Project description:Understanding the detectability of breast cancer using mammography is important when considering nation-wide screening programmes. Although the role of imaging settings on image quality has been studied extensively, their role in detectability of cancer at a population level is less well studied. We wish to quantify the association between mammographic screening sensitivity and various imaging parameters. Using a novel approach applied to a population-based breast cancer screening cohort, we specifically focus on sensitivity as defined in the classical diagnostic testing literature, as opposed to the screen-detected cancer rate, which is often used as a measure of sensitivity for monitoring and evaluating breast cancer screening. We use a natural history approach to model the presence and size of latent tumors at risk of detection at mammography screening, and the screening sensitivity is modeled as a logistic function of tumor size. With this approach we study the influence of compressed breast thickness, x-ray exposure, and compression pressure, in addition to (percent) breast density, on the screening test sensitivity. When adjusting for all screening parameters in addition to latent tumor size, we find that percent breast density and compressed breast thickness are statistically significant factors for the detectability of breast cancer. A change in breast density from 6.6 to 33.5% (the inter-quartile range) reduced the odds of detection by 61% (95% CI 48-71). Similarly, a change in compressed breast thickness from 46 to 66 mm reduced the odds by 42% (95% CI 21-57). The true sensitivity of mammography, defined as the probability that an examination leads to a positive result if a tumour is present in the breast, is associated with compressed breast thickness after accounting for mammographic density and tumour size. This can be used to guide studies of setups aimed at improving lesion detection. Compressed breast thickness-in addition to breast density-should be considered when assigning complementary screening modalities and personalized screening intervals.

Project description:Introduction Mammographic density (MD), as assessed from film screen mammograms, is determined by the relative content of adipose, connective and epithelial tissue in the female breast. In epidemiological studies, a high percentage of MD confers a four to six fold risk elevation of developing breast cancer, even after adjustment for other known breast cancer risk factors. However, the biologic correlates of density are little known. Methods Gene expression analysis using whole genome arrays was performed on breast biopsies from 143 women; 79 women with no malignancy (healthy women) and 64 newly diagnosed breast cancer patients, both included from mammographic centres. Percent MD was determined using a previously validated, computerized method on scanned mammograms. Significance analysis of microarrays (SAM) was performed to identify genes influencing MD and generalized regression models were used to assess the independent contribution from different variables to MD. Results SAM-analysis identified 24 genes differentially expressed between samples from breasts with high and low MD. These genes included three uridine 5'-diphospho-glucuronosyltransferase (UGT) genes and the oestrogen receptor gene (ESR1). These genes were down-regulated in samples with high MD compared to those with low MD. The UGT gene products, which are known to inactivate oestrogen metabolites, were also down-regulated in tumour samples compared to samples from healthy individuals. Several single nucleotide polymorphisms (SNPs) in the UGT genes associated with the expression of UGT and other genes in their vicinity were identified. Conclusions Three UGT enzymes were lower expressed both in breast tissue biopsies from healthy women with high MD and in biopsies from newly diagnosed breast cancers. The association was strongest among young women and women using hormonal therapy. UGT2B10 predicts MD independently of age, hormone therapy and parity. Our results indicate that down-regulation of UGT genes in women exposed to female sex hormones is associated with high MD and might increase the risk of breast cancer.

Project description:Introduction Mammographic density (MD), as assessed from film screen mammograms, is determined by the relative content of adipose, connective and epithelial tissue in the female breast. In epidemiological studies, a high percentage of MD confers a four to six fold risk elevation of developing breast cancer, even after adjustment for other known breast cancer risk factors. However, the biologic correlates of density are little known. Methods Gene expression analysis using whole genome arrays was performed on breast biopsies from 143 women; 79 women with no malignancy (healthy women) and 64 newly diagnosed breast cancer patients, both included from mammographic centres. Percent MD was determined using a previously validated, computerized method on scanned mammograms. Significance analysis of microarrays (SAM) was performed to identify genes influencing MD and generalized regression models were used to assess the independent contribution from different variables to MD. Results SAM-analysis identified 24 genes differentially expressed between samples from breasts with high and low MD. These genes included three uridine 5'-diphospho-glucuronosyltransferase (UGT) genes and the oestrogen receptor gene (ESR1). These genes were down-regulated in samples with high MD compared to those with low MD. The UGT gene products, which are known to inactivate oestrogen metabolites, were also down-regulated in tumour samples compared to samples from healthy individuals. Several single nucleotide polymorphisms (SNPs) in the UGT genes associated with the expression of UGT and other genes in their vicinity were identified. Conclusions Three UGT enzymes were lower expressed both in breast tissue biopsies from healthy women with high MD and in biopsies from newly diagnosed breast cancers. The association was strongest among young women and women using hormonal therapy. UGT2B10 predicts MD independently of age, hormone therapy and parity. Our results indicate that down-regulation of UGT genes in women exposed to female sex hormones is associated with high MD and might increase the risk of breast cancer. Gene expression analysis of breast biopsies from 143 women, 79 non-cancer (healthy women with no cancer who had a mammogram taken) and 64 breast cancer.

Project description:Texture patterns have been shown to improve breast cancer risk segregation in addition to area-based mammographic density. The additional value of texture pattern scores on top of volumetric mammographic density measures in a large screening cohort has never been studied.Volumetric mammographic density and texture pattern scores were assessed automatically for the first available digital mammography (DM) screening examination of 51,400 women (50-75 years of age) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. The texture assessment method was developed in a previous study and validated in the current study. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. All screen-detected breast cancers diagnosed at the first available digital screening examination were excluded. During a median follow-up period of 4.2 (interquartile range (IQR) 2.0-6.2) years, 301 women were diagnosed with breast cancer. The associations between texture pattern scores, volumetric breast density measures and breast cancer risk were determined using Cox proportional hazard analyses. Discriminatory performance was assessed using c-indices.The median age of the women at the time of the first available digital mammography examination was 56 years (IQR 51-63). Texture pattern scores were positively associated with breast cancer risk (hazard ratio (HR) 3.16 (95% CI 2.16-4.62) (p value for trend <0.001), for quartile (Q) 4 compared to Q1). The c-index of texture was 0.61 (95% CI 0.57-0.64). Dense volume and percentage dense volume showed positive associations with breast cancer risk (HR 1.85 (95% CI 1.32-2.59) (p value for trend <0.001) and HR 2.17 (95% CI 1.51-3.12) (p value for trend <0.001), respectively, for Q4 compared to Q1). When adding texture measures to models with dense volume or percentage dense volume, c-indices increased from 0.56 (95% CI 0.53-0.59) to 0.62 (95% CI 0.58-0.65) (p?<?0.001) and from 0.58 (95% CI 0.54-0.61) to 0.60 (95% CI 0.57-0.63) (p?=?0.054), respectively.Deep-learning-based texture pattern scores, measured automatically on digital mammograms, are associated with breast cancer risk, independently of volumetric mammographic density, and augment the capacity to discriminate between future breast cancer and non-breast cancer cases.

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Regular physical activity and mammographic density: a cohort study.

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Regular physical activity and mammographic density: a cohort study.

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