Association Of Mammographic Density Research Articles

Association of mammographic density and benign breast calcifications individually or combined with hypertension, diabetes, and hypercholesterolemia in women ≥40 years of age: a retrospective study

Recent evidence has linked certain mammographic characteristics, including breast calcifications (Bcs) and mammographic density (MD), with atherosclerotic cardiovascular disease risk factors in women, but data are limited and inconsistent. We...

Association of Mammographic Density With Risk of Ipsilateral Breast Tumor Recurrence and Contralateral Breast Cancer

Association of Mammographic Density With Risk of Ipsilateral Breast Tumor Recurrence and Contralateral Breast Cancer

Association of mammographic density with blood DNA methylation

ABSTRACT Background: Altered DNA methylation may be an intermediate phenotype between breast cancer risk factors and disease. Mammographic density is a strong risk factor for breast cancer. However, no studies to date have identified an epigenetic signature of mammographic density. We performed an epigenome-wide association study of mammographic density. Methods: White blood cell DNA methylation was measured for 385 postmenopausal women using the Illumina Infinium MethylationEPIC BeadChip array. Differential methylation was assessed using genome-wide, probe-level, and regional analyses. We implemented a resampling-based approach to improve the stability of our findings. Results: On average, women with elevated mammographic density exhibited DNA hypermethylation within CpG islands and gene promoters compared to women with lower mammographic density. We identified 250 CpG sites for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, including HDLBP, TGFB2, CCT4, and PAX8, and were more likely to be located in regulatory regions of the genome. We also identified differential DNA methylation in 37 regions, including within the promoters of PAX8 and PF4, a gene involved in the regulation of angiogenesis. Overall, our results paint a picture of epigenetic dysregulation associated with mammographic density. Conclusion: Mammographic density is associated with differential DNA methylation throughout the genome, including within genes associated with cancer. Our results suggest the potential involvement of several genes in the biological mechanisms behind differences in breast density between women. Further studies are warranted to explore these potential mechanisms and potential links to breast cancer risk.

Abstract 3661: Association of mammographic density with blood DNA methylation

Abstract Background: Mammographic density is a strong risk factor for breast cancer. While numerous genetic variations have been shown to be associated with mammographic density, an epigenetic signature of mammographic density has not yet been identified. The objective of this study was to identify a DNA methylation signature associated with mammographic density. Methods: Blood samples were collected from 197 postmenopausal women 45-65 years old with no personal history of breast cancer. For each participant, mammographic density according to the BI-RADs density classification was obtained from the most recent mammogram report. White blood cell DNA methylation at more than 850,000 CpG sites was measured using the Illumina HumanMethylationEPIC BeadChip. Differential methylation was assessed using genome-wide, probe-level, and regional approaches after filtering and normalization using the recommended steps for DNA methylation microarray data. All analyses were adjusted for appropriate confounding variables. Results: On average, genome-wide DNA methylation was higher in women with elevated mammographic density. Additionally, DNA methylation at 343 individual sites and in 34 regions was significantly associated with mammographic density after false discovery rate correction. Most density-associated sites were hypermethylated. The top differentially methylated sites were located near cell cycle regulatory genes (ICMT, DESI2, TCF21/TARID, ROBO3), as well as those encoding cytoskeletal or plasma membrane proteins (PALLD, ANO7, ATP8B3, MTUS2). We observed hypermethylation near the promoters of genes including RUFY1 and SLFN12 and within the bodies of genes including LCN6, SNED1, and LRFN1. Functional analysis of the differentially methylated sites revealed enrichment of gene ontology categories including angiogenesis and regulation of cell adhesion, as well as apoptotic signaling in response to DNA damage. Conclusions: White blood cell DNA methylation differed according to mammographic density in a sample of postmenopausal women. Probe-based and regional analysis identified differentially methylated regions located near genes implicated in cancer. These differentially methylated regions may serve as a signature of mammographic density, and future studies of the genes implicated may provide a deeper understanding of the connection between mammographic density and breast cancer risk. Citation Format: Rachel McFarland Lucia, Wei-Lin Huang, Andrea Alvarez, Irene Masunaka, Argyrios Ziogas, Deborah Goodman, Andrew O. Odegaard, Trina M. Norden-Krichmar, Hannah Lui Park. Association of mammographic density with blood DNA methylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3661.

The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study

BackgroundMammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these.MethodsWe conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ≥ 2 years after first diagnosis at age <55 years and controls had unilateral breast cancer (UBC) with similar follow-up time. We retrieved film mammograms of the unaffected breast from two time points, prior to/at the time of the first diagnosis (253 CBC cases, 269 UBC controls) and ≥ 6 months up to 48 months following the first diagnosis (333 CBC cases, 377 UBC controls). Mammograms were digitized and percent MD (%MD) was measured using the thresholding program Cumulus. Odds ratios (OR) and 95% confidence intervals (CI) for association between %MD and CBC, adjusted for age, treatment, and other factors related to CBC, were estimated using logistic regression. Linear regression was used to estimate the association between treatment modality and change in %MD in 467 women with mammograms at both time points.ResultsFor %MD assessed following diagnosis, there was a statistically significant trend of increasing CBC with increasing %MD (p = 0.03). Lower density (<25%) was associated with reduced risk of CBC compared to 25 to < 50% density (OR 0.69, 95% CI 0.49, 0.98). Similar, but weaker, associations were noted for %MD measurements prior to/at diagnosis. The relationship appeared strongest in women aged < 45 years and non-existent in women aged 50 to 54 years. A decrease of ≥ 10% in %MD between first and second mammogram was associated marginally with reduced risk of CBC (OR 0.63, 95% CI 0.40, 1.01) compared to change of <10%. Both tamoxifen and chemotherapy were associated with statistically significant 3% decreases in %MD (p < 0.01).ConclusionsPost-diagnosis measures of %MD may be useful to include in CBC risk prediction models with consideration of age at diagnosis. Chemotherapy is associated with reductions in %MD, similar to tamoxifen.

Comparison of the association of mammographic density and clinical factors with ductal carcinoma in situ versus invasive ductal breast cancer in Korean women

BackgroundIn spite of the increasing incidence of in situ breast cancer, the information about the risk factors of in situ breast cancer (DCIS) is scarce as compared to the information available for invasive ductal breast cancer (IDC), with inconsistent findings regarding the difference in risk factors between DCIS and IDC.MethodsWe enrolled 472 women with IDC and 90 women with DCIS and 1088 controls matching for age and menopausal status. Information on risk factors was collected through self-administered questionnaire. Percent mammographic dense area (PDA), absolute mammographic dense area (ADA), and nondense area were assessed using a computer-assisted thresholding technique. Odds ratio (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression model with adjustment for covariates.ResultsLater age at menarche and regular physical exercise were associated with decreased risk of IDC, whereas alcohol consumption, previous benign breast disease, and family history of breast cancer were associated with increased risk of IDC. For DCIS, previous benign breast disease and alcohol consumption were associated with the increased risk, and regular physical exercise was associated with decreased risk. Increase of ADA by 1-quartile level and PDA increase by 10% were associated with 1.10 (95% CI: 1.01, 1.21) and 1.10 (95% CI: 1.01, 1.19) times greater risk of IDC, respectively. The increase of ADA by 1-quartile level and PDA increase by 10% were associated with 1.17 (95% CI: 0.91, 1.50) times and 1.11 (95% CI:0.90,1.37) times greater risk of DCIS, respectively, but the associations were not statistically significant. There was no significant difference in the association with risk factors and mammographic density measures between IDC and DCIS (P > 0.1).ConclusionsDifferential associations of DCIS with mammographic density and risk factors as compared with the associations of IDC were not evident. This finding suggests that IDC and DCIS develop through the shared causal pathways.

37P - Association of mammographic density and fibroglandular tissue volume with the subtype of breast cancer

37P - Association of mammographic density and fibroglandular tissue volume with the subtype of breast cancer

The Association of Mammographic Density and Molecular Breast Cancer Subtype.

Background: Mammographic density (MD) is associated with increased breast cancer risk, yet limited data exist on an association between MD and breast cancer molecular subtypes.Methods: Women ages 18 years and older with breast cancer and available mammograms between 2003 and 2012 were enrolled in a larger study on MD. MD was classified by the Breast Imaging Reporting and Data System (BI-RADS) classification and by volumetric breast percent density (Volpara Solutions). Subtype was assigned by hormone receptor status, tumor grade, and mitotic score (MS). Subtypes included: Luminal-A (ER/PR+ and grade = 1; ER/PR+ and grade = 2 and MS = 1; ER+/PR- and grade = 1; n = 233); Luminal-B (ER+ and grade = 3 or MS = 3; ER+/PR- and grade = 2; ER/PR+ and grade = 2 and MS = 2; n = 79); Her-2-neu+ (H2P; n = 59); triple-negative (ER/PR-, Her-2-; n = 86). Precancer factors including age, race, body mass index (kg/m2), family history of breast cancer, and history of lobular carcinoma in situ were analyzed.Results: A total of 604 patients had invasive cancer; 457 had sufficient information for analysis. Women with H2P tumors were younger (P = 0.011) and had the highest volumetric percent density (P = 0.002) among subgroups. Multinomial logistic regression (LA = reference) demonstrated that although quantitative MD does not significantly differentiate between all subtypes (P = 0.123), the association between MD and H2P tumors is significant (OR = 1.06; confidence interval, 1.01-1.12). This association was not seen using BI-RADS classification in bivariable analysis but was statistically significant (P = 0.047) when controlling for other precancer factors.Conclusions: Increased MD is more strongly associated with H2P tumors when compared with LA.Impact: Delineating risk factors specific to breast cancer subtype may promote development of individualized risk prediction models and screening strategies. Cancer Epidemiol Biomarkers Prev; 26(10); 1487-92. ©2017 AACR.

Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes.

We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size≥2cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity=0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41-0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity=0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity=0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity=0.01), even though the interaction was not significant. Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.

Abstract P3-08-05: Association of mammographic density in high risk BRCA mutated tumors compared to average risk tumors and healthy controls: Analysis of Korean Hereditary Breast and Cancer Study (KOHBRA)

Abstract Introduction: Mammographic density is a well-known risk factor of breast cancer as a whole. Nonetheless only few studies have examined the association of density among high risk breast cancer regarding BRCA mutation. We examined mammographic density of 2019 breast cancer patients and 2029 healthy controls, regarding risk factors and BRCA mutation status. Method: Total 2019 breast cancer patients diagnosed between 1980 to 2011 were divided into two groups- high versus average risk group. Women with 1)family history of breast/ovarian cancer or 2)younger than age 40 or 3)bilateral cases were considered high risk group and were participants of ‘Korean Hereditary Breast Cancer study’ (KOHBRA) whom undergone BRCA testing. Density of 2029 healthy women who took screening mammogram during the same period were analyzed for comparison. Density was measured of the unaffected contralateral CC view using computer-assisted method Cumulus by single observer (10% randomly selected, intra-class correlation coefficient=0.96). Percent density (PD, dense area/breast area, %) among three groups, association with BRCA mutation status and breast cancer subtypes were examined. Results and Discussion: Percent density (PD) was significantly higher in high risk group compared to average risk and controls in a consecutive manner. This finding was consistent after adjusting age and BMI (p*&amp;lt;0.001). Mammographic percent density(PD) among three group (high risk cancer vs average risk cancer vs control)High risk cancers (N=1066)Average risk cancers (N=953)Control (N=2029)High vs AverageHigh vs controlAverage vs controlAge(yr)mean±SD41.12±9.8651.03±7.9850.52±9.090.001&amp;lt;0.0010.141PD (%)mean±SD52.90±12.9345.52±16.0441.52±15.80&amp;lt;0.001 (&amp;lt;0.001*)&amp;lt;0.001 (&amp;lt;0.001*)&amp;lt;0.001 (&amp;lt;0.001*)PD_median (%)&amp;lt;50442 (41.5%)567 (59.4%)1414 (69.7%)&amp;lt;0.001&amp;lt;0.001&amp;lt;0.00150≤624 (58.5%)387 (40.6%)615 (30.3%)PD_quartile (%)&amp;lt;2526 (2.4%)106 (11.1%)329 (16.2%)&amp;lt;0.001&amp;lt;0.001&amp;lt;0.00125≤ &amp;lt;50416 (39.0%)461 (48.3%)1085 (53.5%)50≤ &amp;lt;75564 (52.9%)360 (37.7%)570 (28.1%)75≤60 (5.6%)27 (2.8%)45 (2.2%)* adjusted p value by age and BMI High mammographic density showed to be a significant risk factor throughout different subtypes. Magnitude of mammographic density as a risk factor according to receptor statusTNBC (control(ref))Non-TNBCLuminalNon-Luminal25%≤PD&amp;lt;50% (&amp;lt;25%(ref))HR 4.21, 95%CI 2.12-8.38HR 1.91, 95%CI 1.50-2.43HR 1.77, 95%CI 1.38-2.26HR 3.04, 95%CI 2.00-4.6450%≤PD&amp;lt;75%HR 8.85, 95%CI 4.45-17.61HR 3.81, 95%CI 2.98-4.89HR 3.89, 95%C I3.03-5.00HR 5.08, 95%CI 3.32-7.8075%≤PDHR 16.25, 95%CI 6.97-37.87HR 4.09, 95%CI 2.61-6.41HR 4.09, 95%CI 2.61-6.43HR 8.16, 95%CI 4.41-15.07 Among the 1066 high risk group, 81.5% (869) undergone BRCA testing and 70(6.6%) had BRCA1, 78(7.3%) had BRCA2 mutations without significant difference in density. Similar strong magnitude association of mammographic density was observed in both BRCA mutated/non-mutated tumors and among subtypes. The ongoing GWAS and whole exome analysis of this population-subset will give insight into the tumor etiology and how density could stratify breast cancer risk for personalized screening especially in high risk population. Citation Format: Jisun Kim, Jong Won Lee, Sung Won Park, Hee Jung Shin, Hak Hee Kim, Sae-Byul Lee, Jong Han Yu, Hee Jeong Kim, Beom Seok Koh, Byung Ho Son, Sei-Hyun Ahn. Association of mammographic density in high risk BRCA mutated tumors compared to average risk tumors and healthy controls: Analysis of Korean Hereditary Breast and Cancer Study (KOHBRA) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-08-05.

Abstract P2-04-04: Association of mammographic density and molecular breast cancer subtype

Abstract Background: While mammographic density is linked to increased breast cancer risk, limited yet conflicting data exists on an association between density and developing specific molecular subtypes of breast cancer. Methods: Eligible patients were enrolled in a larger study on breast density, diagnosed with cancer between 2003-2013, and had pathology and films available for review. Density was classified qualitatively from existing radiology reports according to Breast Imaging Reporting and Data System (BIRADS) classification and quantitatively by volumetric breast density measurements using Volpara SolutionsTM software. Subtype was assigned by hormone receptor status, tumor grade and mitotic score (MS). Subtype categories included: Luminal A (ER/PR + &amp; grade 1; ER/PR + &amp; grade 2 &amp; MS=1; ER+/PR- &amp; grade 1); Luminal B (ER+ &amp; grade 3 or MS=3; ER+/PR- &amp; grade 2; ER/PR + &amp; grade 2 &amp; MS=2); Her-2 + (ER+ or ER - &amp; Her-2 +); Triple Negative (ER/PR-, Her-2 -). Relevant pre-cancer factors including patient age, race, BMI, family history of breast cancer, and biopsy showing LCIS were included in analysis. Results: Of 604 patients with invasive cancer, 457 had sufficient information for analysis. Among these, 233 (51%) had Luminal A, 79 (17%) Luminal B, 59 (13%) Her-2 +, and 86 (19%) Triple Negative tumors. Younger women and those with denser breasts based on quantitative measurements were more likely to have Her-2+ tumors (Table 1); this association was not seen using the standard BIRADS classification. Triple Negative tumors were less common in patients with LCIS and more common in African Americans. A multinomial logistic regression model controlling for pre-cancer patient factors demonstrated that while quantitative breast density does not significantly differentiate between all molecular subtypes (p=0.140), the association between Her-2+ tumors and denser breasts using continuous quantitative measurements is significant (p=0.035). Conclusion: Women with denser breasts by continuous-scaled quantitative measurements are at higher risk for Her-2+ tumors; an association not delineated using standard BIRADS density classification. Delineating risk factors specific to molecular breast cancer subtype may promote individualized risk prediction models and prevention strategies. Table 1. Association between patient factors and molecular breast cancer subtype Molecular SubtypeVariableLuminal ALuminal BHer-2+Triple NegativeP value (n=233)(n=79)(n=59)(n=86) Age (median,IQR)61 (54,70)58 (50,67)54 (46,70)59 (48,67)0.006BMI (median,IQR)27.1 (22.9,30.5)25.7 (23.0,30.0)26.0 (22.7,32.6)28.1 (24.3,32.6)0.173Volpara density (median,IQR)7.18 (4.74,11.25)8.68 (5.68,14.34)10.25 (5.96,16.51)7.00 (4.97,11.89)0.002BIRADS density (n,%)0.183 Fatty42 (18.0%)15 (19.0%)5 (8.5%)16 (18.6%) Scattered103 (44.2%)27 (34.2%)20 (33.9%)36 (41.9%) Heterogeneous74 (31.8%)30 (38.0%)25 (42.4%)26 *30.2%) Extreme14 (6.0%)6 (7.6%)9 (15.2%)7 (8.1%) Unspecified01 (1.2%)01 (1.2%) Race (n,%)0.002 Caucasian202 (86.7%)65 (82.3%)51 (86.4%)61 (70.9%) African American23 (9.9%)13 (16.5%)6 (10.2%)23 (26.7%) Other2 (0.9%)02 (3.4%)0 Unspecified6 (2.6%)1 (1.2%)02 (2.3%) LCIS (n,%)48 (20.6%)8 (10.1%)8 (13.6%)5 (5.8%)0.004Family history of breast cancer (n,%)107 (45.9%)34 (43.0%)21 (35.6%)39 (45.35%)0.625 Citation Format: Brandy L Edwards, Kristen A Atkins, George J Stukenborg, Wendy M Novicoff, Krista N Larson, Wendy F Cohn, Jennifer A Harvey, Anneke T Schroen. Association of mammographic density and molecular breast cancer subtype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-04-04.

Association of Mammographic Density with Pathologic Findings

BackgroundBreast cancer is one of the most common cancers in the world and is the first cause of death due to cancer among women. Mammography is the best screening method and mammographic density, which determines the percentage of fibro glandular tissue of breast, is one of the strongest risk factors of breast cancer. Because benign and malignant lesions may present as dense lesions in mammography so it is necessary to take a core biopsy of any suspicious lesions to evaluate pathologic findings.ObjectivesThe aim of this study was to assess the association between mammographic density and histopathological findings in Iranian population. Moreover, we assessed the correlation between mammographic density and protein expression profile. We indeed, determined the accuracy and positive predictive value and negative predictive value of mammographic reports in our center.Patients and MethodThis study is a cross-sectional study carried out among 131 eligible women who had referred to imaging center for mammographic examination and had been advised to take biopsy of breast tissue. All participants of the study had filled out the informed consent. Pathologic review was performed blinded to the density status. Patients were divided into low density breast tissue group (ACR density group 1-2) and high density breast tissue group (ACR 3, 4) and data was compared between these two groups. Statistical analysis performed using SPSS for windows, version 11.5. We used chi-square, t-test, and logistic regression test for analysis and Odds Ratio calculated where indicated.ResultsIn patients with high breast densities, malignant cases (61.2%) were significantly more in comparison to patients with low breast densities (37.3%) (P= 0.007, OR=2.66 95% CI=1.29-5.49). After adjusting for age, density was associated with malignancy in age groups <46 years (P=0.007), and 46-60 years (P=0.024) but not in age group >60yrs (P=0.559). Adjusting for menopausal status, density showed association with malignancy in both pre-menopause (P=0.041) and menopause (P=0.010) patients. Using logistic regression test, only age and density showed independent association with risk of breast cancer. No association was found between density and protein profile expression. Mammographic method has a false negative percent of 10.3% for negative BI-RADS group and a Positive Predictive Value (PPV) of 69.6% for positive BI-RADS group. PPVs for BI-RADS 4a, 4b, 4c and 5 were 16%, 87.5%, 84.6%, and 91.5% respectively. NPVs for BI-RADS 1, 2 and 3 were 66.7%, 95.8% and 90.0% respectively.ConclusionsIn this study we found that increasing in mammographic density is associated with an increase in malignant pathology reports. Expression of ER, PR and HER-2 receptors didn't show association with density. Our mammographic reports had a sensitivity of 94.1% and a specificity of 55.6%, which shows that our mammography is an acceptable method for screening breast cancer in this center.

Methods for Assessing and Representing Mammographic Density: An Analysis of 4 Case-Control Studies

To maximize statistical power in studies of mammographic density and breast cancer, it is advantageous to combine data from several studies, but standardization of the density assessment is desirable. Using data from 4 case-control studies, we describe the process of reassessment and the resulting correlation between values, identify predictors of differences in density readings, and evaluate the strength of the association between mammographic density and breast cancer risk using different representations of density values. The pooled analysis included 1,699 cases and 2,422 controls from California (1990-1998), Hawaii (1996-2003), Minnesota (1992-2001), and Japan (1999-2003). In 2010, a single reader reassessed all images for mammographic density using Cumulus software (Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada). The mean difference between original and reassessed percent density values was -0.7% (95% confidence interval: -1.1, -0.3), with a correlation of 0.82 that varied by location (r = 0.80-0.89). Case status, weight status, age, parity, density assessment method, mammogram view, and race/ethnicity were significant determinants of the difference between original and reassessed values; in combination, these factors explained 9.2% of the variation. The associations of mammographic density with breast cancer and the model fits were similar using the original values and the reassessed values but were slightly strengthened when a calibrated value based on 100 reassessed radiographs was used.

Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.

Higher alcohol intake may modify the association between mammographic density and breast cancer: An analysis of three case–control studies

Alcohol consumption and mammographic density are established risk factors for breast cancer. This study examined whether the association of mammographic density with breast cancer varies by alcohol intake. Mammographic density was assessed in digitized images for 1207 cases and 1663 controls from three populations (Japan, Hawaii, California) using a computer-assisted method. Associations were estimated by logistic regression. When comparing ever to never drinking, mean density was similar and consumption was not associated with breast cancer risk. However, within the Hawaii/Japan subset, women consuming >1 drink/day had a non-significantly elevated relative risk compared to never drinkers. Also in the Hawaii/Japan population, alcohol intake only modified the association between mammographic density and breast cancer in women consuming >1 drink/day (pinteraction=0.05) with significant risk estimates of 3.65 and 6.58 for the 2nd and 3rd density tertiles as compared to 1.57 and 1.61 for never drinkers in Hawaii/Japan. Although these findings suggest a stronger association between mammographic density and breast cancer risk for alcohol consumers, the small number of cases requires caution in interpreting the results.

Association of mammographic density with hormone receptors in invasive breast cancers: Results from a case‐only study

For many breast cancer (BC) risk factors, there is growing evidence concerning molecular subtypes for which the risk factor is specific. With regard to mammographic density (MD), there are inconsistent data concerning its association with estrogen receptor (ER) and progesterone receptor (PR) expression. The aim of our study was to analyze the association between ER and PR expression and MD. In our case-only study, data on BC risk factors, hormone receptor expression and MD were available for 2,410 patients with incident BC. MD was assessed as percent MD (PMD) using a semiautomated method by two readers for every patient. The association of ER/PR and PMD was studied with multifactorial analyses of covariance with PMD as the target variable and including well-known factors that are also associated with MD, such as age, parity, use of hormone replacement therapy, and body mass index (BMI). In addition to the commonly known associations between PMD and age, parity, BMI and hormone replacement therapy, a significant inverse association was found between PMD and ER expression levels. Patients with ER-negative tumors had an average PMD of 38%, whereas patients with high ER expression had a PMD of 35%. A statistical trend toward a positive association between PMD and PR expression was also seen. PMD appears to be inversely associated with ER expression and may correlate positively with PR expression. These effects were independent of other risk factors such as age, BMI, parity, and hormone replacement therapy, possibly suggesting other pathways that mediate this effect.

Alcohol consumption: The single most important behavioral risk factor in breast cancer?

176 Background: Breast cancer research has identified certain risk factors over the years, which influence a woman's chance of getting the disease. While factors such as personal history of breast abnormalities, age and the occurrence of breast cancer among first-degree relatives have been identified as estimation factors for breast cancer risk, other factors are less conclusive. Increasingly, obesity is being analyzed as a significant risk factor for many cancers and, after tobacco use, may be one of the most modifiable behavioral cancer risk factors. Interestingly when comparing the incidence rate of breast cancer to the obesity rate nationwide many states show a disparity in the two. It may be that other behavioral risk factors are of greater importance. Methods: The US States Mississippi and West Virginia display the highest rates of obesity (over 29.4% of their population display a BMI over 30.0) and the lowest rates in breast cancer incidence nationwide (under 113.9 and 113.5 people per 100.00. residents are diagnosed with cancer each year respectively). We set out to look at various behavioral risk factors to possibly detect an underlying pattern for breast cancer. Using selected metropolitan/micropolitan area risk trend data from the Behavioral Risk Factor Surveillance System from the CDC, we compared median percentages of the following risk factors: health status, exercise, diabetes, flu vaccination, current smoking, binge drinking and obesity. Results: Both states displayed higher percentages in all risk factors compared to the national average except for one in which they were below the national average: binge drinking. Rhode Island and Connecticut, the two states with the highest incidence rates in breast cancer, in turn displayed slightly higher rates of binge drinking compared to the national average. Conclusions: It appears that binge drinking might weigh more than other behavioral factors in terms of risk associated to breast cancer. Future research will need to analyze the interplay and patterns of the various risk factors as well as evaluate the association of mammographic density and alcohol drinking to further investigate the role of alcohol and binge drinking in the development of breast cancer.

Mammographic density and epithelial histopathologic markers

BackgroundWe explored the association of mammographic density, a breast cancer risk factor, with hormonal and proliferation markers in benign tissue from tumor blocks of pre-and postmenopausal breast cancer cases.MethodsBreast cancer cases were recruited from a case-control study on breast density. Mammographic density was assessed on digitized prediagnostic mammograms using a computer-assisted method. For 279 participants of the original study, we obtained tumor blocks and prepared tissue microarrays (TMA), but benign tissue cores were only available for 159 women. The TMAs were immunostained for estrogen receptor alpha (ERα) and beta (ERβ), progesterone receptor (PR), HER2/neu, Ki-67, and Proliferating Cell Nuclear Antigen (PCNA). We applied general linear models to compute breast density according to marker expression.ResultsA substantial proportion of the samples were in the low or no staining categories. None of the results was statistically significant, but women with PR and ERβ staining had 3.4% and 2.4% higher percent density. The respective values for Caucasians were 5.7% and 11.6% but less in Japanese women (3.5% and -1.1%). Percent density was 3.4% higher in women with any Ki-67 staining and 2.2% in those with positive PCNA staining.ConclusionThis study detected little evidence for an association between mammographic density and expression of steroid receptors and proliferation markers in breast tissue, but it illustrated the problems of locating tumor blocks and benign breast tissue samples for epidemiologic research. Given the suggestive findings, future studies examining estrogen effects in tissue, cell proliferation, and density in the breast may be informative.

Association of Mammographic Density with the Pathology of Subsequent Breast Cancer among Postmenopausal Women

Limited studies have examined the associations between mammographic density and subsequent breast tumor characteristics. Eligible women were part of a case-control study of postmenopausal breast cancer, were 40 years or older and had a routine mammogram 4 years or more before their diagnosis. Mammographic density (percent density, dense area, and nondense area) was estimated using a computer-assisted thresholding program. At the time of cancer diagnosis, cases were classified as asymptomatic or symptomatic based on medical record review and breast imaging workup. Pathologic review was done blinded to the density status. Linear regression models and tests for trend examined the association between pathologic characteristics of the breast tumor and the components of density for all participants, and stratified by symptom status at diagnosis. Of the 286 eligible cases, 77% were 60 years or older and mean percent density was 29.5% (SD, 14.6%). Density was not significantly associated with tumor size (P = 0.22), histologic type (P = 0.77), estrogen receptor (P = 0.11) or progesterone receptor (P = 0.37) status, mitotic activity (P = 0.12), or nuclear pleomorphism (P = 0.09; P values for percent density). An inverse association was suggested between tumor grade and percent density (32.0%, 30.3%, 26.7% for grades 1-3; P = 0.06 for trend). The inverse association with tumor grade and its components (nuclear pleomorphism and tubular differentiation) was only evident among the 97 symptomatic women; positive associations of estrogen receptor (P = 0.009) and progesterone receptor (P = 0.04) were also seen with percent density only in this subgroup. The inverse association between tumor grade and percent density in the symptomatic population could inform the biology of the association between mammographic density and breast cancer risk.

The association of mammographic density with ductal carcinoma in situof the breast: the Multiethnic Cohort

IntroductionIt is well established that women with high mammographic density are at greater risk for breast cancer than are women with low breast density. However, little research has been done on mammographic density and ductal carcinoma in situ (DCIS) of the breast, which is thought to be a precursor lesion to some invasive breast cancers.MethodWe conducted a nested case-control study within the Multiethnic Cohort, and compared the mammographic densities of 482 patients with invasive breast cancer and 119 with breast DCIS cases versus those of 667 cancer-free control subjects. A reader blinded to disease status performed computer-assisted density assessment. For women with more than one mammogram, mean density values were computed. Polytomous logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for two measurements of mammographic density: percentage density and dense area.ResultsMammographic density was associated with invasive breast cancer and breast DCIS. For the highest category of percentage breast density (≥50%) as compared with the lowest (<10%), the OR was 3.58 (95% CI 2.26–5.66) for invasive breast cancer and 2.86 (1.38–5.94) for breast DCIS. Similarly, for the highest category of dense area (≥45 cm2) as compared with the lowest (<15 cm2), the OR was 2.92 (95% CI 2.01–4.25) for invasive breast cancer and 2.59 (1.39–4.82) for breast DCIS. Trend tests were significant for invasive breast cancer (P for trend < 0.0001) and breast DCIS (P for trend < 0.001) for both percentage density and dense area.ConclusionThe similar strength of association for mammographic density with breast DCIS and invasive breast cancer supports the hypothesis that both diseases may have a common etiology.