performed on 426 four-generation families originally ascertained between 1944 and 1952 through a breast cancer proband. Cancer status and risk factor data were collected through interviews of participants or surrogates. When segregation analyses were performed on 10,791 women, without estimation of any covariates, all hypotheses under both models were rejected. Model 1, which required estimation of fewer parameters than model 2, provided a better fit to the data according to Akaike's Information Criterion. Further segregation analyses were performed under model 1 on a subset of women with complete data on education, age at first birth (nulliparous women included), and alcohol use, covariates that were found to significantly (P<0.05) improve the fit over the addition of exam age alone in logistic regression models. All three covariates improved the fit of the models, as did year of birth, but at all stages of model building, all of the hypotheses were still rejected. After the allele frequency was fixed at 0.0033, a subset of families appeared to fit a dominant model. Using this model, risk estimates were calculated based on inferred genotype, age, and covariate values. The penetrance was estimated to be 0.15, much lower than previous estimates based on families ascertained through breast cancer probands with early onset. Moreover, the estimates of penetrance were not greatly influenced by incorporation of the measured risk factors.

Background: The appearance of the female breast viewed by mammography varies considerably from one individual to another because of underlying differences in the relative proportions of fat, connective tissue, and glandular epithelium that combine to create a characteristic pattern of breast density. An association between mammographic patterns and family history of breast cancer has previously been reported. However, this association has not been found in all studies, and few data are available on possible genetic components contributing to mammographic breast density., Purpose: Our purpose was to estimate familial correlations and perform complex genetic segregation analyses to test the hypothesis that the transmission of a major gene influences mammographic breast density., Methods: As part of a cohort study (initiated in 1944) of families with a history of breast cancer, the probands' female relatives who were older than 40 years were asked to obtain a routine mammogram. The mammograms of 1370 women from 258 independent families were analyzed. The fraction of the breast volume occupied by radiographically dense tissue was estimated visually from video displays of left or right mediolateral oblique views by one radiologist experienced in mammography who had no knowledge of individual relationships to the probands. Data on breast cancer risk factors were obtained through telephone interviews and mailed questionnaires. Unadjusted and adjusted familial correlations in breast density were calculated, and complex genetic segregation analyses were performed., Results: Sister-sister correlations in breast density (unadjusted and adjusted for age and either body mass index, menopausal status, hormone replacement therapy, waist-to-hip ratio, number of live births, alcohol consumption, or cigarette smoking status) were all statistically significant (r = .16-.27; all P<.05 [two-sided]). Estimated mother-daughter correlations were smaller in magnitude (r = .01-.17) and not statistically significant. Segregation analyses indicate that a major autosomal gene influences breast density. The mendelian transmission of a dominant gene provided the best fit to the data; however, hypotheses involving the inheritance of either a recessive gene or a codominant gene could not be ruled out. The mendelian dominant hypothesis, accounting for 29% of the variability in breast density, suggests that approximately 12% of the population would be expected to carry at least one variant allele of this putative gene. Women who inherit the variant allele would have a mean breast density about twice that of the rest of the population., Conclusions: Our preliminary findings suggest that, in this cohort of women at risk of breast cancer, mammographic breast density may be genetically influenced.