Reduction In Mammographic Density Research Articles

Mammographic Density Reduction is Associated to the Prognosis in Asian Breast Cancer Patients Receiving Hormone Therapy.

Using mammographic density as a significant biomarker for predicting prognosis in adjuvant hormone therapy patients is controversial due to the conflicting results of recent studies. This study aimed to evaluate hormone therapy-induced mammographic density reduction and its association with prognosis in Taiwanese patients. In this retrospective study, 1941 patients with breast cancer were screened, and 399 patients with estrogen receptor-positive breast cancer who received adjuvant hormone therapy were enrolled. The mammographic density was measured using a fully automatic estimation procedure based on full-field digital mammography. The prognosis included relapse and metastasis during treatment follow-up. The Kaplan-Meier method and Cox proportional hazards model were used for disease-free survival analysis. A mammographic density reduction rate >20.8%, measured preoperatively and after receiving hormone therapy from 12-18 months, was a significant threshold for predicting prognosis in patients with breast cancer. The disease-free survival rate was significantly higher in patients whose mammographic density reduction rate was >20.8% (P = .048). This study's findings could help estimate the prognosis for patients with breast cancer and may improve the quality of adjuvant hormone therapy after enlarging the study cohort in the future.

Topical Endoxifen for Mammographic Density Reduction-A Randomized Controlled Trial.

Although breast cancer incidence is increasing, there are few primary preventive initiatives. Tamoxifen can reduce breast cancer incidence but is rarely used for primary prevention due to adverse events and tolerance issues. We tested if endoxifen, a tamoxifen metabolite, applied directly to the skin of the breast, could reduce mammographic density, a proxy for therapy response. Ninety women were randomized to placebo, 10 and 20 mg of topical Z-endoxifen for 6 months. Mammographic density and symptoms were measured at baseline and study exit. Despite a high discontinuation rate, driven by skin rashes, we found a significant mammographic density decrease, a dose-dependent increase in the concentration of plasma Z-endoxifen but no systemic side effects. Topical application of tamoxifen metabolites has the potential to decrease breast cancer incidence without major systemic side effects. However, endoxifen may not be suitable for topical administration and is unlikely to be used for breast cancer prevention.

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

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

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

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

Abstract PS8-41: Low dose tamoxifen for breast cancer prevention and mammographic density reduction - a randomized controlled trial

Abstract Introduction: Tamoxifen prevents breast cancer in high-risk women and reduces recurrence in the adjuvant setting but comes with side-effects. The optimal dose to increase uptake and retain therapeutic effect is unknown. We tested if the efficacy of low-dose tamoxifen is non-inferior to standard dose using mammographic density as a proxy for therapy response and if lower doses are associated with fewer symptoms.Methods: Healthy pre- and postmenopausal women attending a mammography screening program aged 40 to 74 years were invited to participate. N=2,314 screening women were investigated for eligibility. Exclusion criteria were women with a low mammographic density (BI-RADS A), high blood pressure, pregnancy, use of hormonal therapy, previous cardiovascular disorder, uncontrolled diabetes, any previous cancer. N=1,440 women entered a six-months double-blind placebo-controlled randomized dose-determination trial that was conducted in 2016-2019. Women were allocated into six months oral daily administration of 1, 2.5, 5, 10, and 20 mg of tamoxifen or placebo.Mammographic density was assessed as radiographic dense fibro-glandular tissue using a fully automated density tool. Symptoms were assessed using a self-reported questionnaire including vasomotor, gynecological, sexual, and joint pain symptoms. Non-inferior reduction of mammographic density and fewer severe symptoms in lower doses were compared with standard dose 20 mg. Post-hoc analyses were performed by menopause status. Both per protocol and intension to treat populations were analyzed.Results: Premenopausal (N=566) and postmenopausal (N=873) participants were recruited to the study. Premenopausal women showed non-inferior reduction in mammographic density following 2.5, 5 and 10 mg tamoxifen compared with the median 9.7% decrease observed in the 20 mg group (Table 1). No reduction in density was seen in postmenopausal participants. Severe vasomotor symptoms (hot flashes, cold and night seats) were reduced by approximately 50% in the 2.5 mg group compared with the 20 mg group (Table 2).Conclusion: Premenopausal women experienced fewer side effects with non-inferior decrease in breast density at lower dose of tamoxifen (2.5 mg) compared with standard dose (20 mg). A low dose of tamoxifen could be used for prevention and to increase sensitivity of a mammogram in premenopausal women. The table shows the proportions of women that had a larger decrease than median density decreases in the 20 mg arm (-9.7%) at six-months, stratified by menopausal status and tamoxifen dose. The table shows the prevalence ratios (PR) of severe vasomotor symptoms stratified by menopausal status and tamoxifen dose. Table 1. Non-inferior dense area reduction at six-months in the 2.5 mg arm compared with the standard dose 20mg arm.All womenPremenopausalPostmenopausalDoseProportion (97.5%CI)p-valueHolm p-valueProportion (95%CI)Proportion (95%CI)0 mg41.0 (29.2,100)0.1010.20333.9 (15.0,52.8)44.6 (33.3,55.9)1 mg40.8 (28.1,100)0.1250.20333.3 (17.9,48.8)46.1 (31.9,60.3)2.5 mg55.3 (44.2,100)<0.01<0.0171.9 (57.7,86.0)44.2 (31.2,57.2)5 mg54.8 (44.8,100)<0.01<0.0177.3 (64.4,90.1)38.5 (26.8,50.1)10 mg54.5 (42.9,100)<0.01<0.0172.7 (59.6,85.8)42.6 (28.9,56.3)20 mg50.0 (ref.)63.841.2 Table 2. Significantly lower prevalence ratios of severe vasomotor symptoms by 50% at six-months in the 2.5 mg arm compared with the standard dose 20 mg arm.All womenPremenopausalPostmenopausalDosePR (95%CI)PR (95%CI)PR (95%CI)0 mg0.41 (0.27,0.62)0.10 (0.02,0.39)0.56 (0.36,0.88)1 mg0.48 (0.33,0.71)0.37 (0.19,0.75)0.56 (0.35,0.89)2.5 mg0.47 (0.32,0.71)0.37 (0.18,0.78)0.54 (0.33,0.88)5 mg0.72 (0.51,1.01)0.36 (0.18,0.75)0.97 (0.65,1.42)10 mg0.76 (0.55,1.06)0.68 (0.39,1.19)0.81 (0.54,1.22)20 mg1 (ref.)1 (ref.)1 (ref.) Citation Format: Per Hall, Mikael Eriksson, Kamila Czene. Low dose tamoxifen for breast cancer prevention and mammographic density reduction - a randomized controlled trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-41.

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

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

Adjuvant Therapy and Mammographic Density Changes in Women With Breast Cancer.

BackgroundTamoxifen decreases mammographic density. Whether compliance affects this relationship is unclear as is the relationship between other types of adjuvant treatment and changes in mammographic density.MethodsThis prospective cohort study included 2490 women diagnosed with breast cancer during 2001–2015 in Sweden. Mammographic density was assessed within 3 months of diagnosis and 6–36 months post diagnosis. Logistic regression was performed to study the association between each respective adjuvant treatment and mammographic density reduction (annual dense area decrease >15%).ResultsIntention-to-treat analyses using treatment information from the regional cancer registries showed that tamoxifen-treated patients more frequently experienced mammographic density reductions compared with nontreated patients (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.25 to 1.99), as did chemotherapy-treated patients (OR = 1.28, 95% CI = 1.06 to 1.54). For chemotherapy, the association was mainly seen in premenopausal women. Neither aromatase inhibitors nor radiotherapy was associated with density change. Tamoxifen use based on prescription and dispensation data from the Swedish Prescribed Drug Register showed that users were more likely to have density reductions compared with nonusers (adjusted OR = 2.24, 95% CI = 1.40 to 3.59). Moreover, among tamoxifen users, tamoxifen continuers were more likely than discontinuers to experience density reductions (adjusted OR = 1.50, 95% CI = 1.04 to 2.17).ConclusionsOur results indicate that adherence influences the association between tamoxifen and mammographic density reduction. We further found that chemotherapy was associated with density reductions and propose that this is largely secondary to chemotherapy-induced ovarian failure.

Abstract 3262: Biomarkers of response to deslorelin in women at high risk of breast cancer

Abstract Women with BRCA1 or BRCA2 mutations have a high breast cancer (BC) risk. Breast density is an independent biomarker of BC risk. We demonstrated that deslorelin (D), a gonadotropin-releasing hormone agonist (GnRHA), reduced mammographic breast density among BRCA1 carriers (Weitzel, CCR 2007). We report here on correlative studies in a Phase II chemoprevention study of intranasal D plus low-dose add-back estradiol and testosterone for 10 months in 10 premenopausal high-risk women. Pre- and post-study measures included mammographic and MRI breast density; serum hormone levels; breast tissue gene expression by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array; Q-PCR to validate the top genes; analysis of sera by 2D-PAGE and LC-MS/MS Mass Spectrometry, validated by a marker specific ELISA. Nine of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammographic density of 31.9% (p=0.0033). The top five differentially expressed genes in breast tissue were: FOS, EGR1, FABP3, COL3A1 and COL1A1. From seven protein spots up-regulated following treatment, 65 sera proteins were initially identified as response biomarkers, with two of these, adiponectin and Vitamin D-binding protein, predicted by Ingenuity Pathway Analyses (IPA) to have a direct role in reducing breast density by possibly altering stromal and epithelial tissue viability and fat metabolism. FOS was identified through IPA in the Vitamin D-binding protein network and both COL3A1 and COL1A1 were identified in the adiponectin network. Of the nine subjects two had an increase of ≥ 5% BMI and two had a decrease of ≥ 5% BMI. There was no significant correlation between adiponectin level changes and BMI changes.Tissue micro-array gene expression and proteomic analyses of sera identified changes in biomarkers that correlated with reduced breast density among young high-risk women receiving a GnRHA-based chemoprevention regimen. Pre/Post Human Serum Adiponectin LevelsA_Pre: 0 MB_ Post: 10 MFold (Post/Pre)Log A (0M)Log B (10M)T-Test (p) pairedS10.4630.3860.835-0.335-0.4130.014S20.3760.4131.097-0.425-0.385S30.2620.3671.403-0.583-0.435S40.6640.8021.209-0.178-0.096S50.2450.6082.487-0.612-0.216S60.3150.7552.399-0.502-0.122S70.4130.7991.936-0.385-0.098S80.5750.6461.123-0.240-0.190S90.4360.7331.680-0.361-0.135Average1.574224 Citation Format: Jeffrey N. Weitzel, Michael F. Press, Sharon R. Sand, Lei Zhang, Catherine Klifa, Malcolm Pike, Giske Ursin, Darcy V. Spicer, AnnaMarie Daniels, Josef Herzog, Yunan Miao, Gerald Wuenschell, Chun Li, Robert Hickey. Biomarkers of response to deslorelin in women at high risk of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3262.

RAZOR: A Phase II Open Randomized Trial of Screening Plus Goserelin and Raloxifene Versus Screening Alone in Premenopausal Women at Increased Risk of Breast Cancer

Background: Ovarian suppression in premenopausal women is known to reduce breast cancer risk. This study aimed to assess uptake and compliance with ovarian suppression using the luteinizing hormone releasing hormone (LHRH) analogue, goserelin, with add-back raloxifene, as a potential regimen for breast cancer prevention.Methods: Women at ≥30% lifetime risk breast cancer were approached and randomized to mammographic screening alone (C-Control) or screening in addition to monthly subcutaneous injections of 3.6 mg goserelin and continuous 60 mg raloxifene daily orally (T-Treated) for 2 years. The primary endpoint was therapy adherence. Secondary endpoints were toxicity/quality of life, change in bone density, and mammographic density.Results: A total of 75/950 (7.9%) women approached agreed to randomization. In the T-arm, 20 of 38 (52%) of women completed the 2-year period of study compared with the C-arm (27/37, 73.0%). Dropouts were related to toxicity but also the wish to have established risk-reducing procedures and proven chemoprevention. As relatively few women completed the study, data are limited, but those in the T-arm reported significant increases in toxicity and sexual problems, no change in anxiety, and less cancer worry. Lumbar spine bone density declined by 7.0% and visually assessed mammographic density by 4.7% over the 2-year treatment period.Conclusions: Uptake is somewhat lower than comparable studies with tamoxifen for prevention with higher dropout rates. Raloxifene may preserve bone density, but reduction in mammographic density reversed after treatment was completed.Impact: This study indicates that breast cancer risk reduction may be possible using LHRH agonists, but reducing toxicity and preventing bone changes would make this a more attractive option. Cancer Epidemiol Biomarkers Prev; 27(1); 58-66. ©2017 AACR.

Mammographic Density Reduction as a Prognostic Marker for Postmenopausal Breast Cancer: Results Using a Joint Longitudinal-Survival Modeling Approach.

Previous studies have linked reductions in mammographic density after a breast cancer diagnosis to an improved prognosis. These studies focused on short-term change, using a 2-stage process, treating estimated change as a fixed covariate in a survival model. We propose the use of a joint longitudinal-survival model. This enables us to model long-term trends in density while accounting for dropout as well as for measurement error. We studied the change in mammographic density after a breast cancer diagnosis and its association with prognosis (measured by cause-specific mortality), overall and with respect to hormone replacement therapy and tamoxifen treatment. We included 1,740 women aged 50–74 years, diagnosed with breast cancer in Sweden during 1993–1995, with follow-up until 2008. They had a total of 6,317 mammographic density measures available from the first 5 years of follow-up, including baseline measures. We found that the impact of the withdrawal of hormone replacement therapy on density reduction was larger than that of tamoxifen treatment. Unlike previous studies, we found that there was an association between density reduction and survival, both for tamoxifen-treated women and women who were not treated with tamoxifen.

Abstract IA11: Life course epidemiology and breast cancer: translating risk into prevention

Abstract Molecular histology may be conceptualized as the microscopic and molecular characteristics of normal tissues that are required for physiologic function. Over the life course, the molecular histology of the breast changes in response to physiological alterations, imparting spatial and temporal heterogeneity within the breasts of individuals and among women. These transitions contribute to the enormous range and imprecisely defined limits of what pathologists consider normal. Appreciation that molecular histology may reflect the cumulative influence of prior exposures linked to breast cancer risk, and may provide information about risk of developing breast cancer in the future, has stimulated interest in this topic. Unlike the study of breast cancer or its precursors, which represents a focal pathophysiologic deviation from normal, molecular histology, if assessable, would represent the state of the entire at-risk organ, based upon examination of a small tissue sample. The adult breast is characterized by well-developed terminal duct lobular units (TDLUs), which comprise the functional unit of milk production and represent the source of nearly all breast cancer precursors. Physiological changes in human breasts are likely driven by paracrine mechanisms, suggesting that tissue context and cellular topography are critical elements in physiology and pathophysiology. The breast undergoes profound changes with completion of childbearing and aging. Age-related TDLU involution may be conceptualized as a protective mechanism that lowers breast cancer risk following completion of childbearing, and in this context, delayed or incomplete involution is a breast cancer risk factor. With aging, the percent of the breast comprised of fibroglandular tissue declines, which is associated with a reduction in mammographic density, a strong breast cancer risk factor. Mammographic density is also imperfectly correlated with epithelial content in the breast. Women with benign breast disease whose surrounding normal breast tissue does not undergo age-appropriate TDLU involution are at increased risk of developing breast cancer, and both breast density and TDLU involution are independent markers of breast cancer risk. However, an important challenge is to understand the markers and mechanisms that underlie breast involution with aging, including both the epithelial and non-epithelial components, and to learn why both density and TDLU content decline with aging as breast cancer incidence rises. The thesis of this presentation is that understanding the amount of epithelium at-risk, the insults it sustains and the mechanisms that lead to its elimination, persistence or expansion may provide a window into the development of integrative biomarkers of risk that can translate into improved screening and prevention. However, progress towards this goal is quite early. Citation Format: Mark E. Sherman. Life course epidemiology and breast cancer: translating risk into prevention. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA11.

Effect of mammographic density change on endocrine responsiveness independent of tumor biology associated with 21-gene recurrence score.

e12066Background: Mammographic density reduction is known to be a predictive marker for endocrine responsiveness in estrogen receptor (ER)-positive patients with breast cancer. Also, it is well est...

Abstract P5-12-01: Predicting the effect of tamoxifen on the breast: Change in measures of breast density, serum markers and SNPs

Abstract Body: Introduction In the IBIS I Prevention Trial we demonstrated that tamoxifen prevented breast cancer in women with greater than 9 % absolute reduction in visually assessed mammographic density over a 12-18 month period as assessed by an expert radiologist, RW (1). In this study we investigated: whether RW obtained similar results in a different group of women treated with tamoxifen; how other expert mammographic film readers with experience of density assessment (radiologists, advanced practitioner radiographers and a breast physician) estimated mammographic change; how visual change relates to change in automated measures of volumetric density; and whether we can predict change by serum markers or SNPs. Methods 105 women aged 33 to 46 at greater than 1 in 6 lifetime breast cancer risk completed one year’s treatment with tamoxifen. RW assessed mammographic percentage density in increments of 5% for baseline and one year mammograms. Two or three of a pool of eight readers estimated % density using a visual analogue scale (VAS). Percent change was also estimated using a computer-assisted thresholding technique (Cumulus). Change in volume of dense tissue (Quantra™ &amp; Volpara™) was measured. Changes in lipids, IGF1, insulin and relevant SNPs were measured to determine whether they predicted density change. Results. Estimates of change obtained by RW were broadly consistent with those from our previous study, as were those from Cumulus, but could not be replicated using estimates from the pooled results of VAS readers. Tamoxifen was associated with marked reductions of dense volume of the breast (Table 1) However the different methods were at best only moderately correlated with RW (r less than 0.6). Change in serum triglycerides significantly predicted density change as measured by RW but none of the other serum measures or SNPs did. Table 1 Numbers of women and percentage change in density measures after one year of tamoxifen% Density changeRW %changeOther radiologists %changeCumulus %change_____% Dense volume change^Quantra %changeVolpara %change40+001 40+15930+503 30+141020+12013 20+202010+35630 10+17260+498143 0+16190-4188 0-1615Number10510598 9899RW = Ruth Warren. CUMULUS was measured by JS, a trained operator of the software. * Percentage point change eg if density changed from 40% to 30% this was regarded as a 10% change.^ Reduction in dense volume expressed as a percentage of baseline dense volume. We used Quantra version 2.0 and Volpara version 1.4.5 Conclusions Whilst RW remained consistent with previous density estimation it was not possible to use a pool of other expert readers to predict change. Cumulus gave similar results to RW but is difficult to use in practice. There was good agreement between the two objective volumetric measures used (r=0.5) and since these are automated they may be suitable for clinical practice. However their relationship to the long term breast cancer preventative effect of tamoxifen needs to be established. Reference 1 Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. Cuzick J, Warwick J, Pinney E, Duffy JW, Cawthorn S, Howell A, Forbes JF, Warren RM. J Natl Cancer Inst. 2011 May 4; 103 (9): 744-52. Citation Format: Anthony Howell, Sue Astley, Elaine Harkness, Julia Wiseman, Jill Fox, Paula Stavrinos, Mary Wilson, Yit Lim, Valerie Reece, Ursula Beetles, Anil Jain, Jamie Sergeant, Jack Cuzick, Ruth Warren, Gareth Evans. Predicting the effect of tamoxifen on the breast: Change in measures of breast density, serum markers and SNPs [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 P5-12-01.

Change in breast density as a response to adjuvant endocrine treatment: An American cohort.

e11523 Background: Anti-estrogen treatment is the cornerstone in adjuvant therapy of estrogen receptor (ER) positive breast cancer. Previous work has demonstrated that endocrine therapy (ET) reduces breast density on subsequent mammograms. Research from Korea and Sweden has shown that decreased mammographic density (MD) after ET is a positive prognostic marker for long-term survival. We seek to validate this finding in a North American cohort. Methods: We identified 102 patients treated at our institution with ER positive breast cancer from 2003-2006, with mammograms available in our system and an intact contralateral breast. MD was measured as percentage volume density using Volpara software (v. 1.2); MD reduction (MDR) was defined as Follow up MD - Baseline MD*100 / Baseline MD. Baseline MD was measured from a preoperative mammogram, and Follow up MD from mammograms taken 1-2 years after start of ET. Logistic regression analysis was performed with endpoint defined as locoregional or distant breast cance...

Mammographic Density Reduction Is a Prognostic Marker of Response to Adjuvant Tamoxifen Therapy in Postmenopausal Patients With Breast Cancer

Tamoxifen treatment is associated with a reduction in mammographic density and an improved survival. However, the extent to which change in mammographic density during adjuvant tamoxifen therapy can be used to measure response to treatment is unknown. Overall, 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up mammogram were eligible for analysis. On the basis of treatment information abstracted from medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic density was measured by using an automated thresholding method and expressed as absolute dense area. Change in mammographic density was calculated as percentage change from baseline. Survival analysis was performed by using delayed-entry Cox proportional hazards regression models, with death as a result of breast cancer as the end point. Analyses were adjusted for a range of patient and tumor characteristics. During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. Women treated with tamoxifen who experienced a relative density reduction of more than 20% between baseline and first follow-up mammogram had a reduced risk of death as a result of breast cancer of 50% (hazard ratio, 0.50; 95% CI, 0.27 to 0.93) compared with women with stable mammographic density. In the no-tamoxifen group, there was no statistically significant association between mammographic density change and survival. The survival advantage was not observed when absolute dense areas at baseline or follow-up were evaluated separately. A decrease in mammographic density after breast cancer diagnosis appears to serve as a prognostic marker for improved long-term survival in patients receiving adjuvant tamoxifen, and these data should be externally validated.

Abstract 2286: Short term reduction in mammographic density predicts survival in breast cancer.

Abstract Back ground: Identification of the factors that predict response to treatment in breast cancer patients early after diagnosis is important in guiding the treatment strategy. High mammographic density (MD) is a risk factor for breast cancer. However no study has examined the association between change in MD and death in breast cancer survivors. We hypothesized that a short-term change in breast density may be a surrogate biomarker predicting risk of death from breast cancer and all causes. Methods: We evaluated the relationship between reduction in MD and risk of death from all causes within the Health, Eating, Activity, and Lifestyle (HEAL) Study. In a prospective observational study, we studied 403 women diagnosed with primary invasive breast carcinoma between 1995 and 1998 and followed until death or September 2009. We collected mammograms and prognostic, demographic, and lifestyle factors as well as treatments at the time of diagnosis and two years after the diagnosis was made. Mammograms were digitized and MD was measured on cranio-caudal (CC) images of the unaffected breast using a computer assisted program developed at the University of Toronto. MD reduction (MDR) was evaluated based on two mammograms; the first was taken 12 months before diagnosis, and the second approximately 24 months after diagnosis. MDR was defined as the difference between the MD of these two images (% MDR = % preMD -% postMD). Reduction in MD was categorized into a binary variable as women who had a MDR ≥5% compared to those with less than 5% reduction in MD. Cox proportional hazards models were used to estimate the Hazard ratios and 95% confidence intervals. Results: Breast cancer patients with 5% or more reduction in MD were younger (mean age was 55.7 compared to 58.9), more likely to be premenopausal at diagnosis (36.7% compared to 24.0%), and more likely to have a history of oral contraception (73.9% compared to 63.3%). Women with MDR ≥5% were 49% less likely to die from any cause after adjustment for age, BMI, estrogen receptor status, progesterone receptor status, menopausal status at baseline, smoking, stage, tamoxifen use, chemotherapy, radiation therapy, and study center (HR=0.51 CI: 0.3-0.86). The results were stronger when we restricted the analysis to women who were premenopausal at diagnosis. When we restricted the analysis to women who had taken tamoxifen a similar direction was observed but the results were not statistically significant. Conclusion: Result from our data suggests that reduction in mammographic density few years after breast cancer diagnosis may be used as a predictor of overall survival. Citation Format: Ali Ozhand, Roberta Mckean-Cowdin, Leslie Bernstein, Rachel Ballard-Babash, Anne McTiernan, Kathy B. Baumgartner. Short term reduction in mammographic density predicts survival in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2286. doi:10.1158/1538-7445.AM2013-2286

Abstract 3557: Reduced ovarian hormones &amp; reduced mammographic &amp; MRI determined breast density in BRCA carriers following a hormonal chemo-prevention regimen of gonadotropin releasing hormone agonist (GnRHA) &amp; low-dose add-back estrogen &amp; testosterone

Abstract Young women at high risk of breast and/or ovarian cancer due to a BRCA mutation need risk-reducing options that preserve childbearing capacity. Purpose: Correlate changes in breast tissue determined by magnetic resonance imaging (MRI) &amp; mammography with ovarian hormone levels following GnRHA treatment. Methods: In this prospective phase 2 biomarker chemoprevention trial, 10 premenopausal high-risk women, mean age 29.4 (21-43), were treated with intranasal GnRHA (deslorelin), low-dose add-back estradiol &amp; testosterone once daily for 10 months. MPA was given for 10 days starting Day 140. Serum hormone levels were measured pre-administration of study drugs on Day 1, 29, 169 &amp; 300. All participants underwent mammography, breast MRI &amp; breast biopsy before &amp; after 300 days of treatment. Mammographic density was measured &amp; compared to volumetric breast density from MRI at both time points for all participants &amp; fibroglandular tissue volume was also determined. Results: Significant decreases (p &amp;lt; .05) were shown in estradiol (-61%) and testosterone (-41%) over time. Nine out of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammographic density of 31.9% (p=0.0033). Conclusion: Changes in breast tissue composition were significant after 10 months of hormonal chemoprevention, validating the proof of principle that density as a risk biomarker can be manipulated in BRCA carriers. We documented reduction in breast density by both mammographic and MRI assessment. While greater quantitative change in density was detected by mammography, MRI yields additional qualitative structural observations. Our findings confirm that MRI can be used to measure hormonal chemoprevention effects in women at high-risk of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3557. doi:1538-7445.AM2012-3557

Tamoxifen-Induced Reduction in Mammographic Density and Breast Cancer Risk Reduction: A Nested Case-Control Study

Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug. We conducted a nested case-control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12-18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided. In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction. The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.

Abstract P1-07-03: Effect of Exemestane on Mammographic Density in Postmenopausal Women at Risk for Breast Cancer

Abstract Background: A reduction in mammographic density(MD) has been associated with the reduction in breast cancer risk among those taking tamoxifen. Aromatase inhibitors (AIs) show promise for breast cancer prevention in postmenopausal women. We are conducting a phase II trial of exemestane in women at increased risk for breast cancer. The primary endpoint for this study is change in MD. Methods: Subjects were screened and enrolled at two sites: Center for Cancer Research, National Cancer Institute and Lombardi Comprehensive Cancer Center, Georgetown University Hospital. Eligible participants are at increased risk for breast cancer by virtue of: Gail model risk ≥1. 7% over 5 years; high risk pathological lesion (e.g. lobular neoplasia, ductal carcinoma in situ); known BRCA1/2 deleterious mutation or prior stage I/II breast cancer at least 2 years from breast cancer treatment and not treated with AIs. Women were excluded if AP spine T-score was &amp;lt;-2.5 (osteoporosis). Study participants received exemestane 25 mg, calcium carbonate 1200 mg and vitamin D 400 IU daily for two years. Mammograms were conducted at baseline, 1 and 2 years. MD was calculated using the semi-automated Cumulus software. The cranio-caudal view of one breast was selected for analysis. For patients who had had no prior surgery or radiation, the side with greater density at baseline was selected. For patients who had undergone significant breast surgery or radiation, mammograms of the unaffected side were selected. Percent MD was determined by one investigator (C.B.) who read each image twice and was masked to the subject's time on exemestane. The mean change in paired images was tested for a mean change of zero using the Wilcoxon signed rank test. As of June 2010, 42 women have enrolled in the trial and we have analyzed change in MD at one year in the first 22 subjects. Results:For the 22 subjects included in this analysis 15 were eligible due to a high risk pathological lesion, 4 by Gail Model and 3 by prior breast cancers. 18 had film screen mammograms at baseline and 12 months, 4 had film screen mammograms at baseline and digital mammogram at 12 months. Mammographic density declined 7% (p=0.0006, 95% CI −11% to −3%) at one year. The change in MD ranged from −26% to +14% and the standard deviation was 9%. In regard to the four subjects who had film screen mammograms at baseline and digital at follow up, the baseline percent dense areas were slightly higher than average but this did not reach statistical significance (p=0.32 by the Wilcoxon rank sum test). The 12 month MD comparison was similar to the 18 subjects with film images (p=0.90). Conclusions: Exemestane use was associated with a statistically significant decrease in MD at one year. Prior evaluations of AI therapy in high risk women have not shown a significant decline in MD, however time on treatment was shorter and other third generation AIs were used. Although the number of subjects is small, MD did not differ significantly between film screen and digital mammograms. We will further evaluate change in MD in the entire cohort at 1 and 2 years and between film screen and digital mammography. Phase III trials are on-going to evaluate the effect of exemestane on breast cancer prevention. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-03.

Mammographic density, lobular involution, and risk of breast cancer

In this review, we propose that age-related changes in mammographic density and breast tissue involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer. We propose that the reduction in mammographic density that occurs with increasing age, parity and menopause reflects the involution of breast tissue. We further propose that age-related changes in both mammographic density and breast tissue composition are observable and measurable phenomena that resemble Pike's theoretical construct of ‘breast tissue ageing’. Extensive mammographic density and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypothesis of the Pike model that cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence.