An overview of mammographic density and its association with breast cancer

In 2017, breast cancer became the most commonly diagnosed cancer among women in the US. After lung cancer, breast cancer is the leading cause of cancer-related mortality in women. The breast consists of several components, including milk storage glands, milk ducts made of epithelial cells, adipose tissue, and stromal tissue. Mammographic density (MD) is based on the proportion of stromal, epithelial, and adipose tissue. Women with high MD have more stromal and epithelial cells and less fatty adipose tissue, and are more likely to develop breast cancer in their lifetime compared to women with low MD. Because of this correlation, high MD is an independent risk factor for breast cancer. Further, mammographic screening is less effective in detecting suspicious lesions in dense breast tissue, which can lead to late-stage diagnosis. Molecular differences between dense and non-dense breast tissues explain the underlying biological reasons for why women with dense breasts are at a higher risk for developing breast cancer. The goal of this review is to highlight the current molecular understanding of MD, its association with breast cancer risk, the demographics pertaining to MD, and the environmental factors that modulate MD. Finally, we will review the current legislation regarding the disclosure of MD on a traditional screening mammogram and the supplemental screening options available to women with dense breast tissue.     

Risk of subsequent breast cancer in relation to characteristics of screening mammograms from women less than 50 years of age.

This investigation was conducted to assess the predictive value of calcifications and densities in mammograms from women <50 years of age for subsequent diagnosis of breast cancer. In a population-based study, prior screening mammograms taken before age 50 in 547 women with breast cancer and 472 controls were reviewed by a single radiologist. The relative risk (RR) of subsequent breast cancer increased with the percentage of the area of the mammogram that was mammographically dense [RR in succeeding quartiles of density = 1.0, 1.7 (1.1-2.6), 3.3 (2.2-5.0), and 4.0 (2.7-6.0)]; in relation to Wolfe parenchymal pattern class P2 [RR = 3.1 (2.2-4.3)] or DY [RR = 5.6 (3.2-10.0)]; and in relation to calcifications of class 1 (pleomorphic of any distribution) or class 2 (various morphological types that are regional, grouped, clustered, segmental, or linear in distribution) [RR = 3.0 (1.4-7.1), and 1.8 (1.2-2.6), respectively]. Women with radiographically dense mammograms and class 1 or 2 calcifications were at >10- and approximately 6-fold greater risk, respectively, than women with breasts of low density and no calcifications. Densities and parenchymal patterns were most strongly associated with breast cancer being diagnosed in the next 3 years. Class 1 and 2 calcifications were most strongly predictive of an increased risk in 3-6 years. Class 1 calcifications were strongly predictive of the breast in which the subsequent cancer occurred. Women <50 years of age with class 1 or 2 calcifications or mammographically dense breasts, or both, should receive high priority for further evaluation and regular breast cancer screening.     

Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers

BACKGROUND: Screening mammography is the best method to reduce mortality from breast cancer, yet some breast cancers cannot be detected by mammography. Cancers diagnosed after a negative mammogram are known as interval cancers. This study investigated whether mammographic breast density is related to the risk of interval cancer. METHODS: Subjects were selected from women participating in mammographic screening from 1988 through 1993 in a large health maintenance organization based in Seattle, WA. Women were eligible for the study if they had been diagnosed with a first primary invasive breast cancer within 24 months of a screening mammogram and before a subsequent one. Interval cancer case subjects (n = 149) were women whose breast cancer occurred after a negative or benign mammographic assessment. Screen-detected control subjects (n = 388) were diagnosed after a positive screening mammogram. One radiologist, who was blinded to cancer status, assessed breast density by use of the American College of Radiology Breast Imaging Reporting and Data System. RESULTS: Mammographic sensitivity (i.e., the ability of mammography to detect a cancer) was 80% among women with predominantly fatty breasts but just 30% in women with extremely dense breasts. The odds ratio (OR) for interval cancer among women with extremely dense breasts was 6.14 (95% confidence interval [CI] = 1.95-19.4), compared with women with extremely fatty breasts, after adjustment for age at index mammogram, menopausal status, use of hormone replacement therapy, and body mass index. When only those interval cancer cases confirmed by retrospective review of index mammograms were considered, the OR increased to 9.47 (95% CI = 2.78-32.3). CONCLUSION: Mammographic breast density appears to be a major risk factor for interval cancer.     

Mammographic Density: Potential as a Risk Factor and Surrogate Marker in the Clinical Setting

Mammographic breast density reflects the relative proportions of fat, connective, and epithelial tissue on the mammogram. Studied for over 30 years, breast density continues to be one of the strongest risk factors for all types of breast cancer. Recent evidence suggests breast density may be a useful surrogate marker for response to endocrine therapies and potentially, a marker of local recurrence as well. High density is also prevalent in the population, with 32 % of women estimated to have breasts over 50 % dense. Because of the importance and prevalence of breast density, state and federal governments have proposed or passed legislation to mandate physicians to provide information on a woman’s breast density, especially if increased. We review the evidence and clinical utility for mammographic breast density in context of breast cancer risk, outcomes, and response to therapy. Further, we describe the implications of high density for screening, and include a discussion of potential supplemental screening strategies for women with high density.     

Detection of malignant breast tumours in dense breast tissue: results of 99mTc-tetrofosmin scintimammography related to surgery.

AIMS: To assess the contribution of 99mTechnetium tetrofosmin (99mTc-TF) scintimammography for staging of breast lesions in patients with a suspicious or non-diagnostic mammogram to reduce unnecessary surgical procedures in future. METHODS: Fifty patients with suspicious physical examinations and/or mammography underwent 99mTc-TF breast imaging. RESULTS: Scintimammography with 99mTc-TF was positive in 37 patients (36 true positive, one false positive) and negative in 13 patients (12 true negative, one false negative). The detection of a malignant tumour by 99mTc-TF was independent of the density of the breast tissue. In 33 patients with a malignant breast tumour 99mTc-TF was diagnostic with respect to axillary status, but in four out of 19 patients with a histologically positive axillary lymph node status, tumour involvement remained undetected by scintigraphy. Moreover, in four patients, scintimammography revealed an additional discrete area of increased 99mTc-TF uptake, which proved to be second primary breast cancers. CONCLUSIONS: 99mTc-TF scintimammography appears to be an accurate diagnostic test in patients with a symptomatic breast lesion and a non-diagnostic mammogram, also in those patients with dense breast tissue. This procedure may also have potential for the detection of second primary breast cancers in an early stage.     

Role of Breast Tomosynthesis in Diagnosis of Breast Cancer for Japanese Women

Introduction: Mammography is the most basic modality in breast cancer imaging. However, the overlap ofbreast tissue depicted on conventional two-dimensional mammography (2DMMG) may create significant obstaclesto detecting abnormalities, especially in dense or heterogeneously dense breasts. In three-dimensional digital breasttomosynthesis (3DBT), tomographic images of the breast are reconstructed from multiple projections acquired atdifferent angles. It has reported that this technology allows the generation of 3D data, therefore overcoming thelimitations of conventional 2DMMG for Western women. We assessed the detectability of lesions by conventional2DMMG and 3DBT in diagnosis of breast cancer for Japanese women. Methods: The subjects were 195 breastsof 99 patients (median age of 48 years, range 34~82 years) that had been pathologically diagnosed with breastcancer from December 20, 2010 through March 31, 2011. Both conventional 2DMMG and 3DBT imaging wereperformed for all patients. Detectability of lesions was assessed based on differences in category class. Results:Of the affected breasts, 77 (75.5%) had lesions assigned to the same categories by 2DMMG and 3DBT. For 24(23.5%) lesions, the category increased in 3DBT indicating improvement in diagnostic performance comparedto 2DMMG. 3DBT improved diagnostic sensitivity for patients with mass, focal asymmetric density (FAD), andarchitectural distortion. However, 3DBT was not statistically superior in diagnosis of the presence or absence ofcalcification. Conclusions: In this study, 3DBT was superior in diagnosing lesions in form of mass, FAD, and/orarchitectural distortion. 3DBT is a novel technique that may provide a breakthrough in solving the difficultiesof diagnosis caused by parenchyma overlap for Japanese women.     

Growth factors and stromal matrix proteins associated with mammographic densities.

Extensive radiologically dense breast tissue is associated with a marked increase in breast cancer risk. To explore the biological basis for this association, we have examined the association of growth factors and stromal matrix proteins in breast tissue with mammographic densities. Ninety-two formalin-fixed paraffin blocks of breast tissues surrounding benign lesions were obtained, half from breasts with little or no density and half from breasts with extensive density, matched for age at biopsy. Sections were stained for cell nuclei, total collagen, the stromal matrix regulatory protein tissue metalloproteinase-3 (TIMP-3), and the growth factors, transforming growth factor-alpha and insulin-like growth factor (IGF-I). The area of immunoreactive staining was measured using quantitative microscopy. Breast tissue from subjects with extensive densities had a greater nuclear area (P = 0.007), as well as larger stained areas of total collagen (P = 0.003), TIMP-3 (P = 0.08), and IGF-I (P = 0.02) when compared with subjects with little breast density. Differences were greater for subjects less than 50 years of age. These data indicate that increased tissue cellularity, greater amounts of collagen, and increased IGF-I and TIMP-3 expression are found in tissue from mammographically dense breasts and suggest mechanisms that may mediate the associated increased risk of breast cancer.     

Mammographic breast density: effect on imaging and breast cancer risk

Mammographic breast density has been studied for more than 30 years. Greater breast density not only is related to decreased sensitivity of mammograms because of a masking effect but also is a major independent risk factor for breast cancer. This article defines breast density and reviews literature on quantification of mammographic density that is key to future clinical and research protocols. Important influences on breast density are addressed, including age, menopausal status, exogenous hormones, and genetics of density. Young women with dense breasts benefit from digital mammographic technique. The potential use of supplemental MRI and ultrasound screening techniques in high-risk women and women with dense breasts is explored, as are potential risk reduction strategies.     

PET probe-guided surgery

Intraoperative localization of PET-positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe. PET probe is a high-energy gamma probe designed to process the 511 keV photons of PET tracers. Intraoperative gamma probe performance is a function of radiopharmaceutical uptake, clearance kinetics, and probe engineering, all determining the target to background ratio (TBR) and detection threshold. A minimum TBR of 1.5:1 is needed in the operative field for the operating surgeon to be comfortable the differences between tumor tissue and normal adjacent tissue are real. Due to high-energy photon fluxes, achieving a satisfactory TBR intraoperatively is challenging and requires development of a clinically feasible PET-probe guided surgery protocol.     

New modalities in breast imaging: Digital mammography and magnetic resonance imaging

Summary Mammography is currently the only screening method available with proven capability to diagnose nonpalpable breast cancer. However, mammography does not detect all cancers. Cancers are more difficult to detect in radiographically dense breasts because lesions are obscured by breast tissue. Digital mammography and magnetic resonance imaging of the breast may minimize the problems associated with screening dense breasts. If these methods prove to be useful, more cancers could be detected at an earlier stage.     

Quantitative assessment of percent breast density: analog versus digital acquisition

Breast density is a moderate risk factor for breast cancer based on quantitative measurement of percent breast density from film-screen mammograms. In this study, percent breast density was determined using computer-assisted interactive thresholding software from sixty consecutive mammograms of women undergoing digital screening mammography with a prior film-screen mammogram obtained within the last two years. Observations were made regarding discrepancies in density readings. Percent breast density was significantly lower for digital mammograms (mean 32.2%) compared to analog mammograms (mean 40.3%) (p<0.0001). This was not significant for women with less than 20% breast density (range +0.3 to -2.7%), but larger differences were seen with increasing density (12.5-14.9% lower for >50% density). Differences in density readings between analog and digital mammography were largely observed to be due to better recognition of the skin line on digital mammograms resulting in inclusion of more subcutaneous fat. Difficulties with appropriate recognition of subcutaneous breast tissue and fatty tissue near the chest wall were present for both analog and digital mammography. In conclusion, percent breast density is significantly lower when the mammogram is acquired in digital format compared to film-screen, largely due to better recognition of the skin line with resultant inclusion of more subcutaneous fat. Breast cancer risk predictions based on computerized assessment of breast density may be underestimated when applied to digital mammography.     

Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50

Mammographic density is a strong risk factor for breast cancer but its underlying biology in healthy women is not well-defined. Using a novel collection of core biopsies from mammographically dense versus non-dense regions of the breasts of healthy women, we examined histologic and molecular differences between these two tissue types. Eligible participants were 40 + years, had a screening mammogram and no prior breast cancer or current endocrine therapy. Mammograms were used to identify dense and non-dense regions and ultrasound-guided core biopsies were performed to obtain tissue from these regions. Quantitative assessment of epithelium, stroma, and fat was performed on dense and non-dense cores. Molecular markers including Ki-67, estrogen receptor (ER) and progesterone receptor (PR) were also assessed for participants who had >0% epithelial area in both dense and non-dense tissue. Signed rank test was used to assess within woman differences in epithelium, stroma and fat between dense and non-dense tissue. Differences in molecular markers (Ki-67, ER, and PR) were analyzed using generalized linear models, adjusting for total epithelial area. Fifty-nine women, mean age 51 years (range: 40-82), were eligible for analyses. Dense tissue was comprised of greater mean areas of epithelium and stroma (1.1 and 9.2 mm(2) more, respectively) but less fat (6.0 mm(2) less) than non-dense tissue. There were no statistically significant differences in relative expression of Ki-67 (P = 0.82), ER (P = 0.09), or PR (P = 0.96) between dense and non-dense tissue. Consistent with prior reports, we found that mammographically dense areas of the breast differ histologically from non-dense areas, reflected in greater proportions of epithelium and stroma and lesser proportions of fat in the dense compared to non-dense breast tissue. Studies of both epithelial and stromal components are important in understanding the association between mammographic density and breast cancer risk.     

Digital volumetric measurement of mammographic density and the risk of overlooking cancer in Japanese women

Background

Breast density often affects cancer detection via mammography (MMG). Because of this, additional tests are recommended for women with dense breasts. This study aimed to reveal trends in breast density among Japanese women and determine whether differences in breast density differentially affected the detection of abnormalities via MMG.

Methods

We retrospectively analyzed 397 control women who underwent MMG screening as well as 269 patients who underwent surgery for breast cancer for whom preoperative MMG data were available. VolparaDensity? (Volpara), a three-dimensional image analysis software with high reproducibility, was used to calculate breast density. Breasts were categorized according to the volumetric density grade (VDG), a measure of the percentage of dense tissue. The associations between age, VDG, and MMG density categories were analyzed.

Results

In the control group, 78% of women had dense breasts, while in the breast cancer group, 87% of patients had dense breasts. One of 36 patients with non-dense breasts (2.7%) was classified as category 1 or 2 (C-1 or C-2), indicating that abnormal findings could not be detected by MMG. The proportion of patients with breast cancer who had dense breasts and were classified as C-1 or C-2 was as high as 22.3%.

Conclusions

The proportions of Japanese women with dense breasts were high. In addition, the false-negative rate for women with dense breasts was also high. Owing to this, Japanese women with dense breasts may need to commonly undergo additional tests to ensure detection of breast cancer in the screening MMG.

     

Previous pregnancy outcome and breast density (United States)

Objective: We evaluated the association of pre-term delivery (PTD), low birth weight (LBW), and fetal death with breast density by age at mammogram and years since birth. Methods: Subjects were women aged ≤55 years who had a screening mammogram between 1 June 1996 and 1 August 1997 in Seattle, Washington, and whose records were linked to their previous state birth (1 January 1968 to 1 August 1997) or fetal death (1/1/1984–8/1/1997) records. We used unconditional logistic regression, adjusting for age at mammogram, body mass index, age at first birth, and menopausal status, to calculate the odds of dense (extremely or heterogeneously dense by BI-RADS) (n=3593) versus fatty breasts (scattered fibroglandular tissue or almost entirely fat) (n=2378) for women with a prior PTD (<34, 34–36 versus ≥37 weeks gestation), LBW (<2500 versus ≥2500 g), or fetal death (stillborn 20 weeks gestation versus live birth). Results: The odds for denser breasts increased among women with PTD at <34 weeks gestation who were ≤45 years at time of mammogram (odds ratio (OR) and 95 confidence interval (CI)=2.8 (1.3–6.1)) and for whom <10 years had elapsed since pregnancy (OR=8.8 (1.7–45.8)). We observed similar increases in density among women with LBW (OR=3.3 (1.3–8.2)) when <10 years had elapsed. Conclusions: PTD and LBW may have a transitory effect on breast density.     

Interval breast cancer risk associations with breast density,family history and breast tissue aging

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first-degree family history by questionnaire, measured body mass index (BMI) and calculated age-adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age-adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer.     

A review of the cost-effectiveness of Tc-99m sestamibi scintimammography in diagnosis of breast cancer in Taiwanese women with indeterminate mammographically dense breast

In general, biopsy is the preferred management method for women with indeterminate mammographically dense breasts. In this review, we describe a decision analysis model comparing technetium-99m methoxyisobutylisonitrile (Tc-99m sestamibi) scintimammography and excisional biopsy as breast cancer evaluation strategies for hypothetical cohorts of estimated 16,000-40,000 women with indeterminate mammographic probability of malignancy because of mammographically dense breasts. In cost-effectiveness analysis, quantitative decision tree sensitivity analysis was used to compare the conventional excision biopsy alone strategy (strategy A) with decision strategy for screening with Tc-99m sestamibi scintimammography before excision biopsy (strategy B) after an indeterminate mammogram. Strategy B showed a cost saving of US dollars 649,600-1,624,000 in reducing the cost of unnecessary biopsies. The total cost of strategy B showed a cost saving of US dollars 123,075-307,776 compared to strategy A. The analysis data indicate that Tc-99m sestamibi scintimammography can save the cost of unnecessary biopsies in Taiwanese women with non-diagnostic mammogram because of mammographically dense breasts.     

Mammographic density and breast cancer after ductal carcinoma in situ

Women with ductal carcinoma in situ (DCIS) are at substantially increased risk for a second breast cancer, but few strong predictors for these subsequent tumors have been identified. We used Cox regression modeling to examine the association between mammographic density at diagnosis of DCIS of 504 women from the National Surgical Adjuvant Breast and Bowel Project B-17 trial and risk of subsequent breast cancer events. In this group of patients, mostly 50 years old or older, approximately 6.6% had breasts categorized as highly dense (i.e., > or =75% of the breast occupied by dense tissue). After adjusting for treatment with radiotherapy, age, and body mass index, women with highly dense breasts had 2.8 (95% confidence interval [CI] = 1.3 to 6.1) times the risk of subsequent breast cancer (DCIS or invasive), 3.2 (95% CI = 1.2 to 8.5) times the risk of invasive breast cancer, and 3.0 (95% CI = 1.2 to 7.5) times the risk of any ipsilateral breast cancer, compared with women with less than 25% of the breast occupied by dense tissue. Our results provide initial evidence that the risk of second breast cancers may be increased among DCIS patients with highly dense breasts.     

The relationship between terminal duct lobular unit features and mammographic density among Chinese breast cancer patients

Extensive mammographic density (MD), a well-established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low-risk population but with high prevalence of dense breasts. Diagnostic pre-treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI-RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm², span [μm], and acini count/TDLU) in benign tissues. Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI-RADS, c-d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 μm [SE = 24.6] vs. 393.8 μm [SE = 31.8]; p = 0.03), and greater acini count (OR_trend = 16.1; 95%CI = 4.08–63.1; p_trend < 0.0001) compared to those with non-dense breasts (BI-RADS, a-b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of “at-risk” epithelium.     

Mammographic features and subsequent risk of breast cancer: a comparison of qualitative and quantitative evaluations in the Guernsey prospective studies.

Mammographic features are known to be associated with breast cancer but the magnitude of the effect differs markedly from study to study. Methods to assess mammographic features range from subjective qualitative classifications to computer-automated quantitative measures. We used data from the UK Guernsey prospective studies to examine the relative value of these methods in predicting breast cancer risk. In all, 3,211 women ages > or =35 years who had a mammogram taken in 1986 to 1989 were followed-up to the end of October 2003, with 111 developing breast cancer during this period. Mammograms were classified using the subjective qualitative Wolfe classification and several quantitative mammographic features measured using computer-based techniques. Breast cancer risk was positively associated with high-grade Wolfe classification, percent breast density and area of dense tissue, and negatively associated with area of lucent tissue, fractal dimension, and lacunarity. Inclusion of the quantitative measures in the same model identified area of dense tissue and lacunarity as the best predictors of breast cancer, with risk increasing by 59% [95% confidence interval (95% CI), 29-94%] per SD increase in total area of dense tissue but declining by 39% (95% CI, 53-22%) per SD increase in lacunarity, after adjusting for each other and for other confounders. Comparison of models that included both the qualitative Wolfe classification and these two quantitative measures to models that included either the qualitative or the two quantitative variables showed that they all made significant contributions to prediction of breast cancer risk. These findings indicate that breast cancer risk is affected not only by the amount of mammographic density but also by the degree of heterogeneity of the parenchymal pattern and, presumably, by other features captured by the Wolfe classification.     

The need for supplemental breast cancer screening modalities: a perspective of population-based breast cancer screening programs in Japan

Purpose

This article discusses possible supplemental breast cancer screening modalities for younger women with dense breasts from a perspective of population-based breast cancer screening program in Japan.

Conclusion

Supplemental breast cancer screening modalities have been proposed to increase the sensitivity and detection rates of early stage breast cancer in women with dense breasts; however, there are no global guidelines that recommend the use of supplemental breast cancer screening modalities in such women. Also, no criterion standard exists for breast density assessment. Based on the current situation of breast imaging in Japan, the possible supplemental breast cancer screening modalities are ultrasonography, digital breast tomosynthesis, and breast magnetic resonance imaging. An appropriate population-based breast cancer screening program based on the balance between cost and benefit should be a high priority. Further research based on evidence-based medicine is encouraged. It is very important that the ethnicity, workforce, workflow, and resources for breast cancer screening in each country should be considered when considering supplemental breast cancer screening modalities for women with dense breasts.