Changes In Mammographic Density Research Articles

Change in mammographic density across birth cohorts of Dutch breast cancer screening participants.

High mammographic density is a well‐known risk factor for breast cancer. This study aimed to search for a possible birth cohort effect on mammographic density, which might contribute to explain the increasing breast cancer incidence. We separately analyzed left and right breast density of Dutch women from a 13‐year period (2003–2016) in the breast cancer screening programme. First, we analyzed age‐specific changes in average percent dense volume (PDV) across birth cohorts. A linear regression analysis (PDV vs. year of birth) indicated a small but statistically significant increase in women of: 1) age 50 and born from 1952 to 1966 (left, slope = 0.04, p = 0.003; right, slope = 0.09, p < 0.0001); 2) age 55 and born from 1948 to 1961 (right, slope = 0.04, p = 0.01); and 3) age 70 and born from 1933 to 1946 (right, slope = 0.05, p = 0.002). A decrease of total breast volume seemed to explain the increase in PDV. Second, we compared proportion of women with dense breast in women born in 1946–1953 and 1959–1966, and observed a statistical significant increase of proportion of highly dense breast in later born women, in the 51 to 55 age‐groups for the left breast (around a 20% increase in each age‐group), and in the 50 to 56 age‐groups for the right breast (increase ranging from 27% to 48%). The study indicated a slight increase in mammography density across birth cohorts, most pronounced for women in their early 50s, and more marked for the right than for the left breast.

Abstract P2-06-01: The effect of a subcutaneous combination of testosterone (T) and anastrozole (Ai) (HAVAHT+Ai™) on volumetric mammographic breast density (MBD); an open labelled cohort study

Abstract MBD is the single greatest modifiable risk factor for the development of breast cancer; this risk can be lessened by reducing MBD. Previous studies suggest breast cancer risk is reduced in women treated with subcutaneous HAVAHT+Ai™. As well, HAVAHT+Ai™ has been suggested to be effective in managing hormone deprivation symptoms in women who have had breast cancer and in perimenopausal women with hormonal dysfunction. HAVAHT+Ai™alters the androgen/estrogen (A/E) ratio in breast tissue by delivering more bioavailable T in the presence of Ai to tissue known to contain high levels of 5alpha-reductase and aromatase, respectively facilitating production of the potent androgen dihydrotestosterone and diminishing conversion of T to estradiol. Alteration of the A/E ratio in favor of an androgenic environment reduces MBD. This study evaluates the effect of HAVAHT+Ai™on volumetric MBD. Methods: 652 women attending Wellend Health Clinic (a clinic that manages perimenopausal symptoms and/or high risk of breast cancer) received HAVAHT+Ai™and evaluated for MBD change as determined by a fully-automated volumetric density analysis (VolparaDensity™). Women received a HAVAHT+Ai™subcutaneous implant every 3-4 month containing 1mg/kg T and a fixed dose of Ai 1-4mg. 142 women had 2 or more mammograms within the analysis period and were included in the final analysis. A restricted analysis set (RAS) of 89 of these women were compared with a matched 65 women undergoing mammographic screening for high risk, but not receiving hormonal therapy. Safety and tolerability data were collected and analyzed. Results: Least squares mean estimated (LSME) change in % volumetric breast density (%VBD), by cumulative testosterone dose and time from first implant. table 1Cumulative testosterone doseTime from first implant (yrs)LSME (%)Lower 95% CIUpper 95% CIp-value500 - &amp;lt;700mg1-1.13-2.420.170.087500 - &amp;lt;700mg2-1.69-3.01-0.380.012500 - &amp;lt;700mg3-2.26-4.23-0.290.025700+mg1-1.87-3.62-0.120.036700+mg2-2.34-3.88-0.790.003700+mg3-2.80-4.66-0.950.003 LSME change in absolute mammographic breast density (AVBD), by cumulative testosterone dose and time from first implant. table 2Cumulative testosterone doseTime from first implant (yrs)LSME (cm3)Lower 95% CIUpper 95% CIp-value500 - &amp;lt;700mg10.3-12.312.80.965500 - &amp;lt;700mg2-4.2-19.811.40.595500 - &amp;lt;700mg3-8.7-34.116.70.499700+mg1-7.8-26.310.70.405700+mg2-22.0-39.5-4.50.014700+mg3-36.2-59.7-12.70.003 Comparison with control group:Analysis of RAS (n=89) versus untreated controls (N=65) revealed statistically significantly different from zero for both %VBD and AVBD between the 2 groups, respectively 2.36%, (95% CI on the difference, from 1.15 to 3.56) and 18.0cm3, (95% CI on the difference, from 4.8 cm3 to 31.1cm3). Summary of safety: The treatment was well tolerated with no serious adverse events. Conclusions: HAVAHT+Ai™ therapy significantly reduces volumetric MBD with good safety and tolerability. An accumulative dose of greater than 700mg of T and 30mg of Ai over 2-3 years is required to achieve a similar reduction in MBD as that demonstrated with tamoxifen as a preventative agent for breast cancer. Citation Format: Birrell SN, Dougherty D, Good SB, Birrell NJ, Rolan P. The effect of a subcutaneous combination of testosterone (T) and anastrozole (Ai) (HAVAHT+Ai™) on volumetric mammographic breast density (MBD); an open labelled cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-01.

A Longitudinal Study of the Association between Mammographic Density and Gene Expression in Normal Breast Tissue

High mammographic density (MD) is associated with a 4–6 times increase in breast cancer risk. For post-menopausal women, MD often decreases over time, but little is known about the underlying biological mechanisms. MD reflects breast tissue composition, and may be associated with microenvironment subtypes previously identified in tumor-adjacent normal tissue. Currently, these subtypes have not been explored in normal breast tissue. We obtained biopsies from breasts of healthy women at two different time points several years apart and performed microarray gene expression analysis. At time point 1, 65 samples with both MD and gene expression were available. At time point 2, gene expression and MD data were available from 17 women, of which 11 also had gene expression data available from the first time point. We validated findings from our previous study; negative correlation between RBL1 and MD in post-menopausal women, indicating involvement of the TGFβ pathway. We also found that breast tissue samples from women with a large decrease in MD sustained higher expression of genes in the histone family H4. In addition, we explored the previously defined active and inactive microenvironment subtypes and demonstrated that normal breast samples of the active subtype had characteristics similar to the claudin-low breast cancer subtype. Breast biopsies from healthy women are challenging to obtain, but despite a limited sample size, we have identified possible mechanisms relevant for changes in breast biology and MD over time that may be of importance for breast cancer risk and tumor initiation.

Growth factor genes and change in mammographic density after stopping combined hormone therapy in the California Teachers Study

BackgroundThe contribution of genetic polymorphisms to the large inter-individual variation in mammographic density (MD) changes following starting and stopping use of estrogen and progestin combined therapy (EPT) has not been well-studied. Previous studies have shown that circulating levels of insulin-like growth factors are associated with MD and cross-talk between estrogen signaling and growth factors is necessary for cell proliferation in the breast. We evaluated single nucleotide polymorphisms (SNPs) in growth factor genes in association with MD changes after women stop EPT use.MethodsWe genotyped 191 SNPs in 13 growth factor pathway genes in 284 non-Hispanic white California Teachers Study participants who previously used EPT and collected their mammograms before and after quitting EPT. Percent MD was assessed using a computer-assisted method. Change in percent MD was calculated by subtracting percent MD of an ‘off-EPT’ mammogram from percent MD of an ‘on-EPT’ (i.e. baseline) mammogram. We used multivariable linear regression analysis to investigate the association between SNPs and change in percent MD. We calculated P-values corrected for multiple testing within a gene (Padj).ResultsRs1983210 in INHA and rs35539615 in IGFBP1/3 showed the strongest associations. Per minor allele of rs1983210, the absolute change in percent MD after stopping EPT use decreased by 1.80% (a difference in absolute change in percent MD) (Padj= 0.021). For rs35539615, change in percent MD increased by 1.79% per minor allele (Padj= 0.042). However, after applying a Bonferroni correction for the number of genes tested, these associations were no longer statistically significant.ConclusionsGenetic variation in growth factor pathway genes INHA and IGFBP1/3 may predict longitudinal MD change after women quit EPT. The observed differences in EPT-associated changes in percent MD in association with these genetic polymorphisms are modest but may be clinically significant considering that the magnitude of absolute increase in percent MD reported from large clinical trials of EPT ranged from 3% to 7%.

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.

Mammographic density changes in surgical weight loss-an indication for personalized screening

BackgroundObesity and high radiologic breast density independently increase breast cancer risk. We evaluated the effect of surgical weight loss on mammographic density (MD).MethodsPatients undergoing bariatric surgery and screening mammography (MG) were identified, data regarding demographics, comorbidities, calculated and genetic breast cancer risk was collected. Patients had a MG before and after surgery. Fellowship-trained breast radiologists assigned Breast Imaging Reporting and Data System density categories.ResultsPatients underwent sleeve gastrectomy (n = 56) or gastric bypass (n = 7), 78% had hypertension, 48% had diabetes. Four had deleterious BRCA mutations, four were calculated high risk. Mean weight loss = 28.7 kg. Mean initial BMI = 44.3 kg/m2 (range:33–77), final BMI = 33.6 kg/m2 (range:20–62;p < 0.01). Density was unchanged in 53, decreased in 1, increased in 9. Of these 9(14%), 5 changed from almost entirely fatty to scattered MD, and 4 changed from scattered MD to heterogeneously dense. Mean weight loss of the 9 with increased MD was greater than the cohort (37.7vs.28.7 kg;p < 0.01).ConclusionsSurgical weight loss increased MD in 14%. Increased MD masks malignancies, patients may benefit from additional screening based on calculated risk assessments that include MD.

Mammographic density changes following discontinuation of tamoxifen in premenopausal women with oestrogen receptor-positive breast cancer.

To evaluate the changes in mammographic density after tamoxifen discontinuation in premenopausal women with oestrogen receptor-positive breast cancers and the underlying factors METHODS: A total of 213 consecutive premenopausal women with breast cancer who received tamoxifen treatment after curative surgery and underwent three mammograms (baseline, after tamoxifen treatment, after tamoxifen discontinuation) were included. Changes in mammographic density after tamoxifen discontinuation were assessed qualitatively (decrease, no change, or increase) by two readers and measured quantitatively by semi-automated software. The association between % density change and clinicopathological factors was evaluated using univariate and multivariate regression analyses. After tamoxifen discontinuation, a mammographic density increase was observed in 31.9% (68/213, reader 1) to 22.1% (47/213, reader 2) by qualitative assessment, with a mean density increase of 1.8% by quantitative assessment compared to density before tamoxifen discontinuation. In multivariate analysis, younger age (≤ 39 years) and greater % density decline after tamoxifen treatment (≥ 17.0%) were independent factors associated with density change after tamoxifen discontinuation (p < .001 and p = .003, respectively). Tamoxifen discontinuation was associated with mammographic density change with a mean density increase of 1.8%, which was associated with younger age and greater density change after tamoxifen treatment. • Increased mammographic density after tamoxifen discontinuation can occur in premenopausal women. • Mean density increase after tamoxifen discontinuation was 1.8%. • Density increase is associated with age and density decrease after tamoxifen.

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.

A comprehensive tool for measuring mammographic density changes over time

BackgroundMammographic density is a marker of breast cancer risk and diagnostics accuracy. Density change over time is a strong proxy for response to endocrine treatment and potentially a stronger predictor of breast cancer incidence. We developed STRATUS to analyse digital and analogue images and enable automated measurements of density changes over time.MethodRaw and processed images from the same mammogram were randomly sampled from 41,353 healthy women. Measurements from raw images (using FDA approved software iCAD) were used as templates for STRATUS to measure density on processed images through machine learning. A similar two-step design was used to train density measures in analogue images. Relative risks of breast cancer were estimated in three unique datasets. An alignment protocol was developed using images from 11,409 women to reduce non-biological variability in density change. The protocol was evaluated in 55,073 women having two regular mammography screens. Differences and variances in densities were compared before and after image alignment.ResultsThe average relative risk of breast cancer in the three datasets was 1.6 [95% confidence interval (CI) 1.3–1.8] per standard deviation of percent mammographic density. The discrimination was AUC 0.62 (CI 0.60–0.64). The type of image did not significantly influence the risk associations. Alignment decreased the non-biological variability in density change and re-estimated the yearly overall percent density decrease from 1.5 to 0.9%, p < 0.001.ConclusionsThe quality of STRATUS density measures was not influenced by mammogram type. The alignment protocol reduced the non-biological variability between images over time. STRATUS has the potential to become a useful tool for epidemiological studies and clinical follow-up.

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 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.

Sample size and power determination when limited preliminary information is available

BackgroundWe describe a novel strategy for power and sample size determination developed for studies utilizing investigational technologies with limited available preliminary data, specifically of imaging biomarkers. We evaluated diffuse optical spectroscopic imaging (DOSI), an experimental noninvasive imaging technique that may be capable of assessing changes in mammographic density. Because there is significant evidence that tamoxifen treatment is more effective at reducing breast cancer risk when accompanied by a reduction of breast density, we designed a study to assess the changes from baseline in DOSI imaging biomarkers that may reflect fluctuations in breast density in premenopausal women receiving tamoxifen.MethodWhile preliminary data demonstrate that DOSI is sensitive to mammographic density in women about to receive neoadjuvant chemotherapy for breast cancer, there is no information on DOSI in tamoxifen treatment. Since the relationship between magnetic resonance imaging (MRI) and DOSI has been established in previous studies, we developed a statistical simulation approach utilizing information from an investigation of MRI assessment of breast density in 16 women before and after treatment with tamoxifen to estimate the changes in DOSI biomarkers due to tamoxifen.ResultsThree sets of 10,000 pairs of MRI breast density data with correlation coefficients of 0.5, 0.8 and 0.9 were simulated and generated and were used to simulate and generate a corresponding 5,000,000 pairs of DOSI values representing water, ctHHB, and lipid. Minimum sample sizes needed per group for specified clinically-relevant effect sizes were obtained.ConclusionThe simulation techniques we describe can be applied in studies of other experimental technologies to obtain the important preliminary data to inform the power and sample size calculations.

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk.

Estrogen plus progestin therapy increases both mammographic density and breast cancer incidence. Whether mammographic density change associated with estrogen plus progestin initiation predicts breast cancer risk is unknown. We conducted an ancillary nested case-control study within the Women's Health Initiative trial that randomly assigned postmenopausal women to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. Mammographic density was assessed from mammograms taken prior to and one year after random assignment for 174 women who later developed breast cancer (cases) and 733 healthy women (controls). Logistic regression analyses included adjustment for confounders and baseline mammographic density when appropriate. Among women in the estrogen plus progestin arm (97 cases/378 controls), each 1% positive change in percent mammographic density increased breast cancer risk 3% (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01 to 1.06). For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased 3.6-fold (95% CI = 1.52 to 8.56). The effect of estrogen plus progestin use on breast cancer risk (OR = 1.28, 95% CI = 0.90 to 1.82) was eliminated in this study, after adjusting for change in mammographic density (OR = 1.00, 95% CI = 0.66 to 1.51). We found the one-year change in mammographic density after estrogen plus progestin initiation predicted subsequent increase in breast cancer risk. All of the increased risk from estrogen plus progestin use was mediated through mammographic density change. Doctors should evaluate changes in mammographic density with women who initiate estrogen plus progestin therapy and discuss the breast cancer risk implications.

Abstract OT3-06-01: KARISMA, The karma intervention study. - A tamoxifen dose determination trial

Abstract Background: Breast cancer incidence is increasing throughout the world. Despite remarkable risk reducing effects demonstrated in preventive randomised endocrine trials; primary preventive strategies are scarcely part of clinical routine. Putative reasons for reluctance may be inadequate tools for identification of women at high risk of breast cancer and reluctance to prescribe pharmaceuticals with considerable side effects in the preventive setting. Trial Design: A randomized, double blinded, six-armed placebo controlled dose determination study to investigate the optimal dose of tamoxifen with the most favorable side effect spectra. To reduce the number of participants, costs and to shorten the trial period; change in mammographic density will be used as clinical outcome. After randomization and baseline mammography, women will be treated with placebo, 1mg, 2.5mg, 5mg, 10mg or 20mg of tamoxifen for six months where after a subsequent mammogram is performed. Eligibility criteria: 1) Attending the national Swedish mammography screening program, 2) Having a measurable mammographic density, i.e. ≥4.5 % density (volumetric) measured by Volpara. Specific aims: The primary aim is to identify the minimum dose of tamoxifen non-inferior in its ability to reduce mammographic density and with fewer side effects compared to 20 mg of tamoxifen. Secondarily, to study the associations between different doses of tamoxifen and changes in circulating levels of a number of proteins, lipids, hormones, and tamoxifen metabolites, including the impact of polymorphisms in the CYP2D6 gene. A translational aim is to study molecular changes in the healthy breast tissue as a result of tamoxifen exposure. Statistical Methods: Previous studies have shown that ∼ 50% of women treated with 20mg of tamoxifen have a reduction in density and respond to therapy. We therefore use the median density decrease in women treated with 20mg tamoxifen as the predefined response threshold. The primary efficacy endpoint is thus the proportion of responders that reaches this threshold. We will test for non-inferiority after treatment with placebo, 1mg, 2.5mg, 5mg, and 10mg compared to the group of women treated with 20mg tamoxifen. Per definition 50% of the women in the 20mg group are responders. The non-inferiority margin is defined to be 16.7 percentage points; that is the fraction of responders is not less than one third of the treated individuals (50% minus 16.7% = 33.3%).The null hypothesis is thus that the proportion of responders in women treated with placebo, 1mg, 2.5mg, 5mg, and 10mg is 33.3% or higher. Power calculations have determined a need of 1200 participants corresponding to 200 participants in each treatment arm. Present accrual and target accrual: The trial will start recruiting as of September 2016. Eligible women are identified from the Swedish mammographic screening cohort, i.e. women age 40-74 years invited for biennial screening. Contact information for people with a specific interest in the trial: Signe.Borgquist@med.lu.se &amp; Per.Hall@ki.se. Citation Format: Borgquist S, Eriksson M, Czene K, Hall P. KARISMA, The karma intervention study. - A tamoxifen dose determination trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-06-01.

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies.

Increased mammographic density (MD) has been shown beyond doubt to be a marker for increased breast cancer risk, though the underpinning pathobiology is yet to be fully elucidated. Estrogenic activity exerts a strong influence over MD, which consequently has been observed to change predictably in response to tamoxifen anti-estrogen therapy, although results for other selective estrogen receptor modulators and aromatase inhibitors are less consistent. In both primary and secondary prevention settings, tamoxifen-associated MD changes correlate with successful modulation of risk or outcome, particularly among pre-menopausal women; an observation that supports the potential use of MD change as a surrogate marker where short-term MD changes reflect longer-term anti-estrogen efficacy. Here we summarize endocrine therapy-induced MD changes and attendant outcomes and discuss both the need for outcome surrogates in such therapy, as well as make a case for MD as such a monitoring marker. We then discuss the process and steps required to validate and introduce MD into practice as a predictor or surrogate for endocrine therapy efficacy in preventive and adjuvant breast cancer treatment settings.

A5242 - Effects of Weight Loss on Mammographic Density Change Over 1 Year

A5242 - Effects of Weight Loss on Mammographic Density Change Over 1 Year

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...

The Effect of Atorvastatin on Breast Cancer Biomarkers in High-Risk Women.

Statins have the potential to reduce breast cancer incidence and recurrence as shown in both epidemiologic and laboratory studies. The purpose of this study was to evaluate the effect of a lipophilic statin, atorvastatin, on breast cancer biomarkers of risk [mammographic density (MD) and insulin growth factor 1 (IGF-1)] in high-risk premenopausal women.Premenopausal women at increased risk for breast cancer received either 40 mg of atorvastatin or placebo for 1 year. Biomarker assessment was performed prior to initiation and at completion of study medication. MD was determined using both Breast Imaging Reporting and Data System and the visual analogue scale. Serum IGF-1 was determined by ELISA assay at the end of the study.Sixty-three women were enrolled between December 2005 and May 2010. Sixteen (25%) women withdrew. The mean age of participants was 43 (range, 35-50), 100% were white, and the average body mass index (BMI) was 26.4. The statin group demonstrated a significant decrease in cholesterol and low-density lipoprotein (LDL), suggesting compliance with study medication. After accounting for BMI, there was no difference in change in MD between groups. There was a significant increase in serum IGF-1 in the statin group.In this multi-institutional randomized prospective clinical trial of premenopausal women at increased risk for breast cancer, we did not see an effect of atorvastatin on MD. Further investigation of statins may be warranted; however, design of prior trials and potential mechanism of action of the agent need to be considered in the design of future trials. Cancer Prev Res; 9(5); 379-84. ©2016 AACR.

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);