Changes In Breast Density Research Articles

Reproducible automated breast density measure with no ionizing radiation using fat-water decomposition MRI.

Increased breast density is a significant independent risk factor for breast cancer, and recent studies show that this risk is modifiable. Hence, breast density measures sensitive to small changes are desired. Utilizing fat-water decomposition MRI, we propose an automated, reproducible breast density measurement, which is nonionizing and directly comparable to mammographic density (MD). Retrospective study. The study included two sample sets of breast cancer patients enrolled in a clinical trial, for concordance analysis with MD (40 patients) and reproducibility analysis (10 patients). The majority of MRI scans (59 scans) were performed with a 1.5T GE Signa scanner using radial IDEAL-GRASE sequence, while the remaining (seven scans) were performed with a 3T Siemens Skyra using 3D Cartesian 6-echo GRE sequence with a similar fat-water separation technique. After automated breast segmentation, breast density was calculated using FraGW, a new measure developed to reliably reflect the amount of fibroglandular tissue and total water content in the entire breast. Based on its concordance with MD, FraGW was calibrated to MR-based breast density (MRD) to be comparable to MD. A previous breast density measurement, Fra80-the ratio of breast voxels with <80% fat fraction-was also calculated for comparison with FraGW. Pearson correlation was performed between MD (reference standard) and FraGW (and Fra80). Test-retest reproducibility of MRD was evaluated using the difference between test-retest measures (Δ1-2 ) and intraclass correlation coefficient (ICC). Both FraGW and Fra80 were strongly correlated with MD (Pearson ρ: 0.96 vs. 0.90, both P < 0.0001). MRD converted from FraGW showed higher test-retest reproducibility (Δ1-2 variation: 1.1% ± 1.2%; ICC: 0.99) compared to MD itself (literature intrareader ICC ≤0.96) and Fra80. The proposed MRD is directly comparable with MD and highly reproducible, which enables the early detection of small breast density changes and treatment response. 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:971-981.

The Effect of Vitamin D Supplementation on Breast Density Changes: A Clinical Trial Study

ABSTRACTThe aim of this study was to determine the effect of supplementation with 50,000 IU/monthly vitamin D for 1 yr on breast density in Iranian women. Methods: This double-blind, placebo-controlled, single center clinical trial was conducted among 400 women aged 40 yr and older. Participants were allocated to 2 groups. Group 1 received vitamin D (Cholecalciferol) 50,000 IU in tablet form, monthly, for 1 yr. Group 2 received vitamin E 400 IU in tablet form, monthly, for the same period of time. Participants had follow-up clinic visits every 6 mo and received an annual mammogram. Results: Final data were evaluated based on 216 and 194 women in the vitamin D and control groups. The mean decrease in mammographic density was −5.01%(95% CI, −9.9% to −0.01%) and −2.34 %(95% CI, −6.84% to −2.15%) in the vitamin D and control groups, respectively. There was no significant association between vitamin D consumption and breast density after 1 yr (OR = 0.7, 95% CI, 0.46 to 1.06; P = 0.1).Similar results were observed when multivariate model of logistic regression analysis was performed. Conclusions: This study showed that monthly consumption of 50,000 IU of vitamin D supplementation for 1 yr did not affect breast density.

Abstract P5-12-04: The impact of bariatric surgery on mammographic breast density

Abstract Background: Bariatric surgery decreases breast cancer risk, but its impact on mammographic findings is not well understood. Obesity and breast density both increase breast cancer risk, but paradoxically are inversely related. We investigated how mammographic density changes after bariatric surgery, and whether or not that change is related to amount of weight loss. Methods: We reviewed records for 349 prospectively collected patients who underwent bariatric surgery between 2013-2015, and identified 45 women with pre- and post-operative screening mammograms within 1.5 years of surgery. We recorded body mass index (BMI), Breast Imaging-Reporting and Data System density, and calculated excess BMI loss. Data were analyzed in Stata 14.2. Results: Average age was 54 years, mean pre-operative BMI was 44 (range 36-72), and mean percentage excess BMI lost was 73% at 1.3 years. One third had a change in mammographic breast density, which increased 93% of the time (p&amp;lt;0.001). Amount of weight loss was not associated with density change; in fact, weight loss was lower in those with a density change than in those without a density change (68% versus 75% excess BMI lost). Conclusions: The majority of women with a mammographic change had an increase in breast density, despite bariatric surgery being associated with reduced breast cancer risk. Interestingly, the amount of weight loss was not associated with change in breast density. These findings suggest the metabolic effects of bariatric surgery have an effect on breast cancer risk independent of BMI reduction. Future work will include studying mammographic changes associated with non-surgical weight loss. Citation Format: Hosseini A, Khoury AL, Carter J, Wong JM, Alvarado MD, Ewing C, Esserman LJ, Mukhtar RA. The impact of bariatric surgery on mammographic breast density [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-12-04.

Changes in Breast Density Reporting Patterns of Radiologists After Publication of the 5th Edition BI-RADS Guidelines: A Single Institution Experience.

The objective of our study was to determine the impact of 5th edition BI-RADS breast density assessment guidelines on density reporting patterns in our clinical practice. PenRad reporting system was used to collect mammographic breast density data reported by five radiologists: 16,907 density assignments using 5th edition BI-RADS guidelines were compared with 19,066 density assessments using 4th edition guidelines. Changes in the density assessment pattern were noted between the 4th and 5th edition guidelines, and agreement in density distribution was compared using the intraclass correlation coefficient. A chi-square analysis was conducted for each reader to examine the change in the proportion of dense versus nondense assignments and on each category type to examine specific changes in proportion of density assignments from the 4th to the 5th edition. All reported p values are two-sided, and statistical significance was considered at the p < 0.001 threshold. Using the 5th edition, there was an overall 5.0% decrease in fatty assessments (p < 0.001), 2.8% increase in scattered densities (p < 0.001), 2.6% increase in heterogeneously dense (p < 0.001), and 0.4% decrease in extremely dense assessments (p = 0.15). Comparing the dense with nondense categories, there was a 2.3% overall increase in the dense assessments (p < 0.001) using 5th edition guidelines, mainly in the heterogeneously dense category. Two radiologists showed increased dense assessments (p < 0.001) using the 5th edition, and three radiologists showed no change (p = 0.39, 0.67, and 0.76). There was an overall increase in the dense assessments using the 5th edition, but individual radiologists in our clinical practice showed a variable adaptation to new guidelines.

A Randomized Double-Blind Placebo-Controlled Trial of the Effect of Vitamin D3 Supplementation on Breast Density in Premenopausal Women.

Background: This double-blind, placebo-controlled parallel group trial assessed whether oral supplementation with 1,000, 2,000, or 3,000 IU/day vitamin D3 over one year reduces percent mammographic breast density in premenopausal women.Methods: The trial was conducted between October 2012 and June 2015, among premenopausal female volunteers from Quebec City (Quebec, Canada). Women were randomized with ratio 1:1:1:1 to one of four study arms (1,000, 2,000, or 3,000 IU/day vitamin D3 or placebo). The primary outcome was mean change in percent mammographic breast density. Participants and research team were blinded to study arm assignment.Results: Participants (n = 405) were randomized to receive 1,000 (n = 101), 2,000 (n = 104), or 3,000 IU/day (n = 101) vitamin D3, or a placebo (n = 99). The primary analysis included 391 participants (96, 99, 100, and 96, respectively). After the one-year intervention, mean ± SE change in percent breast density in the arms 1,000 IU/day (-5.5% ± 0.5%) and 2,000 IU/day (-5.9% ± 0.5%) vitamin D3 was similar to that in the placebo arm (-5.7% ± 0.5%) (P values = 1.0). In the 3,000 IU/day vitamin D3 arm, percent breast density also declined but slightly less (-3.8% ± 0.5%) compared with placebo arm (P = 0.03). Adherence to intervention was excellent (92.8%), and reporting of health problems was comparable among study arms (P ≥ 0.95). All participants had normal serum calcium.Conclusions: In premenopausal women, one-year supplementation with 1,000, 2,000, or 3,000 IU/day vitamin D3 resulted in a reduction of percent breast density no greater than that seen with the placebo.Impact: At doses of 1,000-3,000 IU/day, vitamin D supplementation will not reduce breast cancer risk through changes in breast density. Cancer Epidemiol Biomarkers Prev; 26(8); 1233-41. ©2017 AACR.

Mammographic breast density decreases after bariatric surgery.

Breast density (BD), an important risk factor for breast cancer, can change over time in some women, but the underlying mechanism is unclear. Very little is known about the impact of surgical weight loss on BD. Our hypothesis is that weight loss after bariatric surgery is associated with a significant and favorable change in mammographic BD. We identified 1097 women 40years of age or older who underwent gastric bypass or sleeve gastrectomy at our institution from 2010 to 2014. Women who did not have either pre- and post-bariatric surgery mammograms performed at our institution were excluded; 110 had both mammograms and comprised the cohort. Breast density was determined both qualitatively, using reported BI-RADS density, and quantitatively, using the Laboratory for Individualized Breast Radiodensity Assessment. Qualitative BI-RADS density, quantitative breast area, and percent BD significantly decreased in post-bariatric surgery mammograms (p=0.009, <0.001, and <0.001, respectively). Our retrospective study demonstrated that surgical weight loss was associated with a significant decrease in breast density. Additional studies are warranted to validate our findings and elucidate the molecular mechanisms underlying breast density change after weight loss surgery.

Longitudinal Changes in Volumetric Breast Density with Tamoxifen and Aromatase Inhibitors.

Background: Reductions in breast density with tamoxifen and aromatase inhibitors may be an intermediate marker of treatment response. We compare changes in volumetric breast density among breast cancer cases using tamoxifen or aromatase inhibitors (AI) to untreated women without breast cancer.Methods: Breast cancer cases with a digital mammogram prior to diagnosis and after initiation of tamoxifen (n = 366) or AI (n = 403) and a sample of controls (n = 2170) were identified from the Mayo Clinic Mammography Practice and San Francisco Mammography Registry. Volumetric percent density (VPD) and dense breast volume (DV) were measured using Volpara (Matakina Technology) and Quantra (Hologic) software. Linear regression estimated the effect of treatment on annualized changes in density.Results: Premenopausal women using tamoxifen experienced annualized declines in VPD of 1.17% to 1.70% compared with 0.30% to 0.56% for controls and declines in DV of 7.43 to 15.13 cm3 compared with 0.28 to 0.63 cm3 in controls, for Volpara and Quantra, respectively. The greatest reductions were observed among women with ≥10% baseline density. Postmenopausal AI users had greater declines in VPD than controls (Volpara P = 0.02; Quantra P = 0.03), and reductions were greatest among women with ≥10% baseline density. Declines in VPD among postmenopausal women using tamoxifen were only statistically greater than controls when measured with Quantra.Conclusions: Automated software can detect volumetric breast density changes among women on tamoxifen and AI.Impact: If declines in volumetric density predict breast cancer outcomes, these measures may be used as interim prognostic indicators. Cancer Epidemiol Biomarkers Prev; 26(6); 930-7. ©2017 AACR.

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen.

Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activityin the breast. There is limited evidence of clinically relevant activity of DIM or long-term safetydata of its regular use. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM® (BR-DIM) with tamoxifen. Women prescribed tamoxifen (n=130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12months. The primary study endpoint was change in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed. Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (-0.7 [-1.7, 0.8], P<0.001). Serum SHBG increased with BR-DIM compared to placebo (+25±22 and+1.1±19nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving BR-DIM versus placebo (P<0.001). Minimal adverse events were reported and did not differ by treatment arm. In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether BR-DIM associateddecreases in tamoxifen metabolites, including effects on endoxifenlevels, attenuates the clinical benefit of tamoxifen. ClinicalTrials.gov NCT01391689.

Ultrasound tomography imaging with waveform sound speed: Parenchymal changes in women undergoing tamoxifen therapy.

Ultrasound tomography (UST) is an emerging modality that can offer quantitative measurements of breast density. Recent breakthroughs in UST image reconstruction involve the use of a waveform reconstruction as opposed to a ray-based reconstruction. The sound speed (SS) images that are created using the waveform reconstruction have a much higher image quality. These waveform images offer improved resolution and contrasts between regions of dense and fatty tissues. As part of a study that was designed to assess breast density changes using UST sound speed imaging among women undergoing tamoxifen therapy, UST waveform sound speed images were then reconstructed for a subset of participants. These initial results show that changes to the parenchymal tissue can more clearly be visualized when using the waveform sound speed images. Additional quantitative testing of the waveform images was also started to test the hypothesis that waveform sound speed images are a more robust measure of breast density than ray-based reconstructions. Further analysis is still needed to better understand how tamoxifen affects breast tissue.

Effect of Diindolylmethane on Estrogen-related Hormones, Metabolites and Tamoxifen Metabolism: Results of a Randomized, Placebo-controlled Trial

Abstract Dietary supplement use is high among breast cancer survivors. One compound natural to cruciferous vegetables, diindolylmethane (DIM), is among the supplements commonly used. This bioactive compound has significant experimental evidence for bioactivity in breast chemoprevention. Sparse evidence in the form of well-designed human clinical trials exist to test its efficacy or safety. Methods: In this double-blind placebo-controlled study women taking tamoxifen for breast cancer primary or tertiary prevention were randomly assigned to receive 150 mg DIM (BioResponse(BR)-DIM) twice daily or a placebo for a minimum period of 12 months. Primary outcome was change in urinary estrogen metabolites 2-hydroxyestrone and 16α-hydroxyestrone (baseline to 6 weeks, 6 and 12 months). Secondary endpoints included breast density by mammogram and fat:water ratio MRI (baseline to 12 months) and serum estrogens (baseline to 6, 12 months). Safety data were also evaluated, including tamoxifen metabolites. Results: Adherence to study pills was &amp;gt;91% by pill count and urinary DIM metabolite assessment. In participants assigned DIM there was a significant and sustained shift in urinary estrogen metabolism favoring a higher 2-OH:16α-OH ratio; sex hormone binding globulin (SHBG) was also increased. No change in breast density was demonstrated. Safety analysis showed no appreciable differences in adverse events by treatment arm; however, tamoxifen metabolism for the parent compound as well as endoxifen and 4-OH endoxifen were appreciably reduced in women assigned to the DIM arm. Conclusions In this first large study of DIM in the setting of breast cancer chemoprevention, a favorable shift in estrogen metabolism and SHBG was demonstrated. However, the reduction in tamoxifen metabolites raises concern regarding the potential interaction between DIM and tamoxifen, an area in need of continued research. Impact Given the widespread and generally unsupported use of dietary supplementation by breast cancer survivors, these data will help to inform the use of DIM as a dietary supplement for breast cancer patients receiving tamoxifen.

Abstract P6-09-19: Breast density change at 6 months is associated with change at 12 months as measured by fat-water decomposition MRI in women on tamoxifen

Abstract P6-09-19: Breast density change at 6 months is associated with change at 12 months as measured by fat-water decomposition MRI in women on tamoxifen

Abstract 3424: Longitudinal changes in volumetric breast density with adjuvant endocrine therapy among women with breast cancer

Abstract Breast density represents the stromal and epithelial tissue in the breast and is a strong risk factor for breast cancer. Reductions in breast density attributable to tamoxifen (TAM) and aromatase inhibitors (AI) may be associated with reduced risk of first primary and subsequent breast cancer. Studies assessing breast density changes have principally used two-dimensional measures. We assess changes in breast density following initiation of TAM and AI using two automated volumetric density measures that have shown strong associations to breast cancer risk. Breast cancer cases with a full field digital mammogram (FFDM) prior to diagnosis (index mammogram) and after initiation of TAM (n = 379) or AI (n = 425) were identified from the Mayo Clinic Mammography Practice and the San Francisco Mammography Registry. Volumetric percent density (VPD) and dense volume (DV) were measured on 4-view FFDM using VolparaTM (Matakina Technology) and QuantraTM (Hologic) automated software. We used linear regression to assess the effect of treatment on mean annualized change in VPD and DV (change from index to last mammogram divided by time interval) for each software type, adjusting for age, body mass index (BMI) and density at index mammogram. The median time between index mammogram and cancer diagnosis was 0.6 months (IQR: 0.2, 2.2) and median time between index and last mammogram was 3 years (IQR: 2.0, 3.9). Women on TAM were younger, had lower BMI and higher baseline VPD and DV relative to women on AI (Table). An annual decrease in VPD and DV was observed with both TAM and AI. Both Volpara and Quantra estimated a similar magnitude of change in VPD in women on TAM and AI, and a greater change in DV with TAM. Our findings suggest that both Volpara and Quantra can assess volumetric changes in breast density among women on hormone therapy. If declines in volumetric density correlate with a reduction in breast cancer risk, these automated measures could be used in clinical practice to assess response to therapy. Annualized changes in volumetric breast density estimated by linear regression.Tamoxifen (n = 379)Aromatase Inhibitors (n = 425)Baseline Median (IQR)Annualized Change (95% CI)*Baseline Median (IQR)Annualized Change (95% CI)*Age at Diagnosis50.0 (45.0, 60.0)–63.0 (58.0, 71.0)–Body Mass Index (BMI)23.6 (21.5, 26.8)–25.7 (22.7, 29.9)–Time Interval¥3.0 (2.1, 3.9)–3.0 (2.1, 3.9)–VolparaPercent Density (VPD,%)11.6 (6.8, 18.8)-0.17 (-0.27, -0.10)7.2 (5.0, 11.0)-0.19 (-0.29, -0.12)Dense Volume (DV, cm3)64.7 (45.4, 90.9)-0.90 (-1.45, -0.48)51.9 (38.9, 69.9)-0.52 (-0.93, -0.23)QuantraPercent Density (VPD,%)14.5 (9.2, 20.2)-0.42 (-0.59, -0.28)9.9 (7.1, 14.5)-0.38 (-0.54, -0.25)Dense Volume (DV, cm3)94.0 (58.0, 144.0)-2.20 (-3.52, -1.19)80.0 (49.0, 128.0)-0.95 (-1.85, -0.35)IQR = Interquartile range ¥ Median number of years between index mammogram and last mammogram post-initiation of therapy. *Annualized change estimated as change from index to last mammogram divided by time interval and adjusted for study site, age at diagnosis, BMI and density at index mammogram. Citation Format: Natalie J. Engmann, Celine M. Vachon, Christopher G. Scott, Matthew R. Jensen, Lin Ma, Kathleen R. Brandt, Amir P. Mahmoudzadeh, Serghei Malkov, Dana H. Whaley, Carrie B. Hruska, Fang F. Wu, Stacey J. Winham, Diana L. Miglioretti, Aaron D. Norman, John J. Heine, John Shepherd, V Shane Pankratz, Karla Kerlikowske. Longitudinal changes in volumetric breast density with adjuvant endocrine therapy among women with breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3424.

Mammographic Density as a Biosensor of Tamoxifen Effectiveness in Adjuvant Endocrine Treatment of Breast Cancer: Opportunities and Implications.

Tamoxifen is highly effective in treating estrogen receptor (ER) –positive breast cancer. Meta-analyses of adjuvant tamoxifen treatment for 5 years have shown reduced breast cancer recurrence at 10 years, with reduced breast cancer mortality observed at 15 years(event rate ratio, 0.70; 95% CI, 0.64 to 0.75). 1 Given thattamoxifenmetabolitesbindtothe ER more avidly than the parent drug, tamoxifen recipients are hypothesized to be divisible into a group of excellent metabolizers, who receive benefit with standard dosing, and poor metabolizers, who do not benefit. 2 Accordingly, the development of validated measures for monitoring tamoxifen effectiveness would have great value, particularly among premenopausal women, a group in which tamoxifen is first-line therapy. We highlight the potential relevance of assessing mammographic breast density as a marker of tamoxifen efficacy, particularly among premenopausal women in a clinical setting. Mammographic density is a radiologic measure of the fibroglandular content within the breast and is usually expressed as the percentage of total breast area composed of dense tissue. 3,4 Women with the highest levels of percent density (ie, . 75%) experience a four- to six-fold increased relative risk of developing breast cancer compared with women who have the lowest percentage mammographic density when adjusted for confounders. 3,4 Amassing data suggest that a decline in mammographic density could serve as a much-needed predictor of a favorable response to the selective ER modulator tamoxifen. The results of four retrospective analyses, which include one that evaluated breast cancer–specific mortality among patients with ER-positive disease treated with tamoxifen, indicated that women whose mammographic density declined in the unaffected breast after initiation of tamoxifen therapy had better outcomes (reduced risk of recurrence 5,6 or death from breast cancer 7,8 ). The magnitude of the observed benefit associated with a decline (approximately 10%) in breast density was remarkably similar across studies, despite differences in the methods of mammographic density assessment and analytic approaches, which suggests that these findings are robust. The results from studies that included premenopausalwomen are shown in Table 1 .Ofthe two prior studies that examined tamoxifen-related changes and breast cancer death, 7,8 one excluded premenopausal women, 7 for whom tamoxifen remains as the primary endocrine therapy. Assessment of mammographic density change after tamoxifen treatment, specifically among younger women, merits further study to maximize the potential translational benefit of monitoring mammographic breast density change as a prognostic indicator in the clinic. In our prior retrospective analysis of patients with ER-positive breast cancer (age range, 32 to 87 years) who were diagnosed at Kaiser Permanente Northwest, 8 we compared the change in mammographic density after 1 year of tamoxifen treatment among 97 patients who died of breast cancer with 252 matched patients who did not. Women who were in the highest tertile of mammographic density decline were less likely to die of breast cancer (odds ratio [OR], 0.44; 95% CI, 0.22 to 0.88). 8 To explore the potential utility of assessing mammographic density decline as a measure of effectiveness among premenopausal women who received adjuvant tamoxifen, we performed a subset analysis that examined recurrences and deaths among 136 women with ER-positive breast cancer diagnosed at age 55 years or younger (a surrogate for premenopausal status) who were included in the initial report. Among these women, there were 34 recurrences or deaths at 5 years of follow-up and 50 such events during the whole study period (1990 to 2010). Although this analysis is limited by statistical power, multivariate Cox proportional hazards regression models demonstrated that patients with $ 10% decline in mammographic density after 1 year of tamoxifen therapy had an onsignificant improvement in disease-free survival (DFS) at 5-year follow-up (hazard ratio [HR], 0.78; 95% CI, 0.38 to 1.61);

Abstract PD1-06: Mammographic breast density as a predictor of hormone receptor positive breast cancer recurrence: A single centre longitudinal analysis

Abstract Mammographic breast density as a predictor of breast cancer recurrence: a single centre longitudinal analysis of women with hormone receptor positive breast cancer Background Mammographic breast density has been associated with risk of development of breast cancer. To date clinical studies examining the use of tamoxifen and fall in mammographic breast density during this treatment have shown reduction in mammographic breast density examining change in mammographic breast density between baseline and a single follow-up mammogram to be predictive for disease recurrence. Aim To examine serial change in mammographic breast density over years to describe the changes which occur with use of aromatase inhibitors and tamoxifen, as well as changes following cessation of this treatment and to determine whether changes observed correlate with outcome. Method Eligible patients were identified from the Royal Perth Hospital breast unit database between January 1994-December 2011. Patient data was prospectively collected through the breast unit database. Additional data regarding endocrine therapy, adherence, weight, height and concomitant medications were obtained from case note review. Recurrence data was obtained from the hospital medical records system, as well as the breast unit database. Mammograms were obtained and mammographic breast density readings undertaken by a single reader using Cumulus. Percentage breast densities were obtained and statistical analysis undertaken to investigate changes in mammographic density on endocrine therapy, at switch of therapy, and cessation of therapy and correlation with disease free and overall survival. Results 1942 eligible patients were identified. 417 were premenopausal at time of diagnosis, 148 perimenopausal, 1328 postmenopausal and the remainder unknown status. 12 declined adjuvant endocrine therapy, 520 received both at least 1 aromatase inhibitor and tamoxifen during follow-up, 1189 tamoxifen only, 56 tamoxifen plus goserelin, and the remainder either aromatase inhibitor only or aromatase inhibitor with ovarian suppression. Over 10,000 mammograms were obtained for analysis. Currently results are available from 4301 mammograms from 689 patients. Mean density change between baseline scan and subsequent imaging after between 11-24 months of patient-reported endocrine adherence was -6.0%, with mean reduction of -11% in patients who were premenopausal at baseline and -4.5% in those who were postmenopausal at baseline. Kaplan Meier analysis showed late separation of overall survival curves favouring those with reduction in mammographic breast density however there was no statistically significant difference in the curves Conclusion Reduction in mammographic breast density was greatest in those who were premenopausal at baseline. Further multivariate analysis and assessment of the additional mammograms in this data set is required to assess the association between mammographic breast density and outcome in this cohort. Citation Format: Redfern AD, Martin HL, Stone J, Davidson JA, Yap F, Chung K. Mammographic breast density as a predictor of hormone receptor positive breast cancer recurrence: A single centre longitudinal analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD1-06.

Abstract P6-10-09: Effect of chemoprevention uptake on mammographic density over time in women at high risk for breast cancer

Abstract Background: Mammographic density (MD) is an independent risk factor for breast cancer, but whether chemoprevention can modify this risk biomarker is unknown. MD naturally declines with age, particularly after menopause. Prior studies have shown a significant decrease in MD with tamoxifen correlated with decreased breast cancer incidence, however, other anti-estrogens, such as aromatase inhibitors (AIs) and raloxifene, have not shown significant effect. No studies have examined the long-term effects (&amp;gt;24 months) of chemoprevention on MD. Methods: We conducted a retrospective cohort study of high-risk women seen at an academic breast center. Patients were considered to be at high risk for breast cancer and eligible for chemoprevention if they had a 5-year predicted breast cancer risk according to the Gail model of ≥1.67%, atypical ductal or lobular hyperplasia, history of ductal or lobular carcinoma in situ, and/or BRCA mutation. We collected demographic, breast cancer risk factor, and clinical data, including prior or current anti-estrogen use, type of anti-estrogen, and duration of use, from a self-administered questionnaire and medical chart review. We dichotomized anti-estrogen use as ever/never. One reader measured MD from digital images using a semiautomated computer-assisted technique with Cumulus software. MD was determined for a baseline mammogram (within 6 months of starting an anti-estrogen), a short-term follow-up (12-24 months) and/or a long-term follow-up (48-60 months) mammogram. We conducted multivariable logistic regression models to assess the association between change in MD over time with and without anti-estrogen use for chemoprevention. Results: Of 190 evaluable women, 86 (45%) women took an anti-estrogen (53 tamoxifen, 25 raloxifene, 4 AI, 4 multiple anti-estrogens) and 104 (55%) did not. Compared to women who did not take an anti-estrogen, those who took chemoprevention were more likely to be older (age 56 vs. 53 years), postmenopausal (65% vs. 51%), have a higher body mass index [BMI] (28.2 vs. 26.8 kg/m2), and had a lower mean baseline MD (12.7% vs. 15.9%). Comparing high-risk women who initiated anti-estrogens to those who did not, mean absolute short-term change in MD (SD) was -0.249% (SD 6.22) vs .057% (10.16) and mean long-term change in MD was -3.25% (8.25) vs. -4.19% (11.98), respectively. There was no significant short-term change in breast density with chemoprevention; however, women who took chemoprevention were 4 times more likely to have at least a 5% decrease in breast density compared to those who did not take chemoprevention after adjustment for age, menopausal status, and baseline MD (OR=4.14, 95% CI=1.03-16.73). Discussion: Among high-risk women who initiated anti-estrogens, we did not observe a significant short-term change in MD, but chemoprevention uptake was associated with a significant decrease in MD with long-term follow-up. Our data suggests that short-term changes in MD with chemoprevention may be too small to be detected by current methods, therefore other risk biomarkers may be needed to assess short-term response to anti-estrogens. Citation Format: Namburi S, Coe AM, Thomas P, Hershman D, Sandoval R, Maria A, Crew KD. Effect of chemoprevention uptake on mammographic density over time in women at high risk for breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-09.

The effect of change in body mass index on volumetric measures of mammographic density.

Understanding how changes in body mass index (BMI) relate to changes in mammographic density is necessary to evaluate adjustment for BMI gain/loss in studies of change in density and breast cancer risk. Increase in BMI has been associated with a decrease in percent density, but the effect on change in absolute dense area or volume is unclear. We examined the association between change in BMI and change in volumetric breast density among 24,556 women in the San Francisco Mammography Registry from 2007 to 2013. Height and weight were self-reported at the time of mammography. Breast density was assessed using single x-ray absorptiometry measurements. Cross-sectional and longitudinal associations between BMI and dense volume (DV), non-dense volume (NDV), and percent dense volume (PDV) were assessed using multivariable linear regression models, adjusted for demographics, risk factors, and reproductive history. In cross-sectional analysis, BMI was positively associated with DV [β, 2.95 cm(3); 95% confidence interval (CI), 2.69-3.21] and inversely associated with PDV (β, -2.03%; 95% CI, -2.09, -1.98). In contrast, increasing BMI was longitudinally associated with a decrease in both DV (β, -1.01 cm(3); 95% CI, -1.59, -0.42) and PDV (β, -1.17%; 95% CI, -1.31, -1.04). These findings were consistent for both pre- and postmenopausal women. Our findings support an inverse association between change in BMI and change in PDV. The association between increasing BMI and decreasing DV requires confirmation. Longitudinal studies of PDV and breast cancer risk, or those using PDV as an indicator of breast cancer risk, should evaluate adjustment for change in BMI.

Abstract B46: The influence of exemestane on breast density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial

Abstract Background: Endogenous estradiol blood levels and high breast density are both associated with an increased risk for breast cancer (BC), but, there is conflicting evidence about whether or not they influence breast cancer risk through a shared pathway. Exemestane is an aromatase inhibitor that blocks the synthesis of estrogen and has been demonstrated to reduce the incidence of breast cancer in postmenopausal women by 65%. However the effects of exemestane on breast density remain unclear. Objectives: The primary objective of this research was to prospectively examine the relationship between exemestane versus placebo and changes in mammographic breast density (BD) in postmenopausal women during 3 or more years of treatment. Methods: The NCIC Clinical Trials Group conducted a phase III randomized controlled trial (RCT) comparing exemestane (E), with placebo (P) in postmenopausal women at higher than average risk for BC (MAP.3). This study was nested within the MAP.3 RCT using data from 568 participants across Canada and Buffalo, New York. Information on treatment allocation and established risk factors for BC was previously collected and data on the outcome measures was obtained from mammograms. Baseline and follow-up mammograms were collected from participating centres and were measured (percent density) using Cumulus software by our team radiologist (DJ). Multivariable linear regression was used to estimate the effect of exemestane treatment on &amp;gt;=3 year change in percent BD from randomization controlling for potential confounding variables. Results: Percent BD was measured for 386 participants (E=200, P=186) with a baseline and &amp;gt;=3 year follow-up mammogram that was matching in format (i.e. film or digital). The average age of women at study entry was 63 years and the average Gail score was 2.8%. The mean BD was similar in both arms at baseline (P: 12.9% (SD: 14.5) and E: 13.7% (SD: 14.4)). Similarly, the annual mean change in percent BD was not significantly different between the two treatment arms (P: 0.63% (SD: 1.82) vs E: .077% (SD: 1.80); p=0.90). After controlling for potential confounders (age, body mass index, first degree family history of BC and prior use of HRT), exemestane was not predictive of change in percent BD (p-value=0.641). Neither age (&amp;lt;60 vs. &amp;gt;=60 yrs) nor BMI modified the exemestane-breast density relationship significantly. Conclusion: We found no association between &amp;gt;=3 years of exemestane use and change in percent BD among a subset of postmenopausal women participating in MAP.3. These results suggest that estrogen and breast density may have independent pathways in breast cancer etiology. Citation Format: Harriet Richardson, Paul E. Goss, Melanie Walker, Doris Jabs, Will King. The influence of exemestane on breast density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B46.

Abstract 1904: Randomized clinical trial testing the efficacy of the combination of omega-3-fatty acids (n-3FA) and the antiestrogen raloxifene in reducing breast density (BD) in postmenopausal women

Abstract Our preclinical data indicate that n-3FA potentiate the chemopreventive effects of the antiestrogen (AE) Tamoxifen against mammary tumorigenesis induced by 1-methyl-1-nitrosourea in female Sprague Dawley rats.(A. Manni et al. Int. J. of Cancer 2014; 134:1549).To test the clinical impact of this approach we conducted a randomized clinical trial in healthy postmenopausal women at increased risk of breast cancer based on BD ≥ 25% detected at their routine annual screening mammogram. Out of 784 eligible subjects, 266 women were randomly assigned to one of the following groups 1) Control 2) The AE Raloxifene 60mg 3) Raloxifene 30mg 4) Lovaza 4g (the FDA approved n-3FA formulation containing EPA + DHA), 5) Lovaza 4gm plus Raloxifene 30mg. The rationale for choosing a dose of Raloxifene half the conventional dose of 60mg to be tested in combination was in the attempt to reduce toxicity while preserving antitumor action as supported by our preclinical studies with Tamoxifen (A. Manni et al. Canc. Prev. Res 2010; 3:322). The groups were comparable with regard to baseline demographics including age, BMI, parity, age at first child birth, family history of breast cancer, and history of prior breast biopsies. The duration of the intervention was 2 years and the change in breast density at year one and two was the primary endpoint. Breast density, a well established biomarker of breast cancer risk, was measured by the volumetric method using the Volpara software. Two hundred and fourteen women (∼80%) completed the trial. Compliance was excellent as assessed by pill counts (&amp;gt;95%) and plasma fatty acid analysis using gas chromatography-flame ionization (GC-FID) detection which showed the expected rise in n-3FA levels in the groups receiving Lovaza. Toxicity was minimal with vasomotor symptoms being more frequent in the groups receiving Raloxifene (13.2% with 30mg and 22.6% with 60mg) and gastrointestinal events more frequent in the combination group. No subject experienced thromboembolic events. The combination group exhibited the most beneficial changes in lipid panel with reduction in LDL (low density lipoprotein) cholesterol, triglyceride and increase in HDL (high density lipoprotein) cholesterol. Compared to control, none of the interventions significantly affected percent or absolute breast density at either year one or two. Our results indicate that in this group of healthy postmenopausal women the combination of Lovaza and Raloxifene at less than the conventional dose (e.g. 30mg), while feasible and well tolerated did not reduce breast cancer risk as assessed by a decrease in breast density. (This work has been funded by Susan G. Komen for the Cure, KG081632). Citation Format: Narinder Sandhu, Susann E. Schetter, Jason Liao, Terryl J. Hartman, John P. Richie, Karam El-Bayoumy, Bogdan Prokopczyk, Cindy DuBrock, Carina Signori, Christopher Hamilton, Laurence M. Demers, Andrea Manni. Randomized clinical trial testing the efficacy of the combination of omega-3-fatty acids (n-3FA) and the antiestrogen raloxifene in reducing breast density (BD) in postmenopausal women. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1904. doi:10.1158/1538-7445.AM2015-1904

Abstract P1-01-08: Changes in breast density with mammography and breast MRI among high-risk postmenopausal women

Abstract Background: Mammographic density (MD) represents one of the strongest predictors of breast cancer risk. Tamoxifen, a selective estrogen receptor modulator (SERM) and proven chemopreventive agent, causes reductions in MD which correlate with subsequent breast cancer risk. Current methods for measuring MD, such as the Cumulus technique, are labor intensive and not fully automated, which limits utility in the clinical setting. Breast MRI is being used with increasing frequency in high-risk women for breast cancer screening and yields 3-dimensional views of breast volume. Breast MRI fibroglandular tissue volume (MRIV) has been correlated with MD in cross-sectional studies, but less is known about changes in breast density over time on MRI and its relation to breast cancer risk. One study reported a significant reduction in breast MRIV but not MD with the SERM, raloxifene, in high-risk women. We implemented a novel MRI segmentation method to measure MRIV compared to MD in 20 high-risk postmenopausal women that received high-dose vitamin D supplementation for 1 year. Methods: Twenty high-risk postmenopausal women [defined as a 5-year breast cancer risk per the Gail model of ≥1.67%, lobular or ductal carcinoma in situ (LCIS/DCIS)] were assigned to a 1-year intervention of vitamin D3 20,000 IU or 30,000 IU weekly. Other eligibility criteria included baseline MD ≥25% (as assessed qualitatively by BIRADS category) and no current SERM use. Women underwent a digital mammogram and breast MRI at baseline and 12 months. MD was evaluated by the Cumulus technique and MRIV was measured using a novel segmentation method on noncontrast T1-weighted images from breast MRIs. The method incorporated two well-established image analysis techniques, the region-based active contour model and watershed algorithm, into a unified framework. Specific anatomical landmarks were introduced into the algorithm to consistently identify breast boundaries on longitudinal MRI slices. For fibroglandular tissue segmentation, an algorithm combining region-based active contours and level-set approach was used to allow for easy initialization and fast speed. Correlation coefficients and paired t-tests were used to compare MD and MRIV and changes from baseline to 12 months. Results: From Nov 2007 to Jan 2011, 20 postmenopausal women were enrolled and 16 were evaluable at 12 months. Mean baseline breast density measurements were lower for MD compared to MRIV, 12.89% (SD 11.99) vs. 26.64% (SD 6.95), respectively. After 1 year of high-dose vitamin D, there was no significant change in MD or MRIV, mean absolute changes of -0.14% vs. -1.12%, respectively. We did not observe a significant correlation between MD and MRIV density measurements (correlation coefficient= -0.31, p=0.08). Discussion: We observed greater changes over time in breast density on serial breast MRI compared to mammography, however, no significant changes in MD or MRIV was noted after a 1-year intervention of vitamin D. Longer follow-up may be required in order to detect changes in breast density with non-hormonal interventions. Citation Format: Parijatham S Thomas, Mary Beth Terry, Xiaotao Guo, Binsheng Zhao, Richard Ha, Swathi Namburi, Tong Xiao, Dawn Hershman, Susan Refice, Katherine D Crew. Changes in breast density with mammography and breast MRI among high-risk postmenopausal women [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 P1-01-08.

Abstract OT3-2-07: Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study

Abstract Background: The goal of this multi-site prospective study is to validate a safe, painless imaging method to measure the change in breast density caused by hormonal chemotherapy treatments such as tamoxifen. Recent studies have demonstrated that hormonal therapies are more effective at reducing risk in women who exhibit &amp;gt;10% reduction in breast density compared to women who had little or no density change, suggesting that breast density is a predictor of tamoxifen effectiveness. Current methods to measure breast density include MRI and mammography, however frequent applications of these modalities are limited due to cost and x-ray exposure, respectively. Alternatively, we are testing an imaging method that uses safe near-infrared light to measure breast tissue physiology called diffuse optical spectroscopic imaging (DOSI). Trial Design and Eligibility: The primary aim of the study is to determine whether the percentage change in the DOSI measurement of water correlates with the change in the MRI measurement of breast density after 18 months of treatment in the contralateral normal breast of breast cancer patients receiving tamoxifen. Other DOSI-derived parameters such as lipid content and hemoglobin concentration will be examined in secondary aims. Two groups of women are being recruited for the study: Pre-menopausal subjects receiving tamoxifen (treatment group) and pre-menopausal subjects not receiving chemoprevention agents (control group). Participants are measured with DOSI and non-contrast MRI before, and 6, 12 and 18 months after beginning tamoxifen. Eligible subjects are pre- and peri-menopausal females older than 21 years of age who have not and do not intend to receive chemotherapy, radiation, or surgical cancer treatment to the imaged breast, and are not pregnant or nursing. Study sites include the University of California, Irvine and San Francisco campuses. Statistical Methods: At a 5% significance level, the pre-determined power of the study is sufficient to detect the difference between the treatment and control groups by measuring the percentage change of breast tissue water concentration with DOSI. The research hypothesis is that the mean difference from baseline for tissue water concentration from DOSI will be greater for the tamoxifen-treated group than the control group. For water concentration and for MRI breast density, a two-sided independent sample t-test will be used to test the null hypothesis that the mean difference from baseline is the same for the tamoxifen-treated and control groups. As a secondary analysis, a multivariate mixed effects model will be built using the observed DOSI parameter or MRI breast density measured from each patient as the outcome variable, and predictor variables to include treatment group and measurement time, in addition to relevant clinical and demographic variables. Accrual Update: Out of the target accrual of 36, 11 subjects (6 treatment and 5 control group) have been enrolled to date. Enrollment is open until 11/30/2015. Citation Format: Thomas D OSullivan, Anais Leproux, Alice M Police, Dorota Wisner, Christine McLaren, Wen-Pin Chen, Albert E Cerussi, Min-Ying Su, Bruce J Tromberg. Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study [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 OT3-2-07.