Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis.

BACKGROUND: We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials. METHODS: Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated. RESULTS: In BRCA1/2 mutation carriers of all ages (BRCA1 = 1,219 and BRCA2 = 732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P > 0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening. CONCLUSIONS: Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽ 40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering.

Magnetic resonance imaging improves breast screening sensitivity in BRCA mutation carriers age ≥ 50 years: evidence from an individual patient data meta-analysis.

PURPOSE: There is no consensus on whether magnetic resonance imaging (MRI) should be included in breast screening protocols for women with BRCA1/2 mutations age ≥ 50 years. Therefore, we investigated the evidence on age-related screening accuracy in women with BRCA1/2 mutations using individual patient data (IPD) meta-analysis. PATIENTS AND METHODS: IPD were pooled from six high-risk screening trials including women with BRCA1/2 mutations who had completed at least one screening round with both MRI and mammography. A generalized linear mixed model with repeated measurements and a random effect of studies estimated sensitivity and specificity of MRI, mammography, and the combination in all women and specifically in those age ≥ 50 years. RESULTS: Pooled analysis showed that in women age ≥ 50 years, screening sensitivity was not different from that in women age < 50 years, whereas screening specificity was. In women age ≥ 50 years, combining MRI and mammography significantly increased screening sensitivity compared with mammography alone (94.1%; 95% CI, 77.7% to 98.7% v 38.1%; 95% CI, 22.4% to 56.7%; P < .001). The combination was not significantly more sensitive than MRI alone (94.1%; 95% CI, 77.7% to 98.7% v 84.4%; 95% CI, 61.8% to 94.8%; P = .28). Combining MRI and mammography in women age ≥ 50 years resulted in sensitivity similar to that in women age < 50 years (94.1%; 95% CI, 77.7% to 98.7% v 93.2%; 95% CI, 79.3% to 98%; P = .79). CONCLUSION: Addition of MRI to mammography for screening BRCA1/2 mutation carriers age ≥ 50 years improves screening sensitivity by a magnitude similar to that observed in younger women. Limiting screening MRI in BRCA1/2 carriers age ≥ 50 years should be reconsidered.

Optimal age to start preventive measures in women with BRCA1/2 mutations or high familial breast cancer risk.

Women from high-risk families consider preventive measures for breast cancer including screening. Guidelines on screening differ considerably regarding starting age. We investigated whether age at diagnosis in affected relatives is predictive for age at diagnosis. We analyzed the age of breast cancer detection of 1,304 first- and second-degree relatives of 314 BRCA1, 164 BRCA2 and 244 high-risk participants of the Dutch MRI-SCreening study. The within- and between-family variance in the relative's age at diagnosis was analyzed with a random effect linear regression model. We compared the starting age of screening based on risk-group (25 years for BRCA1, 30 years for BRCA2 and 35 years for familial risk), on family history, and on the model, which combines both. The findings were validated in 63 families from the UK-MARIBS study. Mean age at diagnosis in the relatives varied between families; 95% range of mean family ages was 35-55 in BRCA1-, 41-57 in BRCA2- and 44-60 in high-risk families. In all, 14% of the variance in age at diagnosis, in BRCA1 even 23%, was explained by family history, 7% by risk group. Determining start of screening based on the model and on risk-group gave similar results in terms of cancers missed and years of screening. The approach based on familial history only, missed more cancers and required more screening years in both the Dutch and the United Kingdom data sets. Age at breast cancer diagnosis is partly dependent on family history which may assist planning starting age for preventive measures.

Common breast cancer susceptibility variants in LSP1 and RAD51L1 are associated with mammographic density measures that predict breast cancer risk.

BACKGROUND: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. METHODS: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. RESULTS: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). CONCLUSION: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. IMPACT: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.

Assessing the usefulness of a novel MRI-based breast density estimation algorithm in a cohort of women at high genetic risk of breast cancer: the UK MARIBS study.

INTRODUCTION: Mammographic breast density is one of the strongest known risk factors for breast cancer. We present a novel technique for estimating breast density based on 3D T1-weighted Magnetic Resonance Imaging (MRI) and evaluate its performance, including for breast cancer risk prediction, relative to two standard mammographic density-estimation methods. METHODS: The analyses were based on MRI (n = 655) and mammography (n = 607) images obtained in the course of the UK multicentre magnetic resonance imaging breast screening (MARIBS) study of asymptomatic women aged 31 to 49 years who were at high genetic risk of breast cancer. The MRI percent and absolute dense volumes were estimated using our novel algorithm (MRIBview) while mammographic percent and absolute dense area were estimated using the Cumulus thresholding algorithm and also using a 21-point Visual Assessment scale for one medio-lateral oblique image per woman. We assessed the relationships of the MRI and mammographic measures to one another, to standard anthropometric and hormonal factors, to BRCA1/2 genetic status, and to breast cancer risk (60 cases) using linear and Poisson regression. RESULTS: MRI percent dense volume is well correlated with mammographic percent dense area (R = 0.76) but overall gives estimates 8.1 percentage points lower (P < 0.0001). Both show strong associations with established anthropometric and hormonal factors. Mammographic percent dense area, and to a lesser extent MRI percent dense volume were lower in BRCA1 carriers (P = 0.001, P = 0.010 respectively) but there was no association with BRCA2 carrier status. The study was underpowered to detect expected associations between percent density and breast cancer, but women with absolute MRI dense volume in the upper half of the distribution had double the risk of those in the lower half (P = 0.009). CONCLUSIONS: The MRIBview estimates of volumetric breast density are highly correlated with mammographic dense area but are not equivalent measures; the MRI absolute dense volume shows potential as a predictor of breast cancer risk that merits further investigation.

Cancers in BRCA1 and BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features.

PURPOSE: To review imaging features of screening-detected cancers on images from diagnostic and prior examinations to identify specific abnormalities to aid earlier detection of or facilitate differentiation of cancers in BRCA1 and BRCA2 carriers and in women with a high risk for breast cancer. MATERIALS AND METHODS: Informed consent and multicenter and local research ethics committee approval were obtained. Women (mean age, 40.1 years; range, 27-55 years) who had at least a 50% risk of being a BRCA1, BRCA2, or TP53 gene mutation carrier were recruited from August 1997 to March 2003 into the United Kingdom Magnetic Resonance Imaging in Breast Screening Study Group trial and were offered annual magnetic resonance (MR) imaging and two-view mammography (total number of screenings, 2065 and 1973; mean, 2.38 and 2.36, respectively). Images in all 39 cancer cases were reread in consensus to document the morphologic and enhancement imaging features on MR and mammographic images in screening and prior examinations. Cases were grouped into genetic subtypes. RESULTS: With MR imaging, there was no difference in morphologic or enhancement characteristics between the genetic subgroups. Cancers on images from prior examinations were of smaller size, showed less enhancement, and were more likely to have a type 1 enhancement curve compared with those cancers in the subsequent diagnostic screening examinations. The tumor sizes detected by using MR imaging and mammography were not significantly different (P = .46). The cancers in BRCA1 carriers found by using MR imaging tended to be smaller than those detected by using mammography (median, 17 mm vs 30 mm; P = .37), whereas the opposite was true for cancers found in BRCA2 carriers (MR imaging median size = 12.5 mm vs mammographic median size = 6 mm; P = .067); the difference was not significant. Tumors with prior MR imaging abnormalities grew at an average of 5.1 mm/y. CONCLUSION: When undertaking MR imaging surveillance in high-risk women, small enhancing lesions should be regarded with suspicion and biopsied or patients should be followed up at 6 months.

Eligibility for magnetic resonance imaging screening in the United Kingdom: effect of strict selection criteria and anonymous DNA testing on breast cancer incidence in the MARIBS Study.

INTRODUCTION: A UK multicenter study compared the performance of contrast enhanced-magnetic resonance imaging with X-Ray Mammography in women at high-risk of breast cancer commencing in 1997. Selection criteria were used to identify women with at least 0.9% annual risk of breast cancer. METHODS: Women at high breast cancer risk, with a strong family history and/or high probability of a BRCA1/BRCA2/TP53 mutation, were recruited from 22 centers. Those not known as gene carriers were asked to give a blood sample, which was tested anonymously for mutations. Women ages 35 to 49 years were offered annual screening for 2 to 7 years. Study eligibility at entry was assessed retrospectively by detailed examination of pedigrees and overall eligibility accounting for computer risk assessment and mutation results. RESULTS: Seventy-eight of 837 (9%) women entered for screening were ineligible using the strict entry criteria. Thirty-nine cancers were detected in 1,869 women-years in study (incidence 21 per 1,000). Including 3,561 further years follow-up, 28 more breast cancers were identified (12 of 1,000). Incidence rates for 759 eligible women were 22 of 1,000 in study and 13 of 1,000 in total follow-up, compared with 9 of 1,000 and 4 of 1,000, respectively, in 78 ineligible women. Breast cancer rates were higher for BRCA2 than BRCA1 after testing anonymized samples in this selected population at 65 of 1,000 in study and 36 of 1,000 in total follow-up for BRCA2 compared with 44 of 1,000 and 27 of 1,000 for BRCA1. CONCLUSIONS: Strict enforcement of study criteria would have minimally improved the power of the study, whereas testing for BRCA1/2 in advance would have substantially increased the detection rates.

A pilot study of compositional analysis of the breast and estimation of breast mammographic density using three-dimensional T1-weighted magnetic resonance imaging.

PURPOSE: A method and computer tool to estimate percentage magnetic resonance (MR) imaging (MRI) breast density using three-dimensional T(1)-weighted MRI is introduced, and compared with mammographic percentage density [X-ray mammography (XRM)]. MATERIALS AND METHODS: Ethical approval and informed consent were obtained. A method to assess MRI breast density as percentage volume occupied by water-containing tissue on three-dimensional T(1)-weighted MR images is described and applied in a pilot study to 138 subjects who were imaged by both MRI and XRM during the Magnetic Resonance Imaging in Breast Screening study. For comparison, percentage mammographic density was measured from matching XRMs as a ratio of dense to total projection areas scored visually using a 21-point score and measured by applying a two-dimensional interactive program (CUMULUS). The MRI and XRM percent methods were compared, including assessment of left-right and interreader consistency. RESULTS: Percent MRI density correlated strongly (r = 0.78; P < 0.0001) with percent mammographic density estimated using Cumulus. Comparison with visual assessment also showed a strong correlation. The mammographic methods overestimate density compared with MRI volumetric assessment by a factor approaching 2. DISCUSSION: MRI provides direct three-dimensional measurement of the proportion of water-based tissue in the breast. It correlates well with visual and computerized percent mammographic density measurements. This method may have direct application in women having breast cancer screening by breast MRI and may aid in determination of risk.