High Mammographic Breast Density Research Articles

Three-dimensional automated breast ultrasound – a supplemental screening tool

Background. Three-dimensional automated breast ultrasound (ABUS) is an innovative technology that allows global visualization of the breast and eliminates the operator-dependence of hand held ultrasound. Three-projection scanning during ABUS is provided by an ultra-long (15.4 cm) probe with a frequency of 14–16 MHz, and then the slices are reconstructed on a workstation. At the same time, high-frequency converters create high-resolution images. Through a special coronal projection, ABUS identifies variants of minimal, non-palpable breast cancer, including those with women with high mammographic breast density, which makes it a promising additional (supplemental screening) method of oncomammoscreening.Aim. To assess the use of ABUS as a supplemental screening tool in women with high mammographic breast density.Materials and methods. The study was conducted in 2018 at the N.N. Petrov National Medical Research Oncology Center, Ministry of Health of Russia. As part of the study, 192 women underwent mammography, ABUS, and multiparametric ultrasound (B-mode, color Doppler, elatography) in standard manual mode.Results. In the course of the study, in 192 patients, mammography revealed 42 cases of breast cancer, while using the AUS and manual ultrasound, additionally were identified 9 cases of breast cancer. Also, the ABUS showed high accuracy in assessment of the distribution of breast cancer – multifocal, multicentric and bilateral.Conclusion. ABUS is a promising and highly effective diagnostic method in women with high mammographic breast density, with its advantages and disadvantages, which can be used in combination with mammography as a supplemental screening tool, especially in women at high risk of developing breast cancer.

An analysis of the association between breast density and body mass index with breast cancer molecular subtypes in early breast cancer: data from a Spanish population.

Breast cancer is an important health problem, like obesity and dyslipidemia, with a strong association between body mass index (BMI) and breast cancer incidence and mortality. The risk of breast cancer is also high in women with high mammographic breast density (MBD). The purpose of this study was to analyze the association between BMI and MBD according to breast cancer molecular subtypes. This transversal, descriptive, multicenter study was conducted at three Spanish breast cancer units from November 2019 to October 2020 in women with a recent diagnosis of early breast cancer. Data were collected at the time of diagnosis. The study included 162 women with a recent diagnosis of early breast cancer. The median age was 52years and 49.1% were postmenopausal; 52% had normal weight, 32% overweight, and 16% obesity. There was no association between BMI and molecular subtype but, according to menopausal status, BMI was significantly higher in postmenopausal patients with luminal A (p = 0.011) and HER2-positive (p = 0.027) subtypes. There was no association between MBD and molecular subtype, but there were significant differences between BMI and MBD (p < 0.001), with lower BMI in patients with higher MBD. Patients with higher BMI had lower HDL-cholesterol (p < 0.001) and higher insulin (p < 0.001) levels, but there were no significant differences in total cholesterol or vitamin D. This study showed higher BMI in luminal A and HER2-positive postmenopausal patients, and higher BMI in patients with low MBD regardless of menopausal status.

Abstract PO2-23-10: Obesity May Modulate the Relationship Between High Mammographic Breast Density and Neoadjuvant Chemoresistance in Early Breast Cancer

Abstract Background - An inverse association has been described in a number of studies between mammographic breast density (MBD) and pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early breast cancer (BC), implicating high MBD in chemotherapy resistance. However, this effect has not been seen in all there is a paucity of data exploring whether this relationship extends the relationship beyond pCR to overall survival. This study aims to validate the relationship between MBD and pCR in patients undergoing NAC for early BC as well as to assess the relation of MBD with clinical complete response (cCR), relapse-free (RFS) and BC-specific survival (BCSS). Further, this study examines these associations stratified by body mass index (BMI). Methods - MBD was measured in contralateral mammograms in 127 women before NAC, using Cumulus software. As the study spanned the transition period from film to digital mammography, film mammograms were digitised using a high-powered scanner and processed full-field digital mammograms were extracted from the imaging storage facility. Basic patient, tumour and treatment demographics were collated including BMI. Percent dense area (PDA) was correlated with patient and tumour characteristics, short-term (pCR/cCR incidences), and long-term chemotherapy outcomes (RFS and BCSS). Results - Overall rates of cCR and pCR of 49% and 21% were observed across the whole cohort. Mean PDA was higher in those not undergoing cCR (p=0.041) and relapsing patients (p=0.041) but did not significantly vary by pCR or BC-deaths. As a dichotomous variable, high PDA relative to low PDA corresponded to lower cCR (40 v 58%, p=0.027), but no significant difference was seen for pCR (17.5 v 25.0%, p=0.15), BC relapse (38 v 30%, p=0.15) or BC-death (32 v 25%, p=0.20). High PDA (relative to low PDA) in patients with obesity (BMI &amp;gt;30kg/m2) was associated with lower pCR (0% v 28.1%, p=0.036) and numerically higher relapse rates (56% v 28%, p=0.063) and breast cancer deaths (56 v 28%, p=0.071. No such relationship was observed in patients with a BMI&amp;lt; 30kg/m2. Conclusion - Higher MBD associated with lower cCR and higher relapse but not with pCR or BC death. The inferior outcomes with high MBD were confined to patients with obesity in our study. Further analysis of the relationship between MBD and outcomes, including by BMI, is warranted. Citation Format: Andrew Redfern, Veenoo Agarwal, Ellie Darcey, Lisa Spalding, Hilary Martin, Jennifer Stone. Obesity May Modulate the Relationship Between High Mammographic Breast Density and Neoadjuvant Chemoresistance in Early Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-10.

Mammographic features at primary breast cancer diagnosis in relation to recurrence-free survival

PurposeThe number of women living with breast cancer (BC) is increasing, and the efficacy of surveillance programs after BC treatment is essential. Identification of links between mammographic features and recurrence could help design follow up strategies, which may lead to earlier detection of recurrence. The aim of this study was to analyze associations between mammographic features at diagnosis and their potential association with recurrence-free survival (RFS). MethodsWomen with invasive BC in the prospective Malmö Diet and Cancer Study (n = 1116, 1991–2014) were assessed for locoregional and distant recurrences, with a median follow-up of 10.15 years. Of these, 34 women were excluded due to metastatic disease at diagnosis or missing recurrence data. Mammographic features (breast density [BI-RADS and clinical routine], tumor appearance, mode of detection) and tumor characteristics (tumor size, axillary lymph node involvement, histological grade) at diagnosis were registered. Associations were analyzed using Cox regression, yielding hazard ratios (HR) with 95 % confidence intervals (CI). ResultsOf the 1082 women, 265 (24.4 %) had recurrent disease. There was an association between high mammographic breast density at diagnosis and impaired RFS (adjusted HR 1.32 (0.98–1.79). In analyses limited to screen-detected BC, this association was stronger (adjusted HR 2.12 (1.35–3.32). There was no association between mammographic tumor appearance and recurrence. ConclusionRFS was impaired in women with high breast density compared to those with low density, especially among women with screen-detected BC. This study may lead to insights on mammographic features preceding BC recurrence, which could be used to tailor follow up strategies.

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease

IntroductionBenign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD.MethodsWe undertook a nested case–control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970–2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression.ResultsOverall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ − 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99).DiscussionAssessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.

Cigarette smoking and mammographic breast density in post-menopausal women from the EPIC Florence cohort.

Cigarette smoking has been recognized as a risk factor for breast cancer (BC) also if the biological mechanism remains poorly understood. High mammographic breast density (MBD) is associated with BC risk and many BC risk factors, such as genetic, anthropometric, reproductive and lifestyle factors and age, are also able to modulate MBD. The aim of the present study was to prospectively explore, in post-menopausal women, the association between smoking habits and MBD, assessed using an automated software, considering duration and intensity of smoking. The analysis was carried out in 3,774 women enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) Florence cohort in 1993-98, participating in the 2004-06 follow up (FU) and with at least one full-field digital mammography (FFDM) performed after FU. For each woman, detailed information on smoking habits, anthropometry, lifestyle and reproductive history was collected at enrollment and at FU. Smoking information at baseline and at FU was integrated. The fully automated Volpara™ software was used to obtain total breast volume (cm3), absolute breast dense volume (DV, cm3) and volumetric percent density (VPD, %) from the first available FFDM (average 5.3 years from FU). Multivariable linear regression models were applied to evaluate the associations between smoking habits and VPD or DV. An inverse association between smoking exposure and VPD emerged (Diff% -7.96%, p <0.0001 for current smokers and -3.92%, p 0.01 for former smokers, compared with non-smokers). An inverse dose-response relationship with number of cigarettes/day, years of smoking duration and lifetime smoking exposure (pack-years) and a direct association with time since smoking cessation among former smokers emerged. Similar associations, with an attenuated effect, emerged when DV was considered as the outcome variable. This longitudinal study confirms the inverse association between active smoking, a known risk factor for BC, and MBD among post-menopausal women. The inclusion of smoking habits in the existing BC risk prediction models could be evaluated in future studies.

Digital breast tomosynthesis versus X-ray of the breast specimen for intraoperative margin assessment: A randomized trial

BackgroundInvolved resection margins after breast conserving surgery (BCS) often require a re-operation with increased patient anxiety and risk of impaired cosmesis.We investigated the number of re-operations due to involved resection margins after BCS comparing digital breast tomosynthesis(DBT) with X-ray for intraoperative margin evaluation.Furthermore, we assessed the diagnostic accuracy of these methods to predict histopathological margin status. Finally, we evaluated risk factors for re-operation. MethodsIn this randomized, non-blinded study, 250 invasive breast cancer patients were randomized (1:1), whereof 241 were analyzed intraoperatively with either DBT (intervention, n = 119) or X-ray (standard, n = 122). Pearson's chi-squared test, Fisher's exact test, t-test, logistic and ordinal regression analysis was used as appropriate. ResultsNo difference was found in the number of re-operations between the DBT and X-ray group (16.8 % vs 19.7 %, p = 0.57), or in diagnostic accuracy to predict histopathological margin status (77.5 %, CI: 68.6–84.9 %) and (67.3 %, CI: 57.7–75.9 %), respectively. We evaluated 5 potential risk factors for re-operation: Ductal carcinoma in situ (DCIS) outside tumor, OR = 9.4 (CI: 4.3–20.6, p < 0.001); high mammographic breast density, OR = 6.1 (CI: 1.0–38.1, p = 0.047); non-evaluable margins on imaging, OR = 3.8 (CI: 1.3–10.8, p = 0.016); neoadjuvant chemotherapy, OR = 3.0 (CI: 1.0–8.8, p = 0.048); and T2 tumor-size, OR = 2.6 (CI: 1.0–6.4, p = 0.045). ConclusionsNo difference was found in the number of re-operations or in diagnostic accuracy to predict histopathological margin status between DBT and X-ray groups. DCIS outside the tumor showed the highest risk of re-operation. Intraoperative methods with improved visualization of DCIS are needed to obtain tumor free margins in BCS.

The Correlation Between Progesterone and Mammographic Density in Postmenopausal Women: A Systematic Review of the Literature and Meta-Analysis.

Higher mammographic breast density in premenopausal and postmenopausal women is related to a higher breast cancer risk. In this review, we analyze the correlation between estrogen, progesterone, and mammographic density in postmenopausal women and clarify whether these findings are consistent across different types of mammographic breast density. We extracted data concerning mammographic density increases in the populations treated with estrogen-only hormone replacement therapy and those treated with estrogen and progestin hormone replacement therapy. Postmenopausal women treated with estrogen and progesterone regimens had a statistically significant lesser mammographic density increase than estrogen-only hormone replacement therapy regimens.

Abstract 4173: Lipidome of mammographic breast density in premenopausal women

Abstract Introduction: High mammographic breast density (MBD) is a strong risk factor for breast cancer, but the biological mechanisms underlying high MBD are not well understood. We, therefore, comprehensively investigated for the first time the associations of lipid species with volumetric measures of MBD to elucidate potential biological mechanisms of high MBD in premenopausal women. Methods: We performed lipidomic profiling on 705 premenopausal women recruited during their annual screening mammogram at Washington University School of Medicine, St. Louis, MO. Lipidomic profiling for 982 lipid species was completed at Metabolon (Durham, NC®). Lipid species with greater than 300 missing values (N=125) were excluded from the analysis. Using nearest neighbor methods, we imputed the lipid species missing less than 300 values. We used Volpara 1.5 (Volpara Health®) to quantify volumetric measures of MBD - volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV). We investigated the associations of the lipid species with MBD measures using multivariable linear regression models adjusting for age, age at menarche, body shape at age 10, race/ethnicity, body fat %, family history of breast cancer, oral contraceptive use, parity/age at first birth, and alcohol use. MBD measures were log10-transformed, and lipid species were standardized. Linear coefficients were back-transformed to the original scale and considered significant if the Bonferroni corrected p&amp;lt;0.05. Results: In multivariable linear regression models, 34 lipid species were inversely associated with VPD. The lipid species belong to the triacylglycerol (TAG, N=26), diacylglycerol (DAG, N=6), phosphatidylcholine (PC, N=1), and cholesterol ester (N=1) pathways. DAG(16:0/18:2) and TAG54:6-FA20:4 displayed the largest inverse associations with one standard deviation increase in DAG(16:0/18:2), and TAG54:6-FA20:4 corresponding to 9.9% (p=0.002), and 9.6% (p=0.007) decrease in VPD, respectively. Eleven lipid species were significantly associated with NDV, with 10 species (all TAG) having a positive association and 1 inverse association PC(18:1/18:1). The strongest positive association was observed with TAG54:6-FA20:4. One standard deviation increase in TAG54:6-FA20:4 was associated with a 9.8% increase in NDV (p=0.01). Several of the lipid species (N=8, 23.5%) that were associated with VPD were also associated with NDV, but in opposite directions. No lipid species were significantly associated with DV. Conclusions: Our study identified many lipid species, especially in TAG and DAG pathways, that were associated with VPD and NDV and offer new insights into the biological mechanisms underlying high MBD in premenopausal women. Future studies are needed to validate our results and the translational potential. Citation Format: Kayla R. Getz, Myung S. Jeon, Chongliang Luo, Jingqin Luo, Adetunji T. Toriola. Lipidome of mammographic breast density in premenopausal women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4173.

Abstract 1899: Breast density comparison of Hispanic versus Non-Hispanic patients undergoing screening mammograms: Influence of age, parity and breast-feeding

Abstract Background: Higher mammographic breast density is associated with a 4 to 6-fold increased risk of breast cancer. Some single institution retrospective studies show higher breast densities in Hispanic patients (Oppong et al. Breast J. 2018). The prevalence of breast density based on Hispanic ethnicity has not been studied in large database studies. Methods: We performed a retrospective review of women &amp;gt; 40 years undergoing screening mammograms from 2016-2022. Patients with prior history of breast cancer were excluded. We reviewed demographic variables such as race, self-reported ethnicity, body mass index (BMI), parity, breastfeeding and menopausal status. Breast density was characterized as predominantly fatty (PF), scattered fibroglandular (SF), heterogeneously dense (HD) and extremely dense (ED). We used Chi-square and Kruskal-Wallace tests to compare breast density across measured variables, and Ordinal Logistic Regression to compare breast density levels between self-declared ethnicity while adjusting for other variables. Results: 15946 patients were studied; 7317 (46%) identified as Hispanic, the rest non-Hispanic (NH). 6131 (83%) of Hispanics identified as white. Mean age on 1st screening mammogram was 57.64 (SD 7.21). Compared to NH, Hispanics had mean earlier age of 1st mammogram (56.8 vs. 58.3 years), higher BMI (30.5 vs. 28.6) and higher parity (2.53 vs. 1.71). There were significant differences in BI-RADS density categories by Hispanic vs. NH (p&amp;lt;0.001), with differences in PF (20.2% vs. 18.5%), SF (41.7% vs. 39.0%), HD (35.8% vs. 37.2%), and ED (2.3% vs. 5.3%). The ordinal logistic regression model suggests that Hispanics have 17% lower odds than NH of 1 category higher density (OR, 95% CI: 0.83, 0.78-0.88). There were also significant ethnicity differences in age at first exam, BMI, parity, and number of children breast-fed (P&amp;lt;0.001). Adjusting for these ethnicity-associated differences explained the observed differences in density between Hispanic and NH individuals (ORadj, 95% CI: 0.98, 0.92-1.04); adjusting only for BMI served to explain the observed differences in density (ORadj, 95% CI: 0.99, 0.94-1.05). Conclusions: Hispanics were observed to have a lower age of first screening mammogram, higher BMI, higher parity, and breast-fed children compared to non-Hispanics. On univariate analysis, Hispanics were noted to have lower breast density compared to non-Hispanics, these differences do not persist on multivariate analysis. This suggests that BMI likely plays a predominant role in driving the ethnicity-related differences in breast density noted here. Further research efforts should focus on the influence of BMI and other individual-level factors on mammographic density, with a view towards understanding their potential roles in describing differential ethnicity-specific breast cancer risk. Citation Format: Sangeetha Prabhakaran, Vernon S. Pankratz, Jennifer L. Saline, Emily J. Reese. Breast density comparison of Hispanic versus Non-Hispanic patients undergoing screening mammograms: Influence of age, parity and breast-feeding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1899.

Age at first full-term pregnancy and mammographic breast density in postmenopausal women: a systematic review

While mammographic breast density (MBD) is a well-established independent risk factor for breast cancer and age at first full-term pregnancy (FFTP) has been identified as a protective factor, there are very few high-quality studies that address the relationship between these two variables. The goal of this work was to generate a systematic review of published studies that addresses the association between age at FFTP and MBD based on objective mammographic findings in postmenopausal women. The English-language literature published with a cutoff date 31 August 2022 in the PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library databases was searched using relevant keywords. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of all relevant studies identified in this search. Our search yielded 12 original publications (including one conference abstract) that focused on the impact of age at FFTP on MBD in studies that objectively evaluated this condition in women without any form of breast pathology. Of these, six studies revealed a direct association between older age at FFTP and higher MBD in postmenopausal women. The remaining six studies reported either no relationship between these parameters or revealed an inverse association between MBD and older age at FFTP. We concluded that half of the currently-published findings supported an association between older age at FFTP and higher MBD. However, substantial heterogeneity between FFTP and MBD might be explained by different racial clusters, lacking specific information of other reproductive factors and differences in methodology utilized. The goal of this work was to examine whether age at FFTP is associated with MBD in postmenopausal women.

Elevated miR-29c-5p Expression in Nipple Aspirate Fluid Is Associated with Extremely High Mammographic Breast Density.

Simple SummaryHigh mammographic density is a known risk factor for breast cancer. However, the underlying mechanisms of high mammographic density development and breast cancer are unknown. MicroRNAs are potential biomarkers indicative of carcinogenesis and can be assessed in nipple aspirate fluid. We used nipple aspirate fluid from women with very low and extremely high mammographic density to examine differences in expression of multiple miRNAs between both extremes in the spectrum of mammographic density. We found that hsa-miR-29c-5p was upregulated in an extremely high mammographic density context and potential targets were identified that might provide clues of the relationship between high mammographic density and breast cancer risk. Understanding the relationship between high mammographic density and breast cancer is of great value for early breast cancer diagnosis and treatment. With our research we provide new insight into this relationship and further research could determine the effects of dysregulated hsa-miR-29c-5p on the identified candidate targets.High mammographic density (MD) is associated with an increased risk of breast cancer, however the underlying mechanisms are largely unknown. This research aimed to identify microRNAs (miRNAs) that play a role in the development of extremely dense breast tissue. In the discovery phase, 754 human mature miRNAs were profiled in 21 extremely high MD- and 20 very low MD-derived nipple aspirate fluid (NAF) samples from healthy women. In the validation phase, candidate miRNAs were assessed in a cohort of 89 extremely high MD and 81 very low MD NAF samples from healthy women. Independent predictors of either extremely high MD or miRNA expression were identified by logistic regression and linear regression analysis, respectively. mRNA targets and pathways were identified through miRTarBase, TargetScan, and PANTHER pathway analysis. Statistical analysis identified four differentially expressed miRNAs during the discovery phase. During the validation, linear regression (p = 0.029; fold change = 2.10) and logistic regression (p = 0.048; odds ratio = 1.38) showed that hsa-miR-29c-5p was upregulated in extremely high MD-derived NAF. Identified candidate mRNA targets of hsa-miR-29c-5p are CFLAR, DNMT3A, and PTEN. Further validation and exploration of targets and downstream pathways of has-miR-29c-5p will provide better insight into the processes involved in the development of high MD and in the associated increased risk of breast cancer.

Mammographic breast density and survival in women with invasive breast cancer.

We explored the under-debate association between mammographic breast density (MBD) and survival. From the Piedmont Cancer Registry, we identified 693 invasive breast cancer (BC) cases. We analyzed the overall survival in strata of MBD through the Kaplan-Meier method. Using the Cox proportional hazards model, we estimated the hazard ratios (HRs) of death; using the cause-specific hazards regression model, we estimated the HRs of BC-related and other causes of death. Models included term for Breast Imaging-Reporting and Data System (BI-RADS) MBD (categorized as BI-RADS 1 and BI-RADS 2-4) and were adjusted for selected patient and tumour characteristics. There were 102 deaths, of which 49 were from BC. After 5years, the overall survival was 69%in BI-RADS 1 and 88% in BI-RADS 2-4(p < 0.01). Compared to BI-RADS 2-4, the HRs of death for BI-RADS 1 were 1.65 (95% CI 1.06-2.58) in the crude model and 1.35 (95% CI 0.84-2.16) in the fully adjusted model. Compared to BI-RADS 2-4, the fully adjusted HRs for BI-RADS 1 were 1.52 (95% CI 0.74-3.13) for BC-related death and 1.83 (95% CI 0.84-4.00) for the other causes of death. Higher MBD is one of the strongest independent risk factors for BC, but it seems not to have an unfavorable impact on survival.

Breast density reduction as a predictor for prognosis in premenopausal women with hormone receptor–positive breast cancer: A retrospective analysis of the ASTRRA study.

531 Background: While the relationship between mammographic breast density (MD) decline and anti-hormone therapy efficacy has been reported in estrogen-receptor (ER)-positive breast cancer, it is still unclear in premenopausal women and in the case of adding ovarian function suppression (OFS) to anti-hormone therapy. We aimed to investigate the MD reduction (MDR) rate and impact of MDR on prognosis stratified by treatment from the updated result of the ASTRRA trial. Methods: ASTRRA trial, a randomized phase 3 study, showed that adding ovarian function suppression (OFS) to tamoxifen (TAM) improved survival in premenopausal women with ER+ breast cancer after chemotherapy. We updated survival outcomes with a median follow-up of 108 months. We assessed mammography taken before treatment and the follow-up mammography taken annually for up to five years after initiation of treatment. MD was classified into four categories based on the Breast Imaging Reporting and Data System. MDR positivity was defined as a downgrade in MD among follow-up mammography up to two years after randomization, with the pretreatment MD grade as a reference. Results: Among the 1,293 patients from ASTRRA trial, we successfully evaluated MDR in 947 patients, of which 796 (83.4%) belong to high MD (grade C or D). The patient characteristics were similar between the entire ASTRRA trial and the subgroup with available MDR. There was no difference in MDR-positive rate between two treatment groups (106 of 477 [22.2%] in TAM-only group vs. 87 of 470 [18.5%] in TAM + OFS group, P =.156). MDR-positivity was significantly associated with better disease-free survival (DFS) in TAM + OFS group (estimated 8-year DFS: 92.9% in MDR-positive vs. 82.2% in MDR-negative, P =.013), but did not in TAM-only group (estimated 8-year DFS: 80.3% in MDR-positive vs. 80.2% in MDR-negative, P =.927; Pinteraction =.025). Simialr trends were observed in terms of recurrence-free survival, distant metastasis-free survival (DMFS), locoregional-free survival, and overall survival. In addition, MDR-positivity was an independent factor for favorable DFS (adjusted hazard ratio [HR], 0.37; 95% CI, 0.16 to 0.86; P =.021) and DMFS (adjusted HR, 0.35; 95% CI, 0.13 to 0.98; P =.045) in TAM + OFS group. Conclusions: Although the proportion of patients with MDR-positive was comparable between the two treatment groups, MDR-positive was independently associated with favorable outcomes only in TAM + OFS group. Future work is warranted to verify the mechanism by which the association between MDR and clinical benefit differs according to the treatment group. Clinical trial information: NCT00912548.

Relationship of vitamin D deficiency with mammographic breast density and triple-negative breast cancer: A cross-sectional study.

Background As breast epithelium is affected by vitamin D, it may have a direct effect on breast density and the risk of breast cancer. Our aim was to study the serum levels of vitamin D in patients with malignant and benign breast disease, and to study the association, if any, between vitamin D levels, mammographic breast density (MD) and molecular subtypes of breast cancer. Methods In this cross-sectional, observational study, we enrolled 162 consecutive adult women with benign and malignant breast masses subjected to mammography and core-needle biopsy. Serum levels of vitamin D were estimated and correlated with MD and with immunohistochemical subtyping of breast cancer. Results The mean vitamin D level in these 162 patients was 12.44 (5.88) ng/ml, with vitamin D deficiency seen in 98%. The mean (SD) vitamin D level in MD type 1 was 16.19 (4.62) ng/ml and it decreased to 7.54 (2.58) ng/ml in MD type 4. High MD was associated with significantly lower vitamin D levels. The mean vitamin D level in patients with benign breast disease (n=102) was 13.73 (5.68) ng/ml, while it was significantly lower in patients with breast cancer (n=60) at 10.26 (5.61) ng/ml. Among patients with breast cancer, the good prognosis luminal A molecular subtype had mean vitamin D level of 12.94 (6.16) ng/ml, whereas the poor prognosis triple-negative subtype had a significantly lower value of 7.68 (3.42) ng/ml. Conclusion Our study shows that vitamin D deficiency has a significant relationship with breast cancer (v. benign breast disease), high MD (showing increased breast cancer risk) and poor prognosis triple-negative breast cancer. Vitamin D deficiency could be an important, potentially modifiable, risk factor for the prevention of breast cancer in susceptible populations.

Abstract P4-07-24: High Mammographic Breast density was correlated with overall survival of operable breast cancer which expressed CD44+CD24-/ALDH-1+

Abstract Background: Mammographic Breast Density (MBD) was known as a risk of breast cancer in either pre or postmenopausal women. The underlined mechanism remain unclear. Aldehyde dehydrogenase 1 (ALDH-1) and CD44+CD24− are the most consistently used biomarkers to identify and characterize breast cancer stem cells (CSCs). However, correlation between expression of CSCs and MBD remains unclear. We aimed to clarify the association between CD44, CD24 or ALDH-1 and the clinical factors including MBD for investigating their effects on overall survival (OS). Method: 159 operable breast cancers were finally included for double immune-histochemical staining of CD44, CD24 and single expression of ALDH-1. MBD was categorized according to the American College of Radiology Breast Imaging Reporting and Data System. Positive expression of CSC was defined when both Aldehyde dehydrogenase 1 (ALDH-1) and CD44+CD24− were expressed. Clinical values were age, co-morbidity (hypertension, hyperlipidemia, Diabetes Mellitus), body mass index, menopausal status. We also examined overall survival (OS) with the log-rank test. Result: Positive expression of BCSC was 33.3% (53/159 patients). It correlated with premenopausal status, high histologic grade, high Ki-67 expression, and low expression of ER or PR (Table 1). During mean 74 months, High BMD was correlated with worse OS in either pre- or postmenopausal patients (p=0.04) and worse OS in patients with co-morbidity (p=0.08). Expression of CSC was not associated with overall survival. In a group with CSC expression, patients of higher MBD(≥ 51%) was worse OS (p=0.046) compared with a group with non-CSC expression. Co-morbidity was significantly correlated with poor DFS in non-expressed group compared with CSC expressed group (p=0.01). In Cox-regression analysis, co-morbidity (HR=0.05, 95% CI: 0.006-0.44, p=0.007) and MBD ( HR= 0.14, 95% CI: 0.02-1.16, p=0.06) increased risk of OS. Conclusion: High MBD could be a prognostic factor in operable breast cancer. Each risk factor of survival was important, but host factors including comorbidity and MBD might be considered. Table 1.The correlation between BCSC and clinical variables in patient with operable breast cancerCSC(-)CSC(+)Number(%)Number(%)BMINormal68(65.4)36(34.6)0.63Obesity38(69.1)17(30.9)ComorbidityNo57(62.6)34(37.4)0.21Yes49(72.1)19(27.9)MBD≤ 50 %28(77.8)8(22.2)0.13≥ 51 %60(63.8)34(36.2)Age( year)&amp;lt;5040(63.5)23(36.5)0.49≥5066(68.8)30(31.3)MenopausePremenopause46(59.0)32(41.0)0.04Postmenopause60(74.1)21(25.9)HGGrade=116(80.0)4(20.0)0.02Grade=247(75.8)15(24.2)Grade=343(56.6)33(43.4)LVINo73(68.6)33(31.4)0.69Yes33(64.7)18(35.3)ERNegative42(52.5)38(47.5)&amp;lt;0.001Positive64(81.0)15(19.0)PRNegative65(61.3)41(38.7)0.043Positive41(77.4)12(22.6)Her-2/neunot expressed76(63.3)44(36.7)0.14overexpressed29(76.3)9(23.7)Ki-67negative68(80.0)17(20.0)&amp;lt;0.001positive38(51.4)26(48.6) Citation Format: JungSun Lee, Woo-Gyeong Kim. High Mammographic Breast density was correlated with overall survival of operable breast cancer which expressed CD44+CD24-/ALDH-1+ [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-24.

Abstract P2-10-02: Random periareolar fine-needle aspiration (RPFNA) cell number, prior precancerous breast disease and subsequent uptake of a prevention intervention predict short-term breast cancer risk

Abstract Introduction: In 2000 we published initial observations from a high-risk cohort of 480 women that cytologic evidence of hyperplasia with atypia in benign breast tissue obtained by random periareolar fine-needle aspiration (RPFNA) was associated with a five-fold increased risk of developing DCIS or invasive breast cancer at a median follow-up of 45 months [Fabian, JNCI 2000]. Few women in the initial cohort had any exposure to prevention agents, as NSABP-P1 was not reported until 1998. We began a new high-risk cohort in 2002 as the tissue processing changed from a filter technique to Thin PrepTM. The superior nuclear detail permitted assessment of cytologic atypia in the absence of high cellularity. Women in the second cohort were told that RPFNA atypia was a risk factor for developing breast cancer and in addition to standard prevention options were offered participation in clinical trials, if applicable. The purpose of this subsequent analysis was to determine if the predictive value of RPFNA atypia was maintained with change in tissue processing and availability of prevention options. Methods: A total of 1,135 high-risk women, eligible on the basis of family history, BRCA1/2 mutation status, prior biopsy indicating LCIS or atypical hyperplasia (AH), prior contralateral breast cancer and/or high mammographic breast density, underwent baseline RPFNA and were enrolled in our second cohort between 2002 and 2015. As in the earlier study published in 2000, if women had 2 aspirations without an intervening intervention within 21 months the worse result was utilized as baseline. In addition to cytomorphology, breast tissue was also categorized by cellularity of the aspirate (10-100, 100-1000, 1000-5000, and &amp;gt;5000 cells per cytology slide). The primary aspirator (CJF) and cytopathologist (CMZ) were the same for both cohorts. Women were censored at the time of prophylactic mastectomy, development of other site cancer, or death. Kaplan-Meier hazard plots and Cox-regression analysis were used to analyze time to development of DCIS or invasive breast cancer and effect of joint variables, respectively. Results: At a median follow-up of 86 months, 79 cases of DCIS or invasive breast cancer had been diagnosed. By univariate analysis, RPFNA atypia at entry was not predictive of subsequent breast cancer (p=0.58; log-rank test). However, breast cancer risk was increased by a prior breast biopsy with LCIS or AH (HR 2.6, 95% CI 1.6-2.4, p&amp;lt;0.001) or by high RPFNA cellularity, defined as &amp;gt;5000 epithelial cells per RPFNA cytomorphology slide (HR 2.1, 95% CI 1.3-3.5, p=0.0034). Thirty-six percent of women subsequently chose to undergo a prevention intervention, including a standard drug, enrollment in a prevention clinical trial of 6-12 months duration, or a prophylactic bilateral salpingo-oophorectomy (BSO) prior to age 45. Prevention interventions were more prevalent in women with RPFNA atypia (49% vs 30%, p&amp;lt;0.001). Not only was uptake of a prevention intervention associated with reduced breast cancer risk on univariate analysis (p=0.043), it was retained on multivariate analysis. The final Cox Regression risk model included prior breast biopsy with LCIS or AH (HR 2.4, 95% CI 1.5-3.9; p&amp;lt;0.001), high RPFNA cellularity (HR 2.2, 95% CI 1.3-3.7; p=0.003) and prevention intervention (HR 0.54, 95% CI 0.33-0.89; p=0.015). Conclusions: In a second large cohort of high-risk women for whom RPFNA acquired cells were processed to slides via ThinPrep™, high RPFNA cellularity (&amp;gt;5000 epithelial cells/slide) but not cytologic atypia predicted short-term breast cancer risk. However, women with atypia were significantly more likely than women without atypia to participate in a prevention intervention, which in turn was associated with reduced breast cancer risk Citation Format: Whitney L Hensing, Carol J Fabian, Carola M Zalles, Priyanka Sharma, Amy L Kreutzjans, Kandy R Powers, Lynn Chollet-Hilton, Bruce F Kimler. Random periareolar fine-needle aspiration (RPFNA) cell number, prior precancerous breast disease and subsequent uptake of a prevention intervention predict short-term breast cancer risk [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-02.

Cigarette smoking and mammographic breast density among Polish women.

High mammographic breast density (MBD) is one of the strongest breast cancer risk factors. The results of some epidemiological studies suggest that one of the lifestyle factors likely altering breast density is cigarette smoking. The aim of this study was to assess the association between active smoking, considering in detail the duration and intensity of smoking, and MBD among Polish women. A cross-sectional study included 467 women aged 40-60 years who underwent screening mammography in Łódź, Poland. Volumetric mammographic density, fibroglandular tissue volume and non-fibroglandular tissue volume were determined based on the analysis of mammographic image (in the "for processing" format) using Volpara Imaging Software. Current and lifetime intensity of cigarette smoking was assessed based on the data from interviews. Linear and logistic regressions were fitted with estimated MBD parameters as the outcomes, and life-long smoking duration and intensity as the determinants, adjusted for major confounders. The former smokers had a significantly lower volumetric mammographic density compared to the non-smokers in the crude analysis (p = 0.022). However, the associations became insignificant after adjustments for important confounding factors. The analyses adjusted for important confounders revealed an inverse statistically significant association between the number of pack-years and volumetric mammographic density among the current smokers (p = 0.048). The observed result is consistent with the majority of previous studies that analyzed the associations between mammographic density and life-long smoking duration. Int J Occup Med Environ Health. 2021;34(6):805-15.

Prediagnostic circulating metabolites in female breast cancer cases with low and high mammographic breast density

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We designed a matched case–case study in the EPIC Florence cohort, to evaluate possible associations between the pre-diagnostic metabolomic profile and the risk of BC in high- versus low-MBD women who developed BC during the follow-up. A case–case design with 100 low-MBD (MBD ≤ 25%) and 100 high-MDB BC cases (MBD > 50%) was performed. Matching variables included age, year and type of mammographic examination. 1H NMR metabolomic spectra were available for 87 complete case–case sets. The conditional logistic analyses showed an inverse association between serum levels of alanine, leucine, tyrosine, valine, lactic acid, pyruvic acid, triglycerides lipid main fraction and 11 VLDL lipid subfractions and high-MBD cases. Acetic acid was directly associated with high-MBD cases. In models adjusted for confounding variables, tyrosine remained inversely associated with high-MBD cases while 3 VLDL subfractions of free cholesterol emerged as directly associated with high-MBD cases. A pathway analysis showed that the “phenylalanine, tyrosine and tryptophan pathway” emerged and persisted after applying the FDR procedure. The supervised OPLS-DA analysis revealed a slight but significant separation between high- and low-MBD cases. This case–case study suggested a possible role for pre-diagnostic levels of tyrosine in modulating the risk of BC in high- versus low-MBD women. Moreover, some differences emerged in the pre-diagnostic concentration of other metabolites as well in the metabolomic fingerprints among the two groups of patients.

Association between mammographic breast density and achievement of a pathologic complete remission (pCR) after neoadjuvant chemotherapy (NACT) for early breast cancer (EBC).

e12611 Background: Neoadjuvant chemotherapy (NACT) is indicated in early breast cancer (EBC) with an unfavorable tumor biology. Achievement of pathologic complete remission (pCR) after NACT is indicating an improved prognosis. An association between pCR and mammographic breast density as defined by BIRADS (Breast Imaging Reporting and Data System) could be demonstrated. However, the definition of mammographic breast density by the American College of Radiology (ACR) is widely used worldwide and data regarding an association of breast density by this definition and pCR after NACT are missing. Methods: We conducted a retrospective analysis among patients who had received neoadjuvant chemotherapy (NACT) for EBC and had available data regarding mammographic breast density as defined by ACR before therapy, pCR, age, estrogen and progesterone receptor (ER, PR) status, HER2neu status and grading were included. An association between mammographic breast density (ACR) and pCR was analyzed. Results: 185 patients were included in this analysis, 35.7% of whom achieved a pCR. Mammographic breast density was ACR 1 in 15.1%, ACR 2 in 41.6%, ACR3 in 38.4% and ACR 4 in 4.9% of the patients. A negative correlation (Spearman-Rho) between mammographic breast density and pCR (correlation coefficient (CC) -0.240) was highly statistically significant (p = 0.001). The association of decreasing pCR rates with increasing mammographic breast density (pCR rates by ACR 1: 53.6%, ACR 2: 41.6, ACR 3: 25.4% and 11.1 %) was statistically significant (Chi-Square, p = 0.013). These results were independent of age, ER status, PR status, HER2neu status and grading. Conclusions: In our analysis higher mammographic breast density as defined by ACR was significantly correlated with a lower chance of achieving a pCR after NACT. Although this result has to be interpreted with caution due to the small sample size and the retrospective character of our investigation, it is completely in line with other investigations using other definitions of mammographic breast density. The pathophysiological cause of this association should be further elucidated to reveal potential mechanisms of treatment resistance.