Influence of fat–water separation and spatial resolution on automated volumetric MRI measurements of fibroglandular breast tissue

The aim of this study was to investigate the influence of fat–water separation and spatial resolution in MRI on the results of automated quantitative measurements of fibroglandular breast tissue (FGT). Ten healthy volunteers (age range, 28–71 years; mean, 39.9 years) were included in this Institutional Review Board‐approved prospective study. All measurements were performed on a 1.5‐T scanner (Siemens, AvantoFit) using an 18‐channel breast coil. The protocols included isotropic (Di) [TR/TE₁/TE₂ = 6.00 ms/2.45 ms/2.67 ms; flip angle, 6.0°; 256 slices; matrix, 360 × 360; 1 mm isotropic; field of view, 360°; acquisition time (TA) = 3 min 38 s] and anisotropic (Da) (TR/TE₁/TE₂ = 10.00 ms/2.39 ms/4.77 ms; flip angle, 24.9°; 80 slices; matrix 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm³; field of view, 360°; TA = 1 min 25 s) T₁ three‐dimensional (3D) fast low‐angle shot (FLASH) Dixon sequences, and a T₁ 3D FLASH sequence with the same resolution (T₁) without (TR/TE = 11.00 ms/4.76 ms; flip angle, 25.0°; 80 slices; matrix, 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm³; field of view, 360°; TA = 50 s) and with (TR/TE = 29.00 ms/4.76 ms; flip angle, 25.0°; 80 slices; matrix, 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm³; field of view, 360°; TA = 2 min 35 s) fat saturation. Repeating volunteer measurements after 20 min and repositioning were used to assess reproducibility. An automated and quantitative volumetric breast density measurement system was used for FGT calculation. FGT with Di, Da and T₁ measured 4.6–63.0% (mean, 30.6%), 3.2–65.3% (mean, 32.5%) and 1.7–66.5% (mean, 33.7%), respectively. The highest correlation between different MRI sequences was found with the Di and Da sequences (R² = 0.976). Coefficients of variation (CVs) for FGT calculation were higher in T₁ (CV = 21.5%) compared with Dixon (Di, CV = 5.1%; Da, CV = 4.2%) sequences. Dixon‐type sequences worked well for FGT measurements, even at lower resolution, whereas the conventional T₁‐weighted sequence was more sensitive to decreasing resolution. The Dixon fat–water separation technique showed superior repeatability of FGT measurements compared with conventional sequences. A standard dynamic protocol using Dixon fat–water separation is best suited for combined diagnostic purposes and prognostic measurements of FGT. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of taxane‐based neoadjuvant chemotherapy on fibroglandular tissue volume and percent breast density in the contralateral normal breast evaluated by 3T MR

The aim of this study was to evaluate the change of breast density in the normal breast of patients receiving neoadjuvant chemotherapy (NAC). Forty‐four breast cancer patients were studied. MRI acquisition was performed before treatment (baseline), and 4 and 12 weeks after treatment. A computer‐algorithm‐based program was used to segment breast tissue and calculate breast volume (BV), fibroglandular tissue volume (FV), and percent density (PD) (the ratio of FV over BV × 100%). The reduction of FV and PD after treatment was compared with baseline using paired t‐tests with a Bonferroni–Holm correction. The association of density reduction with age was analyzed. FV and PD after NAC showed significant decreases compared with the baseline. FV was 110.0 ml (67.2, 189.8) (geometric mean (interquartile range)) at baseline, 104.3 ml (66.6, 164.4) after 4 weeks (p < 0.0001), and 94.7 ml (60.2, 144.4) after 12 weeks (comparison with baseline, p < 0.0001; comparison with 4 weeks, p = 0.016). PD was 11.2% (6.4, 22.4) at baseline, 10.6% (6.6, 20.3) after 4 weeks (p < 0.0001), and 9.7% (6.2, 17.9) after 12 weeks (comparison with baseline, p = 0.0001; comparison with 4 weeks, p = 0.018). Younger patients tended to show a higher density reduction, but overall correlation with age was only moderate (r = 0.28 for FV, p = 0.07, and r = 0.52 for PD, p = 0.0003). Our study showed that breast density measured from MR images acquired at 3T MR can be accurately quantified using a robust computer‐aided algorithm based on non‐parametric non‐uniformity normalization (N3) and an adaptive fuzzy C‐means algorithm. Similar to doxorubicin and cyclophosphamide regimens, the taxane‐based NAC regimen also caused density atrophy in the normal breast and showed reduction in FV and PD. The effect of breast density reduction was age related and duration related. Copyright © 2013 John Wiley & Sons, Ltd.     

Hormones and mammographic breast density

Mammographic density reveals information about the hormonal environment along with the heritability in which breast cancer develops. This is made possible by the widespread use of population screening by mammography. Increasingly this is an important observation not just for population studies, which reveal disease determinants, but also for the individual. Density reveals the effect of the intrinsic hormonal environment and its background genetics, and also the effect of pharmaceuticals--agents used for disease control and prevention and hormone replacement therapy (HRT) used for well-being around the menopause. Increasingly this focus on the individual will need methods of measurement of density that can be monitored with greater accuracy than the widely used BI-RADS 4 categories. For this purpose studies are under way to measure volume of dense tissue as a continuous variable. In due course, measurement of density will be used as a biomarker of risk, employed in risk models and to monitor interventions. Before this can happen more knowledge will be needed of the change occurring naturally through the menopause and the differences between individuals. This will need specific study backed up with detailed information about the patient on large numbers of women and their mammograms. Currently the widespread use of HRT has increased the prevalence of the dense patterns and potentially may adversely affect the effectiveness of mammographic screening programmes. There is a large literature recording this from which we see that combined continuous preparations of oestrogen progestin are more likely to cause increased density than oestrogen alone or tibolone. Breast density, measured more accurately, has the potential to be an important adjunct to risk estimation and to monitor interventions for breast cancer prevention with pharmaceuticals (such as SERMS) and by change in lifestyle behaviours.     

Postmenopausal hormone therapy and mammographic breast density

OBJECTIVE: The aim of this study was to evaluate the effects of different types of hormone replacement therapy (HRT) on mammographic density. MATERIALS AND METHODS: In a prospective 1-year study, 103 postmenopausal women were randomized to receive tibolone 2.5 mg/die, continuous conjugated equine estrogens 0.625 mg/die plus medroxyprogesterone acetate (MPA) 5mg/die or placebo. Mammograms were performed at baseline and after 12 months of treatment. Mammographic density was quantified according to the Wolfe classification. RESULTS: After 12 months of HRT 16 of the 35 patients (45.1%) receiving continuous combined hormonal therapy showed an increase of breast density change in the Wolfe classification. After treatment with tibolone, an up grading in breast density, according to Wolfe's classification, was found in 2 of the 43 patients (2.3%). No changes were recorded in the 25 patients of the control group. The difference between the group treated with continuous combined hormonal therapy and the control group was highly significant (p<0.001). The difference in breast density between patients in treatment with tibolone and the control group was not statistically significant (p=0.34). DISCUSSION: Continuous combination HRT may be more commonly associated with an increase of mammography density than tibolone treatment.     

Accuracy of fully automated,quantitative, volumetric measurement of the amount of fibroglandular breast tissue using MRI: correlation with anthropomorphic breast phantoms

To demonstrate the accuracy of fully automated, quantitative, volumetric measurement of the amount of fibroglandular breast tissue (FGT), using MRI, and to investigate the impact of different MRI sequences using anthropomorphic breast phantoms as the ground truth. In this study, 10 anthropomorphic breast phantoms that consisted of different known fractions of adipose and protein tissue, which closely resembled normal breast parenchyma, were developed. Anthropomorphic breast phantoms were imaged with a 1.5 T unit (Siemens, Avantofit) using an 18‐channel breast coil. The sequence protocol consisted of an isotropic Dixon sequence (Di), an anisotropic Dixon sequence (Da), and T₁ 3D FLASH sequences with and without fat saturation (T1). Fully automated, quantitative, volumetric measurement of FGT for all anthropomorphic phantoms and sequences was performed and correlated with the amounts of fatty and protein components in the phantoms as the ground truth. Fully automated, quantitative, volumetric measurements of FGT with MRI for all sequences ranged from 5.86 to 61.05% (mean 33.36%). The isotropic Dixon sequence yielded the highest accuracy (median 0.51%–0.78%) and precision (median range 0.19%) compared with anisotropic Dixon (median 1.92%–2.09%; median range 0.55%) and T₁‐weighted sequences (median 2.54%–2.46%; median range 0.82%). All sequences yielded good correlation with the FGT content of the anthropomorphic phantoms. The best correlation of FGT measurements was identified for Dixon sequences (Di, R² = 0.999; Da, R² = 0.998) compared with conventional T₁‐weighted sequences (R² = 0.971). MRI yields accurate, fully automated, quantitative, volumetric measurements of FGT, an increasingly important and sensitive imaging biomarker for breast cancer risk. Compared with conventional T₁ sequences, Dixon‐type sequences show the highest correlation and reproducibility for automated, quantitative, volumetric FGT measurements using anthropomorphic breast phantoms as the ground truth.     

Hormone therapy,mammographic density,and breast cancer risk

Percent mammographic density (PMD) is a strong independent risk factor for breast cancer. The effects of age, parity and menopause on PMD are consistent with it being a marker of susceptibility to breast cancer. In this review, we describe the association of PMD with breast cancer, the biological plausibility of this association, and discuss the extent to which PMD meets the criteria for a surrogate marker for the effects of exogenous hormones on risk of breast cancer.     

The effect of low dose hormone therapy on mammographic breast density

OBJECTIVES: To evaluate the effect of two standard and one low dose continuous hormone therapy regimens on mammography. METHODS: One hundred and thirty-two non-hysterectomized postmenopausal women were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=38), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, n=44) or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA, n=50). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month mammograms. RESULTS: Five (13.2%) women in the CEE/MPA group showed an increase in breast density. Fourteen (31.8%) women on E2/NETA and 6 (12.2%) on low E2/NETA treatment revealed an increase in breast density. No woman exhibited an involution of fibroglandular tissue. CONCLUSIONS: Different hormone therapy regimens have a variable impact on breast density probably depending on the steroid used. Low dose hormone therapy associates with significantly lesser increase in breast density.     

The effects of tibolone and oestrogen-based HT on breast cell proliferation and mammographic density

Tibolone is a tissue-selective compound used for the treatment of climacteric symptoms and the prevention of osteoporosis in post-menopausal women. In this review some in vitro data and clinical studies indicating that the effects of tibolone on breast tissue are different from those seen with oestrogen-based hormone therapy (HT) are briefly discussed. From a clinical perspective, an increase in mammographic density and breast cell proliferation should be regarded as an unwanted side-effect of HT. Efforts should therefore be made to define treatment regimens for post-menopausal women that have minimal effects on the breast but still maintain the many advantages of HT. Data suggest that tibolone may be such an alternative.     

Effect of compression paddle tilt correction on volumetric breast density estimation

For the acquisition of a mammogram, a breast is compressed between a compression paddle and a support table. When compression is applied with a flexible compression paddle, the upper plate may be tilted, which results in variation in breast thickness from the chest wall to the breast margin. Paddle tilt has been recognized as a major problem in volumetric breast density estimation methods. In previous work, we developed a fully automatic method to correct the image for the effect of compression paddle tilt. In this study, we investigated in three experiments the effect of paddle tilt and its correction on volumetric breast density estimation. Results showed that paddle tilt considerably affected accuracy of volumetric breast density estimation, but that effect could be reduced by tilt correction. By applying tilt correction, a significant increase in correspondence between mammographic density estimates and measurements on MRI was established. We argue that in volumetric breast density estimation, tilt correction is both feasible and essential when mammographic images are acquired with a flexible compression paddle.     

Computerized prediction of risk for developing breast cancer based on bilateral mammographic breast tissue asymmetry

This study developed and assessed a computerized scheme to detect breast abnormalities and predict the risk of developing cancer based on bilateral mammographic tissue asymmetry. A digital mammography database of 100 randomly selected negative cases and 100 positive cases for having high-risk of developing breast cancer was established. Each case includes four images of cranio-caudal (CC) and medio-lateral oblique (MLO) views of the left and right breast. To detect bilateral mammographic tissue asymmetry, a pool of 20 computed features was assembled. A genetic algorithm was applied to select optimal features and build an artificial neural network based classifier to predict the likelihood of a test case being positive. The leave-one-case-out validation method was used to evaluate the classifier performance. Several approaches were investigated to improve the classification performance including extracting asymmetrical tissue features from either selected regions of interests or the entire segmented breast area depicted on bilateral images in one view, and the fusion of classification results from two views. The results showed that (1) using the features computed from the entire breast area, the classifier yielded the higher performance than using ROIs, and (2) using a weighted average fusion method, the classifier achieved the highest performance with the area under ROC curve of 0.781 ± 0.023. At 90% specificity, the scheme detected 58.3% of high-risk cases in which cancers developed and verified 6–18 months later. The study demonstrated the feasibility of applying a computerized scheme to detect cases with high risk of developing breast cancer based on computer-detected bilateral mammographic tissue asymmetry.     

The effect of various regimens of hormone replacement therapy on mammographic breast density

OBJECTIVES: To evaluate the effect of three distinct hormone replacement therapy regimens on mammography. METHODS: 121 postmenopausal women who had never received or were past users of hormone replacement therapy were studied prospectively. Women with an intact uterus were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or to 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E(2)/NETA, n=35). Hysterectomized women received CEE 0.625 mg (CEE, n=25). Women who either declined or did not qualify for treatment served as controls (n=27). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month-mammograms. RESULTS: No increase in breast density was identified in any of the women in the control group. Two women (8%) in the CEE group showed an increase in breast density. Four women (11.8%) in the CEE/MPA and 11 women (31.4%) in the E(2)/NETA group revealed an increase in breast density. No woman in the therapy groups showed an involution of fibroglandular tissue while seven women (25.9%) in the control group exhibited involution of breast parenchyma. CONCLUSIONS: Our study suggests that hormone replacement therapy may suspend breast involution but does not increase breast density in the majority of patients. In the minority of patients who show a density increase, the magnitude of this increase varies according to the regimen employed.     

Clinical comparison of a novel breast DXA technique to mammographic density

We compare mammography breast density (BD(MD)) to the measure of breast composition using a clinical dual energy absorptiometry (DXA) system (BD(DXA)) calibrated to measure breast density. A DXA scanning protocol was developed to scan breasts isolated in the DXA scan field in either a prone pendulous or decubitus mediolateral position. A total of 17 participants were recruited among women undergoing clinical mammography examinations. Each participant had duplicate DXA scans and duplicate craniocaudal-view mammograms of their right breast with repositioning between each scan and one DXA and one craniocaudal-view mammogram of their left breast. The in vivo repeatability (RMS SD) of BD(DXA) and BD(MD) on duplicate scans was found to be 1.2% for BD(DXA) and 1.4% for BD(MD) when repeat BD(MD) measures were made on the same day. When repeat BD(MD) measures of the same breast were made more than 50 days apart, the repeatability decreased to 5.5%. Left and right breast measurements were highly correlated with both techniques at r2 = 0.98 for BD(DXA) and r2 = 0.86 for BD(MD). Moderate correlation (r2 = 0.52) was found between BD(DXA) and BD(MD) measurements. However, after recalibrating the DXA system to mammography reference materials, negative percent fibroglandular values were measured for the most fatty breasts. Thus, our results are reproducible and accurate to common mammography tissue standards, but did not accurately reflect true percent fibroglandular levels and further development of phantom standards are necessary. We conclude that breast composition can be precisely evaluated and assessed with clinical DXA densitometers at a lower dose than with mammographic breast density methods.     

A volumetric method for estimation of breast density on digitized screen-film mammograms

A method is described for the quantitative volumetric analysis of the mammographic density (VBD) from digitized screen-film mammograms. The method is based on initial calibration of the imaging system with a tissue-equivalent plastic device and the subsequent correction for variations in exposure factors and film processing characteristics through images of an aluminum step wedge placed adjacent to the breast during imaging. From information about the compressed breast thickness and technique factors used for taking the mammogram as well as the information from the calibration device, VBD is calculated. First, optical sensitometry is used to convert images to Log relative exposure. Second, the images are corrected for x-ray field inhomogeneity using a spherical section PMMA phantom image. The effectiveness of using the aluminum step wedge in tracking down the variations in exposure factors and film processing was tested by taking test images of the calibration device, aluminum step wedge and known density phantoms at various exposure conditions and also at different times over one year. Results obtained on known density phantoms show that VBD can be estimated to within 5% accuracy from the actual value. A first order thickness correction is employed to correct for inaccuracy in the compression thickness indicator of the mammography units. Clinical studies are ongoing to evaluate whether VBD can be a better indicator for breast cancer risk.