Changes In Mammographic Density Research Articles

Abstract 5892: Factors associated with longitudinal changes in mammographic density in a multiethnic breast screening cohort of postmenopausal women

Abstract Mammographic density is an important risk factor for breast cancer and is known to differ in women by characteristics such as age and race/ethnicity. Women who experience longitudinal decreases in breast density have a reduced risk of breast cancer; however, besides age, which correlates with decreases in breast density, it is unclear what other factors contribute to changes in breast density over time. Understanding factors associated with density changes may enable a better understanding of breast cancer risk and potential strategies for prevention. This study investigated factors associated with changes in mammographic density in a cohort of 3,392 postmenopausal women (mean age=61.3±8.8 years) with no history of breast cancer who had at least two mammograms spaced at least three months apart at a University of California, Irvine Health breast imaging facility between 2011-2017. Self-reported information on demographics, breast and reproductive history, and lifestyle factors, including body mass index (BMI), alcohol intake, smoking, and physical activity, was collected by an electronic intake form, and Breast Imaging Reporting and Database System (BI-RADS) mammographic density scores were obtained from electronic medical records. 7.9% of women exhibited a longitudinal decrease in mammographic density, 6.7% exhibited an increase, and 85.4% exhibited no change. Longitudinal changes in mammographic density were statistically significantly correlated with age, race/ethnicity, and age at menopause by univariate analysis using the Fisher’s exact test. Multivariate conditional logistic regression using baseline mammographic density as strata was performed to identify factors associated with a longitudinal increase or decrease in mammographic density. Variables were selected if they were nominally significant (p < 0.10) in the initial univariate analyses of women who exhibited a longitudinal change in mammographic density (race/ethnicity, age at baseline, menopause age) or were otherwise selected a priori based on previous literature showing an association with mammographic density (alcohol, physical activity, BMI). Asian women were more likely to exhibit a longitudinal increase in mammographic density (OR=1.78, 95% CI=1.02-3.09, p=0.04) and less likely to exhibit a decrease (OR = 0.58, 95% CI = 0.40-0.83, p=0.003) compared to white women. On the other hand, overweight and obese women were less likely to exhibit an increase compared to normal weight women (OR = 0.52, 95% CI = 0.31-0.87, p=0.01; OR = 0.41, 95% CI = 0.23-0.75, p=0.004, respectively). Other lifestyle factors (alcohol intake, smoking, and physical activity) were not associated with longitudinal changes in mammographic density. The potential interactions of Asian race and BMI with longitudinal breast density changes in influencing breast cancer risk should be further studied. Citation Format: Roza L. Kirmizi, Christie J. Lee, Hannah Lui Park, Argyrios Ziogas, Andrea Alvarez, Rachel M. Lucia, Deborah Goodman, Kathryn M. Larsen, Richard Kelly, Hoda Anton-Culver, Stephen A. Feig. Factors associated with longitudinal changes in mammographic density in a multiethnic breast screening cohort of postmenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5892.

Time to Mammographic Density Decrease After Exposure to Tamoxifen.

Mammographic density change has proven to be a reliable proxy for tamoxifen therapy response. The primary aim of this study was to identify time to tamoxifen-induced mammographic density change. We also analyzed side effects and adherence to therapy. In all, 42 women were randomized to 10 or 20 mg of daily oral tamoxifen. Mammograms were taken at baseline, 3, 6, and 9 months. Mammographic density change was measured using the automated STRATUS tool. Adverse events were monitored through a web-based questionnaire based on the FACT-ES tool. Nine out of the 42 (21%) participants discontinued therapy due to adverse events leaving 33 women in the study. A significant decrease in density was seen after 3 months of therapy. Dose did not seem to affect density change, side effects or adherence. Given the size of the study, additional studies are needed to confirm our data.

AB168. SOH22ABS231. Does the change in mammographic breast density reflect the response to treatment in breast cancer treated with primary hormonal therapy?

AB168. SOH22ABS231. Does the change in mammographic breast density reflect the response to treatment in breast cancer treated with primary hormonal therapy?

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

Mammographic Density Changes over Time and Breast Cancer Risk: A Systematic Review and Meta-Analysis.

Simple SummaryAlthough mammographic density is strongly linked to the risk of breast cancer, research on the relationship between changes in density over time and the risk of breast cancer has shown conflicting results. We found in the present meta-analysis that increased breast density over time was associated with higher breast cancer risk whereas decreased breast density might be associated with lower breast cancer risk. The results of the meta-analysis constitute a potential opportunity for more individualized screening strategies based on the evolution of breast density during mammography screening.The aim of this meta-analysis was to evaluate the association between mammographic density changes over time and the risk of breast cancer. We performed a systematic literature review based on the PubMed and ISI Web of Knowledge databases. A meta-analysis was conducted by computing extracted hazard ratios (HRs) and 95% confidence intervals (CIs) for cohort studies or odds ratios (ORs) and 95% confidence interval using inverse variance method. Of the nine studies included, five were cohort studies that used HR as a measurement type for their statistical analysis and four were case–control or cohort studies that used OR as a measurement type. Increased breast density over time in cohort studies was associated with higher breast cancer risk (HR: 1.61; 95% CI: 1.33–1.96) whereas decreased breast density over time was associated with lower breast cancer risk (HR: 0.78; 95% CI: 0.71–0.87). Similarly, increased breast density over time was associated with higher breast cancer risk in studies presented ORs (pooled OR: 1.85; 95% CI: 1.29–2.65). Our findings imply that an increase in breast density over time seems to be linked to an increased risk of breast cancer, whereas a decrease in breast density over time seems to be linked to a lower risk of breast cancer.

CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial

Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status is associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were -0.8cm2,-4.5 cm2,-4.1 cm2, and-8.0 cm2 respectively. Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.

Benign breast disease and changes in mammographic breast density

BackgroundMammographic breast density (MBD) and benign breast disease (BBD) are two of the strongest risk factors for breast cancer. Understanding trends in MBD by age and parity in women with BBD is essential to the clinical management and prevention of breast cancer.MethodsUsing data from the Early Determinants of Mammographic Density (EDMD) study, a prospective follow-up study of women born in 1959–1967, we evaluated MBD in 676 women. We used linear regression with generalized estimating equations to examine associations between self-reported BBD and MBD (percent density, dense area, and non-dense area), assessed through a computer-assisted method.ResultsA prior BBD diagnosis (median age at diagnosis 32 years) was reported by 18% of our cohort. The median time from BBD diagnosis to first available study mammogram was 9.4 years (range 1.1–27.6 years). Women with BBD had a 3.44% higher percent MBD (standard error (SE) = 1.56, p-value = 0.03) on their first available mammogram than women without BBD. Compared with parous women without BBD, nulliparous women with BBD and women with a BBD diagnosis prior to first birth had 7–8% higher percent MBD (β = 7.25, SE = 2.43, p-value< 0.01 and β = 7.84, SE = 2.98, p-value = 0.01, respectively), while there was no difference in MBD in women with a BBD diagnosis after the first birth (β = −0.22, SE = 2.40, p-value = 0.93).ConclusionWomen with self-reported BBD had higher mammographic breast density than women without BBD; the association was limited to women with BBD diagnosed before their first birth.

Use of Low-Dose Tamoxifen to Increase Mammographic Screening Sensitivity in Premenopausal Women.

Simple SummaryThis is the first study to model the effects of tamoxifen on mammographic density and screening sensitivity. Low-dose tamoxifen reduces mammographic density in premenopausal women by, on average, 20%. Potential outcome analyses suggest that a reduction in mammographic density improves mammography screening sensitivity, reduces the proportion of large tumors, and subsequent interval cancers.Increased breast density decreases mammographic sensitivity due to masking of cancers by dense tissue. Tamoxifen exposure reduces mammographic density and, therefore, should improve screening sensitivity. We modelled how low-dose tamoxifen exposure could be used to increase mammographic sensitivity. Mammographic sensitivity was calculated using the KARMA prospective screening cohort. Two models were fitted to estimate screening sensitivity and detected tumor size based on baseline mammographic density. BI-RADS-dependent sensitivity was estimated. The results of the 2.5 mg tamoxifen arm of the KARISMA trial were used to define expected changes in mammographic density after six months exposure and to predict changes in mammographic screening sensitivity and detected tumor size. Rates of interval cancers and detection of invasive tumors were estimated for women with mammographic density relative decreases by 10–50%. In all, 517 cancers in premenopausal women were diagnosed in KARMA: 287 (56%) screen-detected and 230 (44%) interval cancers. Screening sensitivities prior to tamoxifen, were 76%, 69%, 53%, and 46% for BI-RADS density categories A, B, C, and D, respectively. After exposure to tamoxifen, modelled screening sensitivities were estimated to increase by 0% (p = 0.35), 2% (p < 0.01), 5% (p < 0.01), and 5% (p < 0.01), respectively. An estimated relative density decrease by ≥20% resulted in an estimated reduction of interval cancers by 24% (p < 0.01) and reduction in tumors >20 mm at detection by 4% (p < 0.01). Low-dose tamoxifen has the potential to increase mammographic screening sensitivity and thereby reduce the proportion of interval cancers and larger screen-detected cancers.

Mammographic density changes following BC treatment

BackgroundMammographic density (MD) reduction is associated with lower risk of breast cancer (BC) recurrence and may be used as a marker of treatment outcome; however, trends in MD following BC therapies and the factors associated with such trends are poorly understood. The aim of this study was to investigate MD changes following BC treatment and the factors associated with these changes. MethodsA total of 226 BC-affected patients who received BC treatments were examined. MD was assessed by the Laboratory for individualized Radiodensity Assessment (LIBRA) software. A Wilcoxon ranked signed test was used to investigate the differences in MD before and after treatment and median independent test to assess the associated factors. ResultsSignificant differences in MD between baseline and follow-up mammograms were observed for all MD measures: percent density (p ≤ 0.005), dense area (p ≤ 0.004), and nondense area (p ≤ 0.02). After adjustment, these differences were more pronounced among younger at BC diagnosis (p ≤ 0.001), premenopausal (p ≤ 0.003), and obese women (p ≤ 0.05). Changes in MD were evident regardless of the treatment regimen. MD reduction was observed among patients with high baseline MD (p < 0.001), younger at BC diagnosis (p ≤ 0.04), premenopausal (p < 0.001), and normal body mass index (p = 0.04). Patients who experienced an increase in nondense area had high percent density at baseline (p ≤ 0.001). ConclusionTwo different MD changes were observed over time: MD increase and decrease. Baseline MD, menopausal status, age at BC diagnosis, and body mass index influenced these changes.

Mammographic density change in a cohort of premenopausal women receiving tamoxifen for breast cancer prevention over 5 years

BackgroundA decrease in breast density due to tamoxifen preventive therapy might indicate greater benefit from the drug. It is not known whether mammographic density continues to decline after 1 year of therapy, or whether measures of breast density change are sufficiently stable for personalised recommendations.MethodsMammographic density was measured annually over up to 5 years in premenopausal women with no previous diagnosis of breast cancer but at increased risk of breast cancer attending a family-history clinic in Manchester, UK (baseline 2010-2013). Tamoxifen (20 mg/day) for prevention was prescribed for up to 5 years in one group; the other group did not receive tamoxifen and were matched by age. Fully automatic methods were used on mammograms over the 5-year follow-up: three area-based measures (NN-VAS, Stratus, Densitas) and one volumetric (Volpara). Additionally, percentage breast density at baseline and first follow-up mammograms was measured visually. The size of density declines at the first follow-up mammogram and thereafter was estimated using a linear mixed model adjusted for age and body mass index. The stability of density change at 1 year was assessed by evaluating mean squared error loss from predictions based on individual or mean density change at 1 year.ResultsAnalysis used mammograms from 126 healthy premenopausal women before and as they received tamoxifen for prevention (median age 42 years) and 172 matched controls (median age 41 years), with median 3 years follow-up. There was a strong correlation between percentage density measures used on the same mammogram in both the tamoxifen and no tamoxifen groups (all correlation coeficients > 0.8). Tamoxifen reduced mean breast density in year 1 by approximately 17–25% of the inter-quartile range of four automated percentage density measures at baseline, and from year 2, it decreased further by approximately 2–7% per year. Predicting change at 2 years using individual change at 1 year was approximately 60–300% worse than using mean change at 1year.ConclusionsAll measures showed a consistent and large average tamoxifen-induced change in density over the first year, and a continued decline thereafter. However, these measures of density change at 1 year were not stable on an individual basis.

Hormonal determinants of mammographic density and density change

BackgroundMammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm2) and annual MD change (cm2/year).MethodsThis study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time.ResultsGreater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm2 per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm2), oesterone sulphate (+ 1.42 cm2), prolactin (+ 2.11 cm2) and SHBG (+ 4.18 cm2), and inversely associated with 11-deoxycortisol (− 1.33 cm2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was − 0.8 cm2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was − 0.96 cm2 and − 1.16 cm2 lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations.ConclusionsOur results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.

Mammographic density changes during neoadjuvant breast cancer treatment: NeoDense, a prospective study in Sweden

ObjectivesTo assess if mammographic density (MD) changes during neoadjuvant breast cancer treatment and is predictive of a pathological complete response (pCR). MethodsWe prospectively included 200 breast cancer patients assigned to neoadjuvant chemotherapy (NACT) in the NeoDense study (2014–2019). Raw data mammograms were used to assess MD with a fully automated volumetric method and radiologists categorized MD using the Breast Imaging-Reporting and Data System (BI-RADS), 5th Edition. Logistic regression was used to calculate odds ratios (OR) for pCR comparing BI-RADS categories c vs. a, b, and d as well as with a 0.5% change in percent dense volume adjusting for baseline characteristics. ResultsThe overall median age was 53.1 years, and 48% of study participants were premenopausal pre-NACT. A total of 23% (N = 45) of the patients accomplished pCR following NACT. Patients with very dense breasts (BI-RADS d) were more likely to have a positive axillary lymph node status at diagnosis: 89% of the patients with very dense breasts compared to 72% in the entire cohort. A total of 74% of patients decreased their absolute dense volume during NACT. The likelihood of accomplishing pCR following NACT was independent of volumetric MD at diagnosis and change in volumetric MD during treatment. No trend was observed between decreasing density according to BI-RADS and the likelihood of accomplishing pCR following NACT. ConclusionsThe majority of patients decreased their MD during NACT. We found no evidence of MD as a predictive marker of pCR in the neoadjuvant setting.

Heritability of Mammographic Breast Density, Density Change, Microcalcifications, and Masses.

Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features among women with a family history of breast cancer (N = 49,674) and a polygenic risk score (PRS, N = 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm2/year) was estimated using 1,940 sister pairs. Heritability was estimated at 58% [95% confidence interval (CI), 48%-67%) for MD, 23% (2%-45%) for microcalcifications, and 13% (1%-25%)] for masses. The estimated heritability for MDC was essentially null (2%; 95% CI, -8% to 12%). The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. In summary, we have confirmed previous findings of heritability in MD, and also established heritability of the number of microcalcifications and masses at baseline. Because these features are associated with breast cancer risk and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer. SIGNIFICANCE: These findings provide novel data on the heritability of microcalcifications, masses, and density change, which are all associated with breast cancer risk and can indicate women at short-term risk.

Abstract OT3-15-02: A randomized, double-blind, placebo-controlled study of 4-hydroxytamoxifen topical gel in women with mammographically dense breasts

Abstract Background: Tamoxifen uptake for risk reduction has remained low due to concerns about toxicity despite the efficacy and effectiveness data available. Studies of tamoxifen in the adjuvant and preventive setting have demonstrated that a decline in mammographic density (MD) of approximately 10% is consistently associated with better outcomes. Additionally, MD is one of the strongest independent predictors of breast cancer risk, apart from older age and BRCA1/2 mutation, among women. 4-hydroxytamoxifen topical gel (4-OHT) is a transdermal agent, shown in preliminary studies to be well-tolerated with similar decreases in Ki-67 to oral tamoxifen in presurgical DCIS studies and significant drug concentration in breast parenchyma but very low levels in the systemic circulation. This study examines changes in MD, a potential surrogate biomarker of prevention activity, as the primary endpoint for this one-year early-phase prevention trial using 4-OHT gel in high risk women. Trial design: Multicenter, randomized, placebo-controlled study of 4-OHT gel (2mg per breast) versus placebo in 152 women with heterogeneously or extremely dense breast tissue for 12 months using standard of care imaging, stratified by enrollment site and baseline breast density category. The primary objective of this study is to evaluate the change in percent MD (using Cumulus software) from baseline to the week 52 in women applying 4 mg (2mg per breast) 4-OHT gel versus placebo. The secondary objectives are to compare the Cumulus vs Volpara breast density measurement methods; evaluate the percentage of women with lowering of BIRADS density; estimate percentage of women with ≥ 10% absolute decrease in quantitative MD percentage; explore patient reported experience assessed by BESS questionnaire; laboratory toxicity assessment (F VIII, vWB factor, SHBG, lipid profile); compare the 2D vs. 3D breast density measurement methods to estimate percent change in mammographic breast density; evaluate serum measurements of parent drug and related metabolite levels and factors related to 4-OHT exposures, such as IGF pathway members, CRP, estradiol, and 4-OHT; collect tissue for biomarkers (among women undergoing optional pre- and post-treatment biopsies); examine the persistence in change of mammographic density one year after 4-OHT vs. placebo gel application has stopped. Eligibility criteria: Inclusion: Women age 40-69 years, or less than 40 years if 5-year breast cancer Gail risk is greater than/equal to 1.66%; heterogeneously or extremely dense breast tissue based on mammography. Exclusion: abnormal uterine bleeding, or prior diagnosis of endometrial hyperplasia, endometrial polyps, or endometrial cancer; prior use of SERMS and AIs, except for a maximum of 3 months and at least 12 months prior. Statistical methods: Considering an attrition rate of 15%, 128 evaluable women are expected to have both baseline and 52-week measurements of percent MD. With 64 women in each group, there is 80% power to detect a decrease of 6% in the 4-OHT group versus 2% in the placebo group with a common standard deviation of 8% using a two-sided t-test with a significance level of 0.05. Study accrual: Activated January 2018, as of July 1, 2019, 92 patients have been recruited and 79 were randomized. Citation Format: Banu K. Arun, Gretchen Gierach, Marion E Scoggins, Seema Khan, Sandra S Rao, Judy Garber, Sughra Raza, Nagi B. Kumar, Heather H Han, John Heine, Bethany Niell, Pavani Chalasani, Kimberly Fitzpatrick, Lee G Wilke, Amy Fowler, Heather C Beckwith, Carrie Mays, Saba Abutaseh, Lana Vornik, Oukseub Lee, Eileen Dimond, Marjorie Perloff, Diane Liu, J. Jack Lee, Powell Brown, Brandy Heckman-Stoddard. A randomized, double-blind, placebo-controlled study of 4-hydroxytamoxifen topical gel in women with mammographically dense breasts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-15-02.

Abstract P2-08-10: Mammographic breast density changes with endocrine therapy (ET) in women with hormone receptor positive (HR+) breast cancer in a Utah population

Abstract Introduction: Women with extremely dense breast tissue on mammography have a higher risk of breast cancer compared to similarly-aged women with less dense breast tissue. Tamoxifen therapy has been observed to reduce breast density among both pre- and postmenopausal women with HR+ breast cancer and may predict benefit of therapy. Studies of aromatase inhibitor (AI) therapy and breast density change, however, are limited and results inconclusive. Factors associated with breast density change with ET, and effect of duration of ET on breast density change, have not been well studied. Methods: Using the Utah Population Database, women were identified who underwent screening mammography in 2005-2016 and who had no personal history of breast cancer. Those who were subsequently diagnosed with HR+ breast cancer and treated in one of the major health care systems in Utah (Intermountain Healthcare or University of Utah Health) were included in the analysis. ET prescription information and duration of ET were obtained from provider records and the Utah All-Payer Claims Database. Women with mammography results in the electronic medical record both before and within 3 years after the breast cancer diagnosis were included. BI-RADS density classification from mammogram reports 6-12 months, 13-24 months, and 25-36 months after ET initiation were compared to pre-diagnosis BI-RADS density classification. Breast density reduction was defined as a decrease of ≥1 BI-RADS category compared to baseline. Fisher’s exact test was used to examine ET and breast density reduction among women ≥55y and &amp;lt;55y. Results: In total, 1328 women with HR+ breast cancer and baseline BI-RADS breast density categories B-D were included. Women with BI-RADS density category A(almost entirely fatty) were excluded. A majority (61%) were age ≥55y at diagnosis, were non-Hispanic white (90%), and had BMI ≥25 kg/m2 (56%); 15% had a first-degree family history of breast cancer. At baseline, 602 (44%) women had scattered fibroglandular densities (BI-RADS category B), 697 (50%) had heterogeneously dense breasts (BI-RADS category C), and 83 (6%) had extremely dense breasts (BI-RADS category D). Half were treated with AI only (49%), 21% with tamoxifen only, and 29% with both during follow-up. In both the age ≥55y and &amp;lt;55y groups, women with BI-RADS category D at baseline were more likely to experience a reduction in breast density with ET compared to women with either BI-RADS categories B or C (Table 1). There were no significant differences in breast density reduction observed between women treated with AI only compared to those treated with tamoxifen only, irrespective of age and baseline density. Breast cancer family history also had no effect on breast density reduction with ET. Conclusion: Baseline breast density is associated with a demonstrable reduction in breast density during ET. Our findings suggest that AI therapy can reduce breast density similar to that seen with tamoxifen therapy. Table 1 Breast Density (BD) changes among women who underwent mammography 6-12 months, 13-24 months, and 25-36 months after ET initiationBaseline BDN≥55 years oldPTotal&amp;lt;55 years oldPNo BD reduction N(%)BD reduction N(%)No BD reduction N(%)BD reduction N(%)6-12 months after ET initiationScattered157152(97)5(3)5452(96)2(3)Heterogeneous148115(78)33(22)10477(74)27(26)Dense144(29)10(71)&amp;lt;0.0001248(33)16(67)&amp;lt;0.0001Total319271(85)48(15)182137 (75)45(25)13-24 months after ET initiationScattered232214(92)18(8)8473(87)11(13)Heterogeneous211144(68)67(32)155107(69)48(31)Dense172(12)15(88)&amp;lt;0.0001287(25)21(75)&amp;lt;0.0001Total460360(78)100(22)267187(70)80(30)25-36 months after ET initiationScattered248220(89)28(11)8374(89)9 (11)Heterogeneous203133(66)70(35)16097(61)63(39)Dense162(13)14(88)&amp;lt;0.00013213(41)19 (59)&amp;lt;0.0001Total467355(76)112(24)275184(67)91(33) Citation Format: Mei Wei, Lisa Pappas, Emily Guinto, Carol Sweeney, Nicola Camp, Phoebe Freer, Saundra Buys, N. Lynn Henry, Karen Curtin. Mammographic breast density changes with endocrine therapy (ET) in women with hormone receptor positive (HR+) breast cancer in a Utah population [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-10.

Mammographic Density Change and Risk of Breast Cancer.

We examined the association between annual mammographic density change (MDC) and breast cancer (BC) risk, and how annual MDC influences the association between baseline mammographic density (MD) and BC risk. We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort of Swedish women (N = 43 810) aged 30-79 years with full access to BC risk factors and mammograms. MD was measured as dense area (cm2) and percent MD using the STRATUS method. We used the contralateral mammogram for women with BC and randomly selected a mammogram from either left or right breast for healthy women. We calculated relative area MDC between repeated examinations. Relative area MDC was categorized as decreased (>10% decrease per year), stable (no change), or increased (>10% increase per year). We used Cox proportional hazards regression to estimate the association of BC with MDC and interaction analysis to investigate how MDC modified the association between baseline MD and BC risk. All tests of statistical significance were two-sided. In all, 563 women were diagnosed with BC. Compared with women with a decreased MD over time, no statistically significant difference in BC risk was seen for women with either stable MD or increasing MD (hazard ratio = 1.01, 95% confidence interval = 0.82 to 1.23, P = .90; and hazard ratio = 0.98, 95% confidence interval = 0.80 to 1.22, P = .90, respectively). Categorizing baseline MD and subsequently adding MDC did not seem to influence the association between baseline MD and BC risk. Our results suggest that annual MDC does not influence BC risk. Furthermore, MDC does not seem to influence the association between baseline MD and BC risk.

Randomized Double-Blind Placebo-Controlled Biomarker Modulation Study of Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer (SWOG S0812).

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of -9.8 versus -1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.

Phase II randomized study of neoadjuvant metformin plus letrozole versus placebo plus letrozole for ER-positive postmenopausal breast cancer [METEOR Study

576 Background: Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in postmenopausal breast cancer. Pre-/Clinical data have shown that metformin, a widely used anti-diabetic drug also one of mTOR inhibitor have shown anti-tumor activity. We report the result of prospective, multicenter, phase II randomized, placebo controlled trial aiming to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with hormone-receptor (HR) positive breast cancer. Methods: 203 postmenopausal women diagnosed with hormone receptor positive, T1-3/N0-2 invasive breast cancer were randomized to 24 weeks of neoadjuvant letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Women with history of diabetes were excluded. Primary endpoint was clinical response rate (complete, partial response by caliper). Secondary endpoint was pathologic complete response rate, breast conservation rate, percent mammographic density change. PEPI score and toxicity profile were compared between two groups. Results: 153 intention-to treat population were analyzed (72 metformin, 75 placebo group). Overall clinical response rate was 61.4% (94/153) by caliper and did not reach statistical significance between metformin versus placebo groups (66.7% versus 56.4%, p = 0.193). Breast conservation rate was 68.0% (100/147) (66.7% versus 69.3%). Overall, 87.3% (103/118) displayed Ki67 &lt; 10% at surgical specimen and 16.7% (21/126) had zero PEPI score. Neither Ki67% nor PEPI score was different between two groups. However, among the 20 patients with core-needle biopsy after 4 weeks of medication, greater number of patients displayed Ki67 &lt; 10% in metformin group than in placebo group (87.5% versus 33.3%, p = 0.017). Patients with 4week Ki67 &lt; 10% had higher clinical response rate (100% versus 57.1%, p = 0.038). Grade 3 side effects were reported in three patients (vomiting, high blood pressure, weight loss) and no hypoglycemia event was observed. Conclusions: 61.7% overall clinical response was achieved with 24-weeks of neoadjuvant letrozole, with numerically &gt; 10% higher response rate in letrozole+metformin group (66.7% versus 56.4%). 4-weeks Ki67 &lt; 10% level was predictive of clinical response. With &lt; 2% grade 3 side effects, preoperative letrozole (with/without metformin) followed by 4-week Ki67 evaluation may indeed serve as primary choice to postmenopausal hormone receptor positive breast cancers. Clinical trial information: NCT01589367.

Changes in mammographic density over time and the risk of breast cancer: An observational cohort study

BackgroundThe effect of changes in mammographic density over time on the risk of breast cancer remains inconclusive. MethodsWe used information from four centres of the Breast Cancer Screening Program in Spain in the period 1996–2015. We analysed individual level data from 117,388 women first screened age 50–54, with at least two screening examinations. Breast density was determined using the BI-RADS classification (A to D in increasing order) at earliest and latest screening examination. Adjusted Poisson regression models were used to estimate the relative risk (RR) and 95% confidence intervals (95%CI) of the association between changes in mammographic density and breast cancer risk over time. ResultsDuring an average 5.8 years of follow-up, 1592 (1.36%) women had a breast cancer diagnosis. An increase in density category increased breast cancer risk, and a decrease in density decreased the risk, compared with women who remained in the same BI-RADS category. Women whose density category increased from B to C or B to D had a RR of 1.55 (95%CI = 1.24–1.94) and 2.32 (95%CI = 1.48–3.63), respectively. The RR for women whose density increased from C to D was 1.51 (95%CI = 1.03–2.22). Changes in BI-RADS density were similarly associated with the risk for invasive cancer than for ductal carcinoma in situ. ConclusionsAlthough a modest proportion of women changed BI-RADS density category, mammographic density changes modulated the risk of breast cancer and identified women at a differential risk. Using two longitudinal measures of BI-RADS density could help target women for risk-based screening strategies.

11P - Mammographic density change and risk of breast cancer

Background We examined the association between annual mammographic density change (MDC) and breast cancer (BC) risk, and how annual MDC influences the association between baseline mammographic density (MD) and BC risk. Methods We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort of Swedish women (N = 43 810) aged 30-79 years with full access to BC risk factors and mammograms. MD was measured as dense area (cm2) and percent MD using the STRATUS method. We used the contralateral mammogram for women with BC and randomly selected a mammogram from either left or right breast for healthy women. We calculated relative area MDC between repeated examinations. Relative area MDC was categorized as decreased (>10% decrease per year), stable (no change), or increased (>10% increase per year). We used Cox proportional hazards regression to estimate the association of BC with MDC and interaction analysis to investigate how MDC modified the association between baseline MD and BC risk. All tests of statistical significance were two-sided. Results In all, 563 women were diagnosed with BC. Compared with women with a decreased MD over time, no statistically significant difference in BC risk was seen for women with either stable MD or increasing MD (hazard ratio = 1.01, 95% confidence interval = 0.82 to 1.23, P = .90; and hazard ratio = 0.98, 95% confidence interval = 0.80 to 1.22, P = .90, respectively). Categorizing baseline MD and subsequently adding MDC did not seem to influence the association between baseline MD and BC risk. Conclusions Our results suggest that annual MDC does not influence BC risk. Furthermore, MDC does not seem to influence the association between baseline MD and BC risk.