Favorable change in mammographic parenchymal patterns and breast cancer risk factors

The aim of our study was to estimate the incidence of favorable mammographic patterns and to assess the incidence by risk factors of breast cancer. Data relate to 1,947 women aged 40–47 years who were screened by mammography every second year and whose mammographic parenchymal pattern at initial screening was either P2 or DY (Wolfe's classification). The pattern was assessed at each screening round. The incidence of N1,P1 parenchymal pattern by risk factors was estimated. The Cox proportional hazards model was applied in univariate and multivariate analyses of the data. The incidence of N1,P1 pattern was 12.5/100 woman years among women with P2,DY pattern at the beginning of follow-up. The relative risk of N1,P1 pattern adjusted for th eother risk factors for women aged 45 years or more was 1.7 [95% confidence interval (CI) 1.5–1.9] compared with younger women. The adjusted relative risk of N1,P1 pattern among women with a body mass index (BMI) of 25 or more was 2.1 (95% CI 1.6–2.8) compared with women with a BMI of less than 20; women with more than 2 pregnancies had a 30% higher adjusted relative risk (RR = 1.3, 95% CI 1.1–1.6) than women with no pregnancies. The incidence of favorable mammographic parenchymal pattern was significantly related to old age, large BMI and multiparity. The effects of age and BMI on incidences of favorable and unfavorable change potentiate each other but not that of parity. Int. J. Cancer 78:410–414, 1998. © 1998 Wiley-Liss, Inc.     

Reproductive and menstrual factors in relation to mammographic parenchymal patterns among perimenopausal women.

The relationship between mammographic patterns and reproductive and menstrual factors was examined in 3640 Norwegian women, aged 40-56 years, participating in the Third Tromsö study conducted in 1986-87. Epidemiological data were obtained from questionnaires. The mammograms were categorised into five groups. This categorisation is based on anatomic-mammographic correlations, following three-dimensional (thick slice technique) histopathologic-mammographic comparisons, rather than simple pattern reading. Patterns 1-3 were combined into a low-risk group and patterns 4 and 5 into a high-risk group for analysis. Women who had more than four children were 90% less likely to have a high-risk pattern than nulliparous women (OR = 0.09, 95% CI 0.04-0.16) controlling for age, weight, height and menopausal status. Furthermore, those who first gave birth over 34 years of age were more than twice as likely to have a high-risk pattern than those giving birth in their teens (OR = 2.37, 95% CI 1.23-4.56) adjusting for parity. Among post-menopausal women, age at menarche was negatively (P for trend = 0.015) and late age at menopause positively (P for trend = 0.072) related to high-risk patterns. Among premenopausal women, age at menarche was positively related to high-risk patterns (P for trend = 0.001). Also, menopausal status rather than age was associated with high-risk patterns. These findings support the opinion that reproductive and menstrual factors are involved in determining the mammographic parenchymal pattern among perimenopausal women.     

Relationship between mammographic and histological risk factors for breast cancer.

BACKGROUND: Information on breast cancer risk can be obtained both from the histological appearance of the breast epithelium in biopsy specimens and from the pattern of parenchymal densities in the breast revealed by mammography. It is not understood, however, how parenchymal densities influence breast cancer risk or whether these densities are associated with histological risk factors. PURPOSE: We have estimated, in a large cohort of women, the relative risk of detecting carcinoma in situ, atypical hyperplasia, hyperplasia without atypia, or nonproliferative disease in biopsy specimens from women with different extents of mammographic density. We also examined the association between these histological classifications and radiological features present specifically at the biopsy site. METHODS: The source of study material was a population of women aged 40-49 years who were enrolled in the Canadian National Breast Screening Study (NBSS). Mammograms from women who had undergone a biopsy (n = 441) and from a comparison group of women (n = 501) randomly selected from the mammography arm of the NBSS were classified according to the extent of mammographic density. The corresponding histological slides were independently classified by a review pathologist. RESULTS: Compared with women showing no mammographic densities, women with the most extensive densities (i.e., occupying greater than 75% of the breast volume) had a 9.7 times greater risk of developing carcinoma in situ or atypical hyperplasia (95% confidence interval [CI] = 1.75-53.97), a 12.2 times greater risk of developing hyperplasia without atypia (95% CI = 2.97-50.14), and a 3.1 times greater risk of developing non-proliferative disease (95% CI = 1.20-8.11). The gradients in risk were not monotonic across the five classifications of mammographic density. The association could not be explained by the presence of mammographic densities at the biopsy site, but calcification at the biopsy site was strongly associated with high-risk histological changes (relative risk = 24; 95% CI = 5.0-156.0). CONCLUSIONS: These results suggest that the radiological patterns referred to as mammographic dysplasia may influence breast cancer risk by virtue of their association with high-risk histological changes in the breast epithelium. IMPLICATIONS: Identification of the factors responsible for high-risk histological changes may offer new insights into the etiology of breast cancer and potentially lead to the development of methods for its prevention.     

Bias and the association of mammographic parenchymal patterns with breast cancer.

We have carried out a case-control study to evaluate the association between Wolfe''s mammographic patterns and the risk of breast cancer, and to examine the influence of control selection and the radiologist who read the films upon the results obtained. Mammograms of the non-cancerous breast of 183 women with unilateral breast cancer were compared with mammograms from two age-matched control groups: a group of asymptomatic women attending a screening centre, and a group of symptomatic women referred for the diagnostic evaluation of suspected breast disease. Films were arranged in random sequence and independently classified by 3 radiologists. A strong and statistically significant association was found between mammographic dysplasia and breast cancer when controls from the screening centre were compared to cases, but not when cases were compared to women referred for the diagnostic evaluation of breast disease. This result appears to arise in part because of an association between symptoms of benign breast disease and mammographic dysplasia, and suggests that some previous negative studies of the association of mammographic patterns with breast cancer may have arisen from the inclusion of symptomatic subjects as controls.     

Unfavourable change in mammographic patterns and the breast cancer risk factors

The purpose of the study was to estimate the incidence of unfavourable mammographic pattern by risk factors of breast cancers. Data consisted of 1890 Finnish women with mammographic pattern of either N1 or P1 (Wolfe's classification) at the initial screening. The screening was repeated every second year from 1982 to 1990 and at each screening round the mammographic pattern was assessed. The incidence rate of P2,DY pattern was 1.9/100 woman years. The incidence of P2,DY pattern was significantly related to age. The ageadjusted odds ratio (OR) (based on logistic regression) was 2.0 (95 CI 1.0–3.9) among women with hormonal replacement therapy (HRT), 0.6 (95 CI 0.4–0.9) among postmenopausal women, 0.2 (95 CI 0.1–0.4) among women with large breasts and 0.2 (95 CI 0.1–0.3) among women with large body mass index (BMI). After multivariate adjustment by logistic regression only the effect of BMI remained statistically significant, odds ratio of P2,DY pattern for women with BMI 25 or more was 0.2 (95 CI 0.1–0.6) compared to women with BMI less than 20.     

Urinary estrogen metabolites and mammographic parenchymal patterns in postmenopausal women.

It has been hypothesized that women who metabolize their endogenous estrogens predominantly via 16(alpha)-hydroxylation rather than via 2-hydroxylation and, as a result, have a low ratio of 2-hydroxyestrone (2-OHE1):16(alpha)-hydroxyestrone (16(alpha)-OHE1) are at an increased risk of breast cancer. Epidemiological evidence in support of this hypothesis is scarce and mostly based on measurements made after the onset of the disease. To gain insight into the role of these metabolites in the etiology of breast cancer, we assessed their relationship with high-density Wolfe mammographic parenchymal patterns (P2/DY), a recognized indicator of risk of this tumor. The study was nested within a large cross-sectional survey on determinants of mammographic patterns carried out in a population-based breast screening program in Northern Greece. Urinary levels of 2-OHE1 and 16(alpha)-OHE1 were measured in a random sample of 70 postmenopausal women with P2/DY mammographic patterns and in a random sample of 70 women with N1 mammographic patterns, individually matched to the P2/DY women on year of birth, years since menopause and date of urine collection. Women with a P2/DY pattern had, on average, 58% higher levels of 2-OHE1 (P = 0.002) and 15% higher levels of 16(alpha)-OHE1 (P = 0.37) than those with an N1 pattern. The ratio of 2-OHE1:16(alpha)-OHE1 was 35% higher (P = 0.005) in women with a P2/DY pattern. Women in the highest one-third of this ratio were six times more likely to have a P2/DY pattern than those in the lowest one-third after adjusting for potential confounders (prevalence odds ratio, 6.2; 95% CI, 1.7-22.9; test for linear trend, P = 0.002). These findings seem to suggest that a high, rather than a low, 2-OHE1:16(alpha)-OHE1 ratio may be associated with an increase in breast cancer risk at postmenopausal ages, unless the pathway through which estrogen metabolites may affect breast cancer risk is unrelated to mammographic parenchymal patterns.     

The effects of exogenous estrogen replacement therapy of the breast: breast cancer risk and mammographic parenchymal patterns

A retrospective pilot study was implemented to better define the potential carcinogenic role of conjugated equine estrogen (Premarin) on the breast, and the influence of these hormone analogues on proliferative and atrophic breast parenchyma as determined by high-quality serial xeromammograms. Four hundred and five postmenopausal (spontaneous and surgical) women (mean age 59.7 years) were group matched for the risk factors of age and parity. The dominant parenchymal pattern (N1P1P2DY) as disclosed mammographically was determined for each patient, who was then categorized into one of four groups: Group 1 Asymptomatic-no hormones, 124 patients; Group 2 Symptomatic-no hormones, 75 patients; Group 3 Asymptomatic-hormones; 152 patients; and Group 4 Symptomatic-hormones, 54 patients. Patients in Groups 3 and 4 were treated with therapeutic estrogens a minimum of 18 months (mean 79 months) and follow-up ranged from 39-344 months. In the entire series, 25 carcinomas (6.2%) were detected. In Group 3, five carcinomas (2.4%) were detected, but two cancers (1.0%) were found in symptomatic estrogen users. The occurrence of carcinoma in Group 2 was greater than the remaining categories; however, cancer risk was not statistically greater in any category with regard to hormone replacement therapy. Patients treated with therapeutic estrogens were observed to have an increase of 8.9% in the frequency of a more glandular (P2,DY) mammographic parenchymal pattern and this was noted to be within the range of interpretation error of the mammographer. This suggests a physiologic effect of therapeutic estrogens on atrophic breast parenchyma with conversion to a glandular, proliferative state. This study suggests that long-term replacement estrogen therapy for postmenopausal symptoms does not significantly alter mammographic parenchymal patterns and that the use of these compounds in therapeutic doses does not increase the risk of breast cancer.     

Breast cancer risk factors and mammographic breast density in women over age 70

SummaryBackground Breast density is a strong risk factor for breast cancer, but little is known about factors associated with breast density in women over 70.Methods Percent breast density, sex hormone levels and breast cancer risk factor data were obtained on 239 women ages 70–92 recruited from 1986 to 1988 in the United States. Multivariable linear regression was used to develop a model to describe factors associated with percent density.Results Median (range) percent density among women was 23.7% (0–85%). Body mass index (β= −0.345, p<0.001 adjusted for age and parity) and parity (β= −0.277, p<0.001 adjusted for age and BMI) were significantly and inversely associated with percent breast density. After adjusting for parity and BMI, age was not associated with breast density (β=0.05, p=0.45). Parous women had lower percent density than nulliparous women (23.7 versus 34.7%, p=0.005). Women who had undergone surgical menopause had greater breast density than those who had had a natural menopause (33.4 versus 24.8%, p=0.048), as did women who were not current smokers (26.0 versus 17.3% for smokers, p=0.02). Breast density was not associated with age at menarche, age at menopause, age at first birth, breastfeeding, estrogen levels or androgen levels. In a multivariable model, 24% of the variance in percent breast density was explained by BMI (β= −0.35), parity (β=−0.29), surgical menopause (β=0.13) and current smoking (β= −0.12).Conclusion Factors associated with breast density in older, post-menopausal women differ from traditional breast cancer risk factors and from factors associated with breast density in pre-menopausal and younger post-menopausal women.     

Relationship between breast cancer risk factors and mammographic breast density in the Fernald Community Cohort

Background:

We investigated associations of known breast cancer risk factors with breast density, a well-established and very strong predictor of breast cancer risk.

Methods:

This nested case–control study included breast cancer-free women, 265 with high and 860 with low breast density. Women were required to be 40–80 years old and should have a body mass index (BMI) <35 at the time of the index mammogram. Information on covariates was obtained from annual questionnaires.

Results:

In the overall analysis, breast density was inversely associated with BMI at mammogram (P for trend<0.001), and parity (P for trend=0.02) and positively associated with alcohol consumption (ever vs never: odds ratio 2.0, 95% confidence interval 1.4–2.8). Alcohol consumption was positively associated with density, and the association was stronger in women with a family history of breast cancer (P<0.001) and in women with hormone replacement therapy (HRT) history (P<0.001). Parity was inversely associated with density in all subsets, except premenopausal women and women without a family history. The association of parity with density was stronger in women with HRT history (P<0.001).

Conclusion:

The associations of alcohol and parity with breast density appear to be in reverse direction, but stronger in women with a family history of breast cancer and women who ever used HRT.     

A comparison of mammographic parenchymal patterns in premenopausal Japanese and British women

Normal premenopausal Japanese women have significantly more favourable mammographic parenchymal patterns (Wolfe Grades) than comparable British women. This finding is unaffected when the women are stratified by age, Quetelet's Index, age at menarche, age at first birth, and parity.     

A comparison of mammographic parenchymal patterns in premenopausal Japanese and British women

Normal premenopausal Japanese women have significantly more favourable mammographic parenchymal patterns (Wolfe Grades) than comparable British women. This finding is unaffected when the women are stratified by age, Quetelet's Index, age at menarche, age at first birth, and parity.     

Risk for breast cancer development determined by mammographic parenchymal pattern.

A classification of risk for developing breast cancer has been devised based solely on the appearance of the breast parenchyma by mammography. Four groups of patients were isolated. The study encompassed a five-year period and was done by reviewing the mammograms of all women over the age of 30 who had been examined at Hutzel Hospital, Detroit. The average time of followup would be approximately 2 1/2 years. Four groups had an incidence of developing breast cancer of 0.1, 0.4, 1.7, and 2.2. These parenchymal patterns are described and criteria for their identification are given.     

High risk mammographic parenchymal patterns and diet: a case-control study

Mammographic parenchymal patterns are related to breast cancer risk and are also thought to be affected by diet. We designed a case-control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of food and nutrient intake on mammographic patterns. Mammograms were evaluated according to the Wolfe classification system. Dietary data were obtained from 7-day food diaries. Mean daily intake of nutrients was computed from standard UK food tables. The adjusted odds ratio (OR) of having a high-risk pattern in women in the highest tertile of total protein and carbohydrate intake was twice that of women in the lowest tertile (OR = 2.00; 95% confidence interval (CI) 1.06-3.77; P = 0.04 and OR = 1.93; 95% CI 1.03-3.59; P = 0.04 respectively). There was no excess risk for fat intake. In addition, there was no association between intake of vitamins and mammographic parenchymal patterns. Total meat intake was strongly and positively associated with high-risk patterns among post-menopausal women (OR = 2.50, 95% CI 1.09-5.69, P = 0.03). Our study suggests that certain macronutrients and foods such as protein, carbohydrate and meat intake influence the risk of breast cancer through their effects on breast tissue morphology, whereas fat and vitamins do not affect mammographic density. It seems that parenchymal pattern acts as an informative biomarker of the effect of some macronutrient and foodstuffs intake on breast cancer risk.     

Relationship between mammographic density and the risk of breast cancer in japanese women: a case-control study

BACKGROUND: The relationship between mammographic density and the risk of breast cancer was examined in Japanese women. The study was a matched case-control study comparing the mammographic densities of both breast cancer cases and healthy controls. MATERIALS AND METHODS: We selected 237 women who were diagnosed with a histologically verified breast cancer, and who underwent surgery at Gihoku General Hospital in Gifu, from January, 1998 to December, 1999. During the time of this study, 3,650 people participated in breast cancer screening with mammography and ultrasound together. We selected 742 women as a control group from the screening participants and matched them by age and the number of deliveries with the cancer patients. The same mammography machine was used for both cases and controls. For evaluation, we used a visual method (Wolfe's classification) and a computer assisted method to classify the mammograms based on mammographic density. RESULTS: (1) According to Wolfe's classification, the DY group had a significantly increased breast cancer risk compared with the N1 group (Relative risk (RR)=2.20, 95% confidence interval (95%CI) (1.02-4.77). (2) The group showing a high mammographic density had a significantly increased risk of breast cancer compared with the group with low mammographic density (RR=2.83, 95%CI=1.33-5.98) as classified by the computer assisted method. CONCLUSION: It is suggested that women with high mammographic densities, classified visually or by computer, have an elevated risk of breast cancer compared with those with low mammographic densities.     

Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women.

p53 mutations may be a fingerprint for cigarette smoking and other environmental carcinogens, including breast carcinogens. This study was undertaken to explore whether p53 mutations are associated with environmental or other suspected or established risk factors for breast cancer. p53 protein detection by immunohistochemistry (which is more easily quantified in large epidemiological studies than are mutations, and are highly correlated with them) was determined for 378 patients from a case-control study of breast cancer. In this population-based sample of women under the age of 45 years, 44.4% (168/378) of the cases had p53 protein detected by immunohistochemistry (p53+). Polytomous logistic regression was used to calculate the odds ratios (ORs) for p53+ and p53- breast cancer, as compared with the controls, in relation to cigarette smoking and other factors. The ratio of the ORs was used as an indicator of heterogeneity in risk for p53+ versus p53- cancer. The ratio of the ORs in a multivariate model was substantially elevated among women with a greater than high school education [2.39; 95% confidence interval (CI), 1.43-4.00], current cigarette smokers (1.96; 95% CI, 1.10-3.52), and users of electric blankets, water beds, or mattresses (1.78; 95% CI, 1.11-2.86). Nonsignificant heterogeneity was noted for family history of breast cancer and ethnicity but not for other known or suspected risk factors. Coupled with the strong biological plausibility of the association, our data support the hypothesis that in breast cancer, as with other tumors, p53 protein immunohistochemical detection may be associated with exposure to environmental carcinogens such as cigarette smoking.     

Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women

Background Endogenous hormones and insulin-like growth factors (IGF) play a central role in breast cancer development. Mammographic density, an important breast cancer risk factor, has been associated with these biomarkers in premenopausal women. The aim of this study was to assess the relationships between circulating hormones, clinical features related to breast cancer risk and mammographic density in postmenopausal women. Subjects and methods The study included 226 postmenopausal women participating in a clinical prevention trial. We performed baseline measurements of mammographic percent density and circulating levels of estradiol, sex-hormone binding globulin (SHBG), follicle stimulating hormone (FSH), prolactin, C-terminal cross-link telopeptide, IGF-I, and IGF binding protein-3. Results Median age and time since last menses were 52 years and 15 months, respectively. Median body mass index was 24.1 kg/m². After adjusting for age and body mass index, estradiol was the only biomarker significantly correlated with mammographic density (r = 0.17; P = 0.04). Women with normal body mass index had higher mammographic density (P < 0.001), higher SHBG (P < 0.0001), higher FSH (P = 0.002) and lower estradiol levels (P = 0.01) than those who were overweight. Women who had previous biopsies for benign breast disease had a higher mammographic density (P = 0.006). Conclusions In these recently postmenopausal women, mammographic percent density is directly associated with circulating estradiol levels. Our results provide further support to the role of circulating hormones in breast cancer risk.     

The risk of breast cancer associated with mammographic parenchymal patterns: a meta-analysis of the published literature to examine the effect of method of classification.

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.     

Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis.

Mammographic features are associated with breast cancer risk, but estimates of the strength of the association vary markedly between studies, and it is uncertain whether the association is modified by other risk factors. We conducted a systematic review and meta-analysis of publications on mammographic patterns in relation to breast cancer risk. Random effects models were used to combine study-specific relative risks. Aggregate data for > 14,000 cases and 226,000 noncases from 42 studies were included. Associations were consistent in studies conducted in the general population but were highly heterogeneous in symptomatic populations. They were much stronger for percentage density than for Wolfe grade or Breast Imaging Reporting and Data System classification and were 20% to 30% stronger in studies of incident than of prevalent cancer. No differences were observed by age/menopausal status at mammography or by ethnicity. For percentage density measured using prediagnostic mammograms, combined relative risks of incident breast cancer in the general population were 1.79 (95% confidence interval, 1.48-2.16), 2.11 (1.70-2.63), 2.92 (2.49-3.42), and 4.64 (3.64-5.91) for categories 5% to 24%, 25% to 49%, 50% to 74%, and > or = 75% relative to < 5%. This association remained strong after excluding cancers diagnosed in the first-year postmammography. This review explains some of the heterogeneity in associations of breast density with breast cancer risk and shows that, in well-conducted studies, this is one of the strongest risk factors for breast cancer. It also refutes the suggestion that the association is an artifact of masking bias or that it is only present in a restricted age range.