R Warren

Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1–7 individual annual screening events. Women aged 35–49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was £28u2009284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to £11u2009731 (CE MRI vs mammography) and £15u2009302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

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. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.

Life course breast cancer risk factors and adult breast density (United Kingdom)

Objective To determine whether risk factors in childhood and early adulthood affect later mammographic breast density. Methods: Subjects were 628 women who attended a medical examination at the University of Glasgow Student Health Service (1948–1968), responded to a questionnaire (2001) and had a screening mammogram in Scotland (1989–2002). Mammograms (median age of 59years) were classified using a six category classification (SCC) of breast density percent. Logistic regression was used to determine associations between risk factors and having a high-risk mammogram (≥25 dense). Results: In multi-variable analyses, high-risk mammograms were associated with parity (adjusted odds ratio (OR) per child: 0.77 (95 confidence interval (CI) 0.61–0.99)), age at first birth, OR per year: 1.05 (0.99–1.11), smoking at university, OR smokers versus non-smokers: 0.58 (0.36–0.92) and body mass index (BMI) while at university, OR per 1kg/m20.75 (0.69–0.82). No associations with SCC were found for age at menarche, birth weight, oral contraceptive (OC) use, height, leg length or exercise at age 20. Conclusions: We confirm previous findings that breast density is affected by reproductive events and some anthropometric measures, however most of the risk factors acting throughout the life course which we examined were not closely related to adult breast density.

Cancers in BRCA1 and BRCA2 Carriers and in Women at High Risk for Breast Cancer: MR Imaging and Mammographic Features

PURPOSEnTo 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.nnnMATERIALS AND METHODSnInformed 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.nnnRESULTSnWith 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.nnnCONCLUSIONnWhen 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.

Breast cancer risk factors and a novel measure of volumetric breast density: cross-sectional study

We conducted a cross-sectional study nested within a prospective cohort of breast cancer risk factors and two novel measures of breast density volume among 590 women who had attended Glasgow University (1948–1968), replied to a postal questionnaire (2001) and attended breast screening in Scotland (1989–2002). Volumetric breast density was estimated using a fully automated computer programme applied to digitised film-screen mammograms, from medio-lateral oblique mammograms at the first-screening visit. This measured the proportion of the breast volume composed of dense (non-fatty) tissue (Standard Mammogram Form (SMF)%) and the absolute volume of this tissue (SMF volume, cm3). Median age at first screening was 54.1 years (range: 40.0–71.5), median SMF volume 70.25u2009cm3 (interquartile range: 51.0–103.0) and mean SMF% 26.3%, s.d.=8.0% (range: 12.7–58.8%). Age-adjusted logistic regression models showed a positive relationship between age at last menstrual period and SMF%, odds ratio (OR) per year later: 1.05 (95% confidence interval: 1.01–1.08, P=0.004). Number of pregnancies was inversely related to SMF volume, OR per extra pregnancy: 0.78 (0.70–0.86, P<0.001). There was a suggestion of a quadratic relationship between birthweight and SMF%, with lowest risks in women born under 2.5 and over 4u2009kg. Body mass index (BMI) at university (median age 19) and in 2001 (median age 62) were positively related to SMF volume, OR per extra kgu2009m−2 1.21 (1.15–1.28) and 1.17 (1.09–1.26), respectively, and inversely related to SMF%, OR per extra kgu2009m−2 0.83 (0.79–0.88) and 0.82 (0.76–0.88), respectively, P<0.001. Standard Mammogram Form% and absolute SMF volume are related to several, but not all, breast cancer risk factors. In particular, the positive relationship between BMI and SMF volume suggests that volume of dense breast tissue will be a useful marker in breast cancer studies.

Comparing measurements of breast density.

Breast density measurements can be made from mammograms using either area-based methods, such as the six category classification (SCC), or volumetric based methods, such as the standard mammogram form (SMF). Previously, we have shown how both types of methods generate breast density estimates which are generally close. In this paper, we switch our attention to the question of why, for certain cases, they provide widely differing estimates. First, we show how the underlying physical models of the breast employed in the methods need to be consistent, and how area-based methods are susceptible to projection effects. We then analyse a set of patients whose mammograms show large differences between their SCC and SMF assessments. More precisely, 12% of 657 patients were found to fall into this category. Of these, 2.7% were attributable to errors either in the SMF segmentation algorithms, human error in SCC categorization or poor image exposure. More importantly, 9.3% of the cases appear to be due to fundamental differences between the area- and volume-based techniques. We conclude by suggesting how we might remove half of those discrepancies by introducing a new categorization of the SMF estimates based on the breast thickness. We note however, that this still leaves 6% of patients with large differences between SMF and SCC estimates. We discuss why it might not be appropriate to assume SMF (or any volume measure) has a similar breast cancer risk prediction capability to SCC.

Determinants and consequences of change in breast density

Single measures of breast density have been consistently related to breast cancer risk, but the role of changes in breast density over the early menopausal period is not clear We investigated determinants and consequences of change in breast density among 493 women in Scotland Using simple measures of change, only hormone replacement therapy use and current body mass index were consistently predictive of breast density change Increases in area-based percent breast density were related to higher breast cancer risk, although the analysis was based on very few women Modeling of change and rate of change in larger datasets is warranted.