Association of area- and volumetric-mammographic density and breast cancer risk in women of Asian descent: a case control study.

BACKGROUND: Mammographic density (MD) has been shown to be a strong and independent risk factor for breast cancer in women of European and Asian descent. However, the majority of Asian studies to date have used BI-RADS as the scoring method and none have evaluated area and volumetric densities in the same cohort of women. This study aims to compare the association of MD measured by two automated methods with the risk of breast cancer in Asian women, and to investigate if the association is different for premenopausal and postmenopausal women. METHODS: In this case-control study of 531 cases and 2297 controls, we evaluated the association of area-based MD measures and volumetric-based MD measures with breast cancer risk in Asian women using conditional logistic regression analysis, adjusting for relevant confounders. The corresponding association by menopausal status were assessed using unconditional logistic regression. RESULTS: We found that both area and volume-based MD measures were associated with breast cancer risk. Strongest associations were observed for percent densities (OR (95% CI) was 2.06 (1.42-2.99) for percent dense area and 2.21 (1.44-3.39) for percent dense volume, comparing women in highest density quartile with those in the lowest quartile). The corresponding associations were significant in postmenopausal but not premenopausal women (premenopausal versus postmenopausal were 1.59 (0.95-2.67) and 1.89 (1.22-2.96) for percent dense area and 1.24 (0.70-2.22) and 1.96 (1.19-3.27) for percent dense volume). However, the odds ratios were not statistically different by menopausal status [p difference = 0.782 for percent dense area and 0.486 for percent dense volume]. CONCLUSIONS: This study confirms the associations of mammographic density measured by both area and volumetric methods and breast cancer risk in Asian women. Stronger associations were observed for percent dense area and percent dense volume, and strongest effects were seen in postmenopausal individuals.

Initiators and promoters for the occurrence of screen-detected breast cancer and the progression to clinically-detected interval breast cancer.

BACKGROUND: The risk factors responsible for breast cancer have been well documented, but the roles of risk factors as initiators, causing the occurrence of screen-detected breast cancer, or promoters, responsible for the progression of the screen-detected to the clinically-detected breast cancer, have been scarcely evaluated. METHODS: We used data from women in a cohort in Kopparberg (Dalarna), Sweden between 1977 and 2010. Conventional risk factors, breast density, and tumor-specific biomarkers are superimposed to the temporal course of the natural history of the disease. RESULTS: The results show that older age at first full-term pregnancy, dense breast, and a family history of breast cancer increased the risk of entering the preclinical screen-detectable phase of breast cancer by 23%, 41%, and 89%, respectively. Overweight/obesity (body mass index ≥25 kg/m2) was a significant initiator (adjusted relative risk [aRR] 1.15; 95% confidence interval [CI], 0.99-1.33), but was inversely associated with the role of promoter (aRR 0.65; 95% CI, 0.51-0.82). Dense breast (aRR 1.46; 95% CI, 1.12-1.91), triple-negative (aRR 2.07; 95% CI, 1.37-3.15), and Ki-67 positivity (aRR 1.66; 95% CI, 1.19-2.30) were statistically significant promoters. When the molecular biomarkers were considered collectively as one classification, the basal-like subtype was the most influential subtype on promoters (aRR 4.24; 95% CI, 2.56-7.02) compared with the Luminal A subtype. DISCUSSION: We ascertained state-dependent covariates of initiators and promoters to classify the risk of the two-step progression of breast cancer. The results of the current study are useful for individually-tailored screening and personalized clinical surveillance of patients with breast cancer that was detected at an early stage.

Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study.

BACKGROUND: Ovarian stimulation drugs, in particular hormonal agents used for controlled ovarian stimulation (COS) required to perform in vitro fertilization, increase estrogen and progesterone levels and have therefore been suspected to influence breast cancer risk. This study aims to investigate whether infertility and hormonal fertility treatment influences mammographic density, a strong hormone-responsive risk factor for breast cancer. METHODS: Cross-sectional study including 43,313 women recruited to the Karolinska Mammography Project between 2010 and 2013. Among women who reported having had infertility, 1576 had gone through COS, 1429 had had hormonal stimulation without COS and 5958 had not received any hormonal fertility treatment. Percent and absolute mammographic densities were obtained using the volumetric method Volpara™. Associations with mammographic density were assessed using multivariable generalized linear models, estimating mean differences (MD) with 95 % confidence intervals (CI). RESULTS: After multivariable adjustment, women with a history of infertility had 1.53 cm(3) higher absolute dense volume compared to non-infertile women (95 % CI: 0.70 to 2.35). Among infertile women, only those who had gone through COS treatment had a higher absolute dense volume than those who had not received any hormone treatment (adjusted MD 3.22, 95 % CI: 1.10 to 5.33). No clear associations were observed between infertility, fertility treatment and percent volumetric density. CONCLUSIONS: Overall, women reporting infertility had more dense tissue in the breast. The higher absolute dense volume in women treated with COS may indicate a treatment effect, although part of the association might also be due to the underlying infertility. Continued monitoring of cancer risk in infertile women, especially those who undergo COS, is warranted.

Shearwave Elastography Increases Diagnostic Accuracy in Characterization of Breast Lesions.

The purpose of this study was to investigate the diagnostic efficacy of shearwave elastography (SWE) in differentiating between benign and malignant breast lesions.One hundred and fifty-nine lesions were assessed using B-mode ultrasound (US) and SWE parameters were recorded (Emax, Emean, Emin, Eratio, SD). SWE measurements were then correlated with histopathological diagnosis.The final sample contained 85 benign and 74 malignant lesions. The maximum stiffness (Emax) with a cutoff point of ≥ 56.0 kPa (based on ROC curves) provided sensitivity of 100.0%, specificity of 97.6%, positive predictive value (PPV) of 97.4%, and negative predictive value (NPV) of 100% in detecting malignant lesions. A cutoff of ≥80 kPa managed to downgrade 95.5% of the Breast Imaging-Reporting and Data System (BI-RADS) 4a lesions to BI-RADS 3, negating the need for biopsy. Using a combination of BI-RADS and SWE, the authors managed to improve the PPV from 2.3% to 50% in BI-RADS 4a lesions.SWE of the breast provides highly specific and sensitive quantitative values that are beneficial in the characterization of breast lesions. Our results showed that Emax is the most accurate value for differentiating benign from malignant lesions.

Mammographic Breast Density as a Predictor of Radiological Findings Requiring Further Investigation.

BACKGROUND: High density breast mammography has been associated with a greater risk for breast cancer and an increased likelihood of false negative results. OBJECTIVES: To assess whether the degree of mammographic breast density correlates with increased risk for the presence of radiographic findings requiring further histological investigation. METHODS: Included in the study were 2760 consecutive screening mammograms performed in a large volume, early detection mammography unit. All mammograms were complemented by high resolution ultrasound and interpreted by a single expert radiologist. Breast density (BD) was evaluated using a semi-quantitative 5 grade scale and grouped into low breast density (LBD) and high breast density (HBD) mammograms. Demographic and all relevant obstetric, personal and family history of breast cancer data were recorded. RESULTS: Of the 2760 mammograms 2096 (76%) were LBD and 664 (24%) were HBD. Mean age of the LBD and HBD groups was 59 ± 10.5 and 50.9 ± 9.3 years respectively (P = 0001). Breast density significantly correlated with presence of mammographic findings requiring further histological assessment (8.7% and 12.3% for LBD and HBD respectively, P < 0.01). In women younger than 60 years in whom histological assessment was required due to these findings, malignant pathology was significantly more prevalent in the HBD group (2.3% and 4.1% respectively, P = 0.03). Age, parity, patient history and HBD were identified as independent risk factors for any pathological mammographic finding. CONCLUSIONS: Highly dense mammography, aside from being an indicator of higher risk for breast cancer, appears to be associated with a significantly higher incidence of findings that will prompt further investigation to achieve a definite diagnosis.

Assessment of Interradiologist Agreement Regarding Mammographic Breast Density Classification Using the Fifth Edition of the BI-RADS Atlas.

OBJECTIVE: The objective of the present study was to assess interradiologist agreement regarding mammographic breast density assessment performed using the rating scale outlined in the fifth edition of the BI-RADS atlas of the American College of Radiology. MATERIALS AND METHODS: Breast density assessments of 1000 cases were conducted by five radiologists from the same institution who together had recently undergone retraining in mammographic breast density classification based on the fifth edition of BI-RADS. The readers assigned breast density grades (A-D) on the basis of the BI-RADS classification scheme. Repeat assessment of 100 cases was performed by all readers 1 month after the initial assessment. A weighted kappa was used to calculate intrareader and interreader agreement. RESULTS: Intrareader agreement ranged from a kappa value of 0.86 (95% CI, 0.77-0.93) to 0.89 (95% CI, 0.81-0.95) on a four-category scale (categories A-D) and from 0.89 (95% CI, 0.86-0.92) to 0.94 (95% CI, 0.89-0.97) on a two-category scale (category A-B vs category C-D). Interreader agreement ranged from substantial (κ = 0.76; 95% CI, 0.73-0.78) to almost perfect (κ = 0.87; 95% CI, 0.86-0.89) on a four-category scale, and the overall weighted kappa value was substantial (0.79; 95% CI, 0.78-0.83). Interreader agreement on a two-category scale ranged from a kappa value of 0.85 (95% CI, 0.83-0.86) to 0.91 (95% CI, 0.90-0.92), and the overall weighted kappa was 0.88 (95% CI, 0.87-0.89). CONCLUSION: Overall, with regard to mammographic breast density classification, radiologists had substantial interreader agreement when a four-category scale was used and almost perfect interreader agreement when a dichotomous scale was used.

TNRC9 rs12443621 and FGFR2 rs2981582 polymorphisms and breast cancer risk.

BACKGROUND: This study is to investigate the association of fibroblast growth factor receptor 2 (FGFR2) rs2981582, trinucleotide-repeat-containing 9 (TNRC9) rs3803662, rs12443621, and leukocyte-specific protein 1 (LSP1) rs3817198 polymorphisms with breast cancer and mammographic density in Han Chinese population. METHODS: TaqMan Single Nucleotide Polymorphism (SNP) Genotyping Assays and unconditional logistic regression analysis were used to examine these SNPs in 105 breast cancer cases and 382 controls. RESULTS: The genotype frequencies of rs12443621 and rs2981582 were significantly different between controls and cases (P=0.017 and 0.006, respectively). Subjects carrying G allele of rs12443621 had increased breast cancer risk (AG vs AA: OR=2.017, 95% CI=0.910-4.471; GG vs AA: OR=2.684, 95% CI=1.318-5.463). Subjects carrying an allele of rs2981582 had reduced breast cancer risk (GA vs GG: OR=0.444, 95% CI=0.262-0.752; AA vs GG: OR=0.579, 95% CI=0.342-0.983). rs3803662 and rs3817198 SNPs did not significantly differ between cases and controls (P=0.408 and 0.116, respectively). Interestingly, the AA genotype of rs2981582 was also associated with reduced mammographic densities (P=0.0092, 95% CI=0.334-0.926). CONCLUSIONS: Our findings indicate that the GG genotype of rs12443621 is associated with increased breast cancer risk whereas the GA and AA genotypes of rs2981582 are reduced risk in Han Chinese population.

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.

Alcohol intake from early adulthood to midlife and mammographic density.

PURPOSE: Moderate alcohol consumption (15 g/day) has been consistently associated with increased breast cancer risk; however, the association between alcohol and mammographic density, a strong marker of breast cancer risk, has been less consistent. Less is known about the effect of patterns of alcohol intake across the lifecourse. METHODS: Using the Early Determinants of Mammographic Density study, an adult follow-up of women born in two US birth cohorts (n = 697; Collaborative Perinatal Project in Boston and Providence sites and the Childhood Health and Development Studies in California), we examined the association between alcohol intake in early adulthood (ages 20-29 years) and at time of interview and mammographic density (percent density and total dense area). We report the difference between nondrinkers and three levels of alcohol intake. We considered confounding by age at mammogram, body mass index, geographic site, race/ethnicity, and reproductive characteristics. RESULTS: Seventy-nine percent of women reported ever consuming alcohol. Compared to nondrinkers in early adulthood, we observed an inverse association between >7 servings/week and percent density in fully adjusted models (ß = -5.1, 95% CI -8.7, -1.5; p for trend = <0.01). Associations with dense area were inverse for the highest category of drinking in early adulthood but not statistically significant (p for trend = 0.15). Compared to noncurrent drinkers, the association for current intake of >7 servings/week and percent density was also inverse (ß = -3.1, 95% CI -7.0, 0.8; p for trend = 0.01). In contrast, moderate alcohol intake (>0-≤7 servings/week) in either time period was positively associated with dense area; but associations were not statistically significant in fully adjusted models. CONCLUSIONS: Our study does not lend support to the hypothesis that the positive association between alcohol intake and breast cancer risk is through increasing mammographic density.

Assessing within-woman changes in mammographic density: a comparison of fully versus semi-automated area-based approaches.

BACKGROUND: Mammographic density (MD) varies throughout a woman's life. We compared the performance of a fully automated (ImageJ-based) method to the observer-dependent Cumulus approach in the assessment of within-woman changes in MD over time. METHODS: MD was assessed in annual pre-diagnostic films (from age 40 to early 50s) from 313 breast cancer cases and 452 matched controls using Cumulus (left medio-lateral oblique (MLO) readings) and the ImageJ-based method (mean left-right MLO readings). Linear mixed models were used to compare within-woman changes in MD among controls. Associations between individual-specific MD trajectories and breast cancer were examined using conditional logistic regression. RESULTS: The age-related trajectories predicted by Cumulus and the ImageJ-based method were similar for all MD measures, except that the ImageJ-based method yielded slightly higher (by 2.54%, 95% CI 2.07%, 3.00%) estimates for percent MD. For both methods, the yearly rate of change in percent MD was twice faster after menopause than before, and higher BMI was associated with lower mean percent MD, but not associated with rate of change. Both methods yielded similar associations of individual-specific MD trajectories with breast cancer risk. CONCLUSIONS: The ImageJ-based method is a valid fully automated alternative to Cumulus for measuring within-woman changes in MD in digitized films. The Age Trial is registered as an International Standard Randomized Controlled Trial, number ISRCTN24647151.

Selective magnetic resonance imaging (MRI) in invasive lobular breast cancer based on mammographic density: does it lead to an appropriate change in surgical treatment?

OBJECTIVE: The purpose of this study was to evaluate whether high mammographic density can be used as one of the selection criteria for MRI in invasive lobular breast cancer (ILC). METHODS: In our institute, high breast density has been used as one of the indications for performing MRI scan in patients with ILC. We divided the patients in two groups, one with MRI performed pre-operatively and other without MRI. We compared their surgical procedures and analyzed whether surgical plan was altered after MRI. In case of alteration of plan, we analyzed whether the change was adequate by comparing post-operative histological findings. RESULTS: Between 2011 and 2015, there were a total of 1601 breast cancers with 97 lobular cancers, out of which 36 had pre-operative MRI and 61 had no MRI scan. 12 (33.3%) had mastectomy following MRI, out of which 9 (25%) had change in surgical plan from conservation to mastectomy following MRI. There were no unnecessary mastectomies in the MRI group. However, utilization of MRI in this cohort of patients did not reduce reoperation rate (19.3%). Lobular carcinoma in situ (LCIS) was identified in 60% of reoperations on post-surgical histology. Patients in the "No MRI" group had higher mastectomy rate 26 (42.6%), which was again appropriate. CONCLUSION: High mammographic density is a useful risk stratification criterion for selective MRI in ILC within a multidisciplinary team meeting setting. Provided additional lesions identified on MRI are confirmed with biopsy, pre-operative MRI does not cause unnecessary mastectomies. Used in this selective manner, reoperation rates were not eliminated, albeit reduced when compared to literature. ADVANCES IN KNOWLEDGE: High mammographic breast density can be used as one of the selection criteria for pre-operative MRI in ILC without an increase in inappropriate mastectomies with potential time and cost savings. In this cohort, re-excisions were not reduced markedly with pre-operative MRI.

Mammographic breast density in infertile and parous women.

BACKGROUND: Mammographic breast density is a useful marker for breast cancer risk, as breast density is considered one of the strongest breast cancer risk factors. The study objective was to evaluate and compare mammographic breast density in infertile and parous women, as infertility may be associated with high breast density and cancer occurrence. METHODS: This study evaluated mammographic breast density using two different systems, BIRADS and Boyd. A selected patient population of 151 women with primary infertility (case group) was compared to 154 parous women who had at least one previous pregnancy (control group). Both groups were premenopausal women aged ≥ 35. RESULTS: Evaluation of mammographic features showed that 66.9% of case group patients and 53.9% of control group patients were classified BIRADS-3/BIRADS-4; p < 0.05. Adjusted Odds ratio for the case group in the categories BIRADS-3/BIRADS-4 was 1.78 (95% CI: 1.10-2.89). Using the Boyd classification system, 53.6% of case group patients and 31.8% of control group patients were classified E/F; p < 0.05. Adjusted Odds ratio for case group patients in Boyd categories E/F was 2.05 (95 % CI: 1.07-3.93). CONCLUSIONS: Both systems yielded a higher percentage of increased breast density in the case group. Boyd and BIRADS classification systems indicate to what extend breast cancer lesions may be missed on mammography due to masking by dense tissue. Therefore, patients with a high BIRADS or Boyd score should undergo further investigation.

Adolescent intake of animal fat and red meat in relation to premenopausal mammographic density.

Adolescence is hypothesized to be a time period of particular susceptibility to breast cancer risk factors. Red meat and fat intake during high school was positively associated with risk of breast cancer among premenopausal women in the Nurses' Health Study II (NHSII). High mammographic density is a strong predictor of breast cancer risk but there is limited research on dietary factors associated with breast density. To test the hypothesis that high intake of animal fat or red meat during adolescence is associated with mammographic density, we analyzed data from premenopausal women in the NHSII. Participants recalled adolescent diet on a high school food frequency questionnaire. We assessed absolute and percent mammographic density on digitized analog film mammograms for 687 premenopausal women with no history of cancer. We used generalized linear regression to quantify associations of adolescent animal fat and red meat intake with mammographic density, adjusting for age, body mass index, and other predictors of mammographic density. Adolescent animal fat intake was significantly positively associated with premenopausal mammographic density, with a mean percent density of 39.2 % in the lowest quartile of adolescent animal fat intake versus 43.1 % in the highest quartile (p trend: 0.03). A non-significant positive association was also observed for adolescent red meat intake (p trend: 0.14). These findings suggest that higher adolescent animal fat intake is weakly associated with percent mammographic density in premenopausal women.

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

Positive predictive values by mammographic density and screening mode in the Norwegian Breast Cancer Screening Program.

OBJECTIVE: To investigate the probability of breast cancer among women recalled due to abnormal findings on the screening mammograms (PPV-1) and among women who underwent an invasive procedure (PPV-2) by mammographic density (MD), screening mode and age. METHODS: We used information about 28,826 recall examinations from 26,951 subsequently screened women in the Norwegian Breast Cancer Screening Program, 1996-2010. The radiologists who performed the recall examinations subjectively classified MD on the mammograms into three categories: fatty (<30% fibroglandular tissue); medium dense (30-70%) and dense (>70%). Screening mode was defined as screen-film mammography (SFM) and full-field digital mammography (FFDM). We examined trends of PPVs by MD, screening mode and age. We used logistic regression to estimate odds ratio (OR) of screen-detected breast cancer associated with MD among women recalled, adjusting for screening mode and age. RESULTS: PPV-1 and PPV-2 decreased by increasing MD, regardless of screening mode (p for trend <0.05 for both PPVs). PPV-1 and PPV-2 were statistically significantly higher for FFDM compared with SFM for women with fatty breasts. Among women recalled, the adjusted OR of breast cancer decreased with increasing MD. Compared with women with fatty breasts, the OR was 0.90 (95% CI: 0.84-0.96) for those with medium dense breasts and 0.85 (95% CI: 0.76-0.95) for those with dense breasts. CONCLUSION: PPVs decreased by increasing MD. Fewer women needed to be recalled or undergo an invasive procedure to detect one breast cancer among those with fatty versus dense breasts in the screening program in Norway, 1996-2010.

Factors Associated With Rates of False-Positive and False-Negative Results From Digital Mammography Screening: An Analysis of Registry Data.

BACKGROUND: Women screened with digital mammography may receive false-positive and false-negative results and subsequent imaging and biopsies. How these outcomes vary by age, time since the last screening, and individual risk factors is unclear. OBJECTIVE: To determine factors associated with false-positive and false-negative digital mammography results, additional imaging, and biopsies among a general population of women screened for breast cancer. DESIGN: Analysis of registry data. SETTING: Participating facilities at 5 U.S. Breast Cancer Surveillance Consortium breast imaging registries with linkages to pathology databases and tumor registries. PATIENTS: 405,191 women aged 40 to 89 years screened with digital mammography between 2003 and 2011. A total of 2963 were diagnosed with invasive cancer or ductal carcinoma in situ within 12 months of screening. MEASUREMENTS: Rates of false-positive and false-negative results and recommendations for additional imaging and biopsies from a single screening round; comparisons by age, time since the last screening, and risk factors. RESULTS: Rates of false-positive results (121.2 per 1000 women [95% CI, 105.6 to 138.7]) and recommendations for additional imaging (124.9 per 1000 women [CI, 109.3 to 142.3]) were highest among women aged 40 to 49 years and decreased with increasing age. Rates of false-negative results (1.0 to 1.5 per 1000 women) and recommendations for biopsy (15.6 to 17.5 per 1000 women) did not differ greatly by age. Results did not differ by time since the last screening. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index. LIMITATIONS: Confounding by variation in patient-level characteristics and outcomes across registries and regions may have been present. Some factors, such as numbers of first- and second-degree relatives with breast cancer and diagnoses associated with previous benign biopsy results, were not examined. CONCLUSION: False-positive mammography results and additional imaging are common, particularly for younger women and those with risk factors, whereas biopsies occur less often. Rates of false-negative results are low. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and National Cancer Institute.

Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force.

BACKGROUND: Screening mammography has lower sensitivity and specificity in women with dense breasts, who experience higher breast cancer risk. PURPOSE: To perform a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results. DATA SOURCES: MEDLINE, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015. STUDY SELECTION: Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts. DATA EXTRACTION: Quality assessment and abstraction of 24 studies from 7 countries; 6 studies were good-quality. DATA SYNTHESIS: Three good-quality studies reported reproducibility of BI-RADS density; 13% to 19% of women were recategorized between "dense" and "nondense" at subsequent screening. Two good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80% to 83%; specificity, from 86% to 94%; and positive predictive value (PPV), from 3% to 8%. The sensitivity of MRI ranged from 75% to 100%; specificity, from 78% to 94%; and PPV, from 3% to 33% (3 studies). Rates of additional cancer detection with ultrasonography were 4.4 per 1000 examinations (89% to 93% invasive); recall rates were 14%. Use of MRI detected 3.5 to 28.6 additional cancer cases per 1000 examinations (34% to 86% invasive); recall rates were 12% to 24%. Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1000 examinations compared with mammography alone (3 studies). Recall rates ranged from 7% to 11%, compared with 7% to 17% with mammography alone. No studies examined breast cancer outcomes. LIMITATIONS: Good-quality evidence was sparse. Studies were small and CIs were wide. Definitions of recall were absent or inconsistent. CONCLUSION: Density ratings may be recategorized on serial screening mammography. Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results. Use of DBT may reduce recall rates. Effects of supplemental screening on breast cancer outcomes remain unclear. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.