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Background: Mammographic density is a strong risk factor for breast cancer that is heritable and associated with blood levels of growth hormone and insulin-like growth factor-I (IGF-I). We tested single nucleotide polymorphisms (SNP) in pituitary growth hormone (GH1) and growth hormone-releasing hormone receptor (GHRHR) genes for an association with mammographic density, hormones of the growth hormone/IGF-I axis, and anthropometric variables., Methods: Mammograms from 348 women were measured using a computer-assisted method, blood collected, and DNA extracted. The SNPs genotyped were GH1 -57G>T, GH1 -75G >A, and GHRHR A57T. ANOVA and covariance were used to examine associations, adjusted for age, body mass index, ethnicity, and menopausal status, between each SNP and three measures of the mammogram: percent density, total dense area, and total nondense area. Similarly, the SNPs were tested for associations with serum growth hormone, IGF-I, IGFBP3, prolactin, and anthropometric variables., Results: GH1 -57G >T and GH1 -75G >A were both associated with percent density and total nondense area. GH1 -57T homozygotes had 5.2 more mean adjusted percent density than other subjects combined (P = 0.03) and 16.2 cm(2) (14.6%) less nondense area (P = 0.01). GH1 -75A homozygotes had 3.4 more percent density than subjects with at least one G allele (P = 0.04) and also had 32% higher serum growth hormone levels (P = 0.02)., Conclusion: We have found associations between mammographic density and two SNPs in the pituitary growth hormone gene, one of them also associated with serum growth hormone levels. These findings suggest that the GH1 gene may also influence breast cancer risk.

Mammographic density is associated with increased breast cancer risk and is influenced by sex hormones. A T27C polymorphism (alleles A1 and A2, respectively) in the 5' promoter region of CYP17 may be associated with elevated sex hormone levels. In a cross-sectional study of 181 pre- and 173 postmenopausal women, we examined the relationship of this polymorphism with mammographic density and other risk factors for breast cancer. Subjects were recruited across five categories of density. Risk factor and dietary information, anthropometric measures, and blood samples were obtained. Sex hormone, lipid, growth factor levels, and CYP17 genotypes were determined. CYP17 genotype was not associated with mammographic density levels before or after adjusting for risk factors for breast cancer. In premenopausal women, the A2 allele was associated with higher levels of dehydroepiandrosterone sulfate, and in postmenopausal women, with higher levels of total estradiol and lower levels of follicle stimulating hormone. Among premenopausal women, interactions were observed between CYP17 genotype and endogenous insulin levels as well as dietary variables associated with mammographic density. Our findings suggest that the CYP17 A2 allele is associated with hormone levels, and interacts with insulin levels and diet to affect breast density levels and potentially breast cancer risk.

Introduction: Breast cancer risk may be determined by various genetic, metabolic, and lifestyle factors that alter sex hormone metabolism. Cytochrome P450 1A2 (CYP1A2) is responsible for the metabolism of estrogens and many exogenous compounds, including caffeine., Methods: In a cross-sectional study of 146 premenopausal and 149 postmenopausal women, we examined the relationships between CYP1A2 activity and known or suspected risk factors for breast cancer. Blood levels of sex hormones, lipids, and growth factors were measured. In vivo CYP1A2 activity was assessed by measuring caffeine metabolites in urine. Stepwise and maximum R regression analyses were used to identify covariates related to CYP1A2 activity after adjustment for ethnicity., Results: In both menopausal groups CYP1A2 activity was positively related to smoking and levels of sex hormone binding globulin. In premenopausal women, CYP1A2 activity was also positively related to insulin levels, caffeine intake, age, and plasma triglyceride levels, and negatively related with total cholesterol levels and body mass index. In postmenopausal women CYP1A2 activity was positively associated with insulin-like growth factor-1, and negatively associated with plasma triglyceride, high-density lipoprotein cholesterol, and age at menarche., Conclusion: These results suggest that CYP1A2 activity is correlated with hormones, blood lipids, and lifestyle factors associated with breast cancer risk, although some of the observed associations were contrary to hypothesized directions and suggest that increased CYP1A2 function may be associated with increased risk for breast cancer.

Extensive mammographic density is heritable, strongly associated with increased breast cancer risk, and is influenced by sex hormone exposure. In a cross-sectional study of 181 pre- and 171 postmenopausal women without breast cancer, we examined the relationship of a functional polymorphism in catechol-O-methyltransferase (COMT; VAL-->MET) to mammographic density and other risk factors for breast cancer. We hypothesized that individuals who inherited the low-activity form of COMT (COMT*2 allele) would have higher levels of breast density, presumably because of reduced inactivation/detoxification of catecholestrogens. Subjects were recruited across five categories of breast density. Risk factor information, anthropometric measures, and blood samples were obtained; sex hormone and growth factor levels were measured, and COMT genotypes determined. Mammograms were digitized and measured using a computer-assisted method. After adjustment for age and ethnicity, among pre- but not postmenopausal subjects, each low-activity COMT*2 allele was associated with lower levels of percentage breast density. The statistical significance of this association was lost after further adjustment for serum growth factors [growth hormone, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3)], hormones [follicle-stimulating hormone (FSH) and progesterone], and body size (body mass index and waist:hip ratio). The low-activity COMT*2 allele was also associated, after adjustment for age and ethnicity in premenopausal women, with lower serum levels of IGF-1, higher levels of FSH and progesterone, and with a larger waist:hip ratio, body mass index, and subscapular skinfold. After adjustment for body size, the associations of genotype with IGFBP-3 and FSH were no longer significant. These findings indicate that COMT genotype is associated with several risk factors for breast cancer and suggest that the low-activity COMT*2 allele is associated with a reduced risk of breast cancer among premenopausal women.

Background: Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30 percent of the age-adjusted variation in the percentage of dense tissue., Methods: We undertook two studies of twins to determine the proportion of the residual variation in the percentage of density measured by mammography that can be explained by unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. Information on putative determinants of breast density was obtained by questionnaire. Mammograms were digitized, randomly ordered, and read by a blinded investigator., Results: After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in North America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variants attributable to additive genetic factors) accounted for 60 percent of the variation in density (95 percent confidence interval, 54 to 66) in Australian twins, 67 percent (95 percent confidence interval, 59 to 75) in North American twins, and 63 percent (95 percent confidence interval, 59 to 67) in all twins studied., Conclusions: These results show that the population variation in the percentage of dense tissue on mammography at a given age has high heritability. Because mammographic density is associated with an increased risk of breast cancer, finding the genes responsible for this phenotype could be important for understanding the causes of the disease., (Copyright 2002 Massachusetts Medical Society)

Background: The appearance of breast tissue on mammography varies according to its composition. Fat is radiolucent and appears dark on mammography, while stromal and epithelial tissue has greater optical density and appears light. Extensive areas of radiologically dense breast tissue seen on mammography are associated with an increased risk of breast cancer., Purpose: The purpose of the present study was to determine whether the adoption of a low-fat, high-carbohydrate diet for 2 years would reduce breast density., Methods: Women with radiologic densities in more than 50% of the breast area on mammography were recruited and randomly allocated to an intervention group taught to reduce intake of dietary fat (mean, 21% of calories) and increase complex carbohydrate (mean, 61% of calories) or to a control group (mean, 32% of calories from fat and 50% of calories from carbohydrates). Mammographic images from 817 subjects were taken at baseline and compared with those taken 2 years after random allocation by use of a quantitative image analysis system, without knowledge of the dietary group of the subjects or of the sequence in which pairs of images had been taken. The effects of the intervention on the mammographic features of breast area, area of dense tissues in the breast, and the percent of the breast occupied by dense tissue were examined using t tests. Multiple regression was used to examine these effects while accounting for age at trial entry, weight change, and menopausal status., Results: After 2 years, the total area of the breast was reduced by an average of 233.7 mm2 (2.4%) (95% confidence interval [CI] = 106.9-360.6) in the intervention group compared with an average increase of 26.3 mm2 (0.3%) (95% CI = -108.0-160.5) in the control group (P = .01). The area of density was reduced by 374.4 mm2 (6.1%) (95% CI = 235.1-513.8) in the intervention group compared with an average of 127.7 mm2 (2.1%) (95% CI = 8.6-246.7) in the control group (P = .01). Weight loss was associated with a reduction in breast area. The effect of the intervention on breast area was only marginally statistically significant after weight change, menopausal status, and age at trial entry were taken into account (P = .06). Greater weight loss and becoming postmenopausal were associated with statistically significant reductions in the area of density on the mammographic image at 2 years (P = .04 and P<.001, respectively). Age at entry into the trial was marginally significant in the same direction (P = .06). The effect of the intervention on area of density remained statistically significant after controlling for weight loss, age at entry, and menopausal status (P = .03). The change in the percentage of dense tissue in the mammographic image was not significantly different between the two groups (P = .71)., Conclusions and Implications: These results show that after 2 years, a low-fat, high-carbohydrate diet reduced the area of mammographic density, a radiographic feature of the breast that is a risk factor for breast cancer. Longer observation of a larger number of subjects will be required to determine whether these effects are associated with changes in risk of breast cancer.

There is strong evidence that the risk of breast cancer in populations is influenced by environmental factors. Plasma lipids and lipoproteins are known to be under environmental control and to have epidemiological and/or biological characteristics that suggest they may be relevant to breast cancer risk. The purpose of the study described here was to determine whether plasma lipids, lipoproteins, and the urinary excretion of the mutagen malondialdehyde (MDA) are associated with differences in breast cancer risk. We measured plasma lipids, lipoproteins, and urinary MDA in women without breast cancer but with different degrees of density of the breast parenchyma on mammography, a strong risk factor for breast cancer. Mammograms from 273 premenopausal women were digitized to high spatial resolution by a scanning densitometer, and images were analyzed to quantify the extent of density. The percentage of the breast occupied by mammographic densities was found, after controlling for the effects of age and the Quetelet index of obesity, to be significantly associated with plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apoprotein B, and urinary excretion of MDA. A multivariate model comprised of the Quetelet index of obesity, alcohol consumption, apoprotein B, parity, daily MDA excretion, and the skinfold thickness sum accounted for 36% of the variation in breast density. These results suggest that differences in lipid metabolism are associated with differences in breast cancer risk as defined by mammographic densities. These findings are consistent with several other observations that show a relationship between plasma lipids, lipoproteins, and risk factors for breast cancer.

The most convincing evidence that a factor such as dietary fat is causally related to breast cancer would be obtained from a randomised controlled trial in which exposure to dietary fat intake was systematically varied. A limitation of randomised controlled trials of breast cancer prevention, however, is the large sample size required to detect plausible reductions in risk resulting from the intervention. We describe here experience over a period of 9 years with the use of one risk factor for breast cancer as a criterion for entry to a clinical trial of breast cancer prevention. The risk factor used was the presence of extensive densities in the breast tissue on mammography, which has been found by several investigators to be strongly associated with risk of breast cancer. Using this criterion for selection, 1800 subjects of mean age 46 years were enrolled between 1982 and 1986, and again between 1988 and the present. Throughout this period, the point estimate of annual invasive cancer incidence was approximately 6 per 1000 per year. The observed cancer incidence has been consistently 4-5 times the incidence expected from age-specific breast cancer incidence data for women living in Ontario. These data show that the selection of subjects for a clinical trial of breast cancer prevention using the criterion of extensive breast parenchymal densities does identify a group at substantially increased risk of breast cancer. Use of this criterion for the selection of subjects can substantially reduce the sample size required for a clinical trial of a preventive strategy.

We have examined the relationship between plasma lipids, lipoproteins, and a family history of breast cancer. We measured the plasma lipids and lipoproteins in unaffected female members of the nuclear family of women with familial breast cancer and compared them with those of the female members of the nuclear family of women with sporadic breast cancer. A mean number of 3.3 relatives of mean age 35 years were studied in 23 pairs of familial and sporadic breast cancer families. After adjustment in multivariate analysis for variables that either differed between high and low risk families, or were significantly associated with plasma levels or lipoproteins, statistically significant differences were found in plasma levels of total cholesterol, low density lipoprotein cholesterol, and apoprotein B, all of which were lower in familial breast cancer than in sporadic breast cancer families. These data suggest that inherited factors associated with breast cancer risk may play a role in determining plasma lipid and lipoprotein levels and that lipid regulatory genes should be considered in this context.

We assessed the validity of information reported by patients with breast cancer on cancer in first- and second-degree relatives. In Toronto, Canada, 165 patients completed mailed questionnaires about cancer in relatives and were then interviewed in person. Their reports were compared with relatives' hospital records, cancer registry or death records for presence of cancer, site and age at diagnosis. Questionnaire and interview reports agreed with records for 82-96% of reports on first-degree and 48-80% on second-degree relatives. Proband reports of cancer sites in first-degree relatives were generally accurate (breast 99%, ovary 100%, prostate 85%, colon 93%). Reports of cancer sites in second-degree relatives were accurate for prostate cancer but only for 85% of breast and 72% of colon cancers. Age at diagnosis of breast cancer was correct in 92% of cases in first-degree and 54% in second-degree relatives. The interview contributed additional information about the presence of cancer in second-degree relatives, and the site and age at diagnosis in first- and second-degree relatives. In a similar population the questionnaire alone should yield adequate data for identifying families that warrant further investigation.

Animal experimental evidence and human ecological data suggest that dietary fat intake is related to breast cancer risk. Epidemiological studies within countries have given inconsistent results but are limited by the restricted range of dietary intake found in Western populations and by error in the measurement of fat consumption. Experimental evidence, derived from controlled clinical trials in which the range of fat intake is increased beyond that seen in most Western populations, is capable of overcoming this limitation of observational epidemiology, and would provide the strongest evidence available concerning the relationship of dietary fat intake to breast cancer risk. Further, such trials are the only means likely to answer the question of whether breast cancer risk in high-risk subjects can be modified by changing dietary fat intake. We describe here several aspects of the feasibility of an experimental approach to this problem, including the identification of subjects at increased risk for breast cancer, and the demonstration that such subjects will enter a clinical trial of dietary fat reduction and comply with a low-fat diet. It is shown that subjects can be recruited and retained in such trials, that satisfactory dietary compliance can be achieved over at least 24 mon and that the subjects selected are at demonstrably increased risk of breast cancer. This finding indicates that it is feasible to test the dietary fat-breast cancer hypothesis experimentally by means of a clinical trial.

The appearance of the breast parenchyma as seen on mammography is known to vary between individuals. The evidence is reviewed that some of the sources of this variation, namely, the densities referred to as "dysplasia", are related to breast cancer risk. We have carried out a meta-analysis of the published literature to determine the magnitude of the risk of breast cancer associated with mammographic densities by calculating summary odds ratios for studies grouped according to their design and the method used to classify mammographic parenchymal patterns. This has shown that subjects with mammographic densities have an increased risk of breast cancer relative to those without densities. Of the studies that used Wolfe's method of classification, cohort studies (n = 8) had a summary odds ratio of 5.19 (95% CI, 3.6 to 7.48); case control studies (n = 13) had a summary odds ratio of 1.8 (95% CI, 1.5 to 2.13); and prevalence surveys had a summary odds ratio of 0.54 (95% CI, 0.4 to 0.7). Other methods of classification, using quantitative estimates of the proportion of the breast occupied by densities, gave substantially higher odds ratios than Wolfe's system. The ability to recognize individuals within the population at different risks for breast cancer could be exploited in studies of potential etiological factors.

There is experimental evidence that fish oils protect against mammary carcinogens in animals. However, there has been little investigation of the possible relevance of this finding to breast cancer in humans. We compared breast cancer incidence and mortality rates with estimates of the consumption of fish and other foods and nutrients in the countries for which reliable data are available. The results showed an inverse association between percent calories from fish and breast cancer rates that was consistent with a protective effect. This analysis confirmed the finding of others that dietary fat is strongly associated with international variation in breast cancer rates. It also showed that of the dietary components considered, percent calories from fish was the factor most strongly correlated with breast cancer rates after statistical adjustment for dietary fat intake. This result is therefore in accord with animal experimental data and suggests that the omega-3 fatty acids contained in certain fish may protect against breast cancer.

Epidemiological evidence indicates that mammographic dysplasia is associated with an increased risk of breast cancer, particularly in premenopausal women. To examine biochemical associations with mammographic dysplasia we have compared premenopausal women with different patterns of the breast parenchyma on mammography. One group had extensive radiological dysplasia (n = 30) and the other no dysplasia (n = 16). Both groups were recruited from mammographic units in the same way and then compared according to epidemiological risk factors, anthropometric measures, nutrient intake and plasma levels of oestradiol, progesterone and prolactin obtained in both follicular and luteal phases of the menstrual cycle as well as total plasma cholesterol and lipid fractions. Women with mammographic dysplasia were found to be leaner, more often nulliparous and to consume more alcohol than women without these radiological changes. Mammographic dysplasia and a family history of breast cancer were found to be independently associated with significantly higher levels of high density lipoprotein cholesterol (HDL-C) after taking into account the possible confounding effects of percentage body fat, parity and consumption of alcohol and dietary fat. Triglyceride levels were also independently associated with a family history of breast cancer. We conclude that further investigation is warranted of the role of plasma lipids in relation to breast cancer risk.