Breast cancer missed at screening; hindsight or mistakes?

PURPOSE: To investigate radiologists' interpretation scores of screening mammograms prior to diagnosis of screen-detected and interval breast cancers retrospectively classified as missed or true negative. METHODS: We included data on radiologists' interpretation scores at screening prior to diagnosis for 1223 screen-detected and 1007 interval cancer cases classified as missed or true negative in an informed consensus-based review. All prior screening examinations were independently scored 1-5 by two radiologists; score 1 by both was considered concordant negative, score ≥ 2 by one radiologist discordant, and score ≥ 2 by both concordant positive. We analyzed associations between interpretation, review categories, mammographic features and histopathological findings using descriptive statistics and logistic regression. RESULTS: Among screen-detected cancers, 31% of missed and 10% of true negative cancers had discordant or concordant positive interpretation at prior screening. The corresponding percentages for interval cancer were 21% and 8%. Age-adjusted odds ratio (OR) and 95% confidence interval (CI) for missed screen-detected cancer was 3.8 (95% CI: 2.6-5.4) after discordant and 5.5 (95% CI: 3.2-9.5) after concordant positive interpretation, using concordant negative as reference. Corresponding ORs for missed interval cancer were 3.0 (95% CI: 2.0-4.5) for discordant and 6.3 (95% CI: 2.3-17.5) for concordant positive interpretation. Asymmetry was the dominating mammographic feature at prior screening for all, except concordant positive screen-detected cancers where a mass dominated. Histopathological characteristics did not vary statistically with interpretation. CONCLUSIONS: Most cancers were interpreted negatively at screening prior to diagnosis. Increased risk for missed screen-detected or interval cancer was observed after positive interpretation at prior screening.

True and Missed Interval Cancer in Organized Mammographic Screening: A Retrospective Review Study of Diagnostic and Prior Screening Mammograms.

RATIONALE AND OBJECTIVES: To explore radiological aspects of interval breast cancer in a population-based screening program. MATERIALS AND METHODS: We performed a consensus-based informed review of mammograms from diagnosis and prior screening from women diagnosed with interval cancer 2004-2016 in BreastScreen Norway. Cases were classified as true (no findings on prior screening mammograms), occult (no findings at screening or diagnosis), minimal signs (minor/non-specific findings) and missed (obvious findings). We analyzed mammographic findings, density, time since prior screening, and histopathological characteristics between the classification groups. RESULTS: The study included 1010 interval cancer cases. Mean age at diagnosis was 61 years (SD = 6), mean time between screening and diagnosis 14 months (SD = 7). A total of 48% (479/1010) were classified as true or occult, 28% (285/1010) as minimal signs and 24% (246/1010) as missed. We observed no differences in mammographic density between the groups, except from a higher percentage of dense breasts in women with occult cancer. Among cancers classified as missed, about 1/3 were masses and 1/3 asymmetries at prior screening. True interval cancers were diagnosed later in the screening interval than the other classification categories. No differences in histopathological characteristics were observed between true, minimal signs and missed cases. CONCLUSION: In an informed review, 24% of the interval cancers were classified as missed based on visibility and mammographic findings on prior screening mammograms. Three out of four true interval cancers were diagnosed in the second year of the screening interval. We observed no statistical differences in histopathological characteristics between true and missed interval cancers.

Digital Breast Tomosynthesis and Synthetic 2D Mammography versus Digital Mammography: Evaluation in a Population-based Screening Program.

Purpose To compare the performance of digital breast tomosynthesis (DBT) and two-dimensional synthetic mammography (SM) with that of digital mammography (DM) in a population-based mammographic screening program. Materials and Methods In this prospective cohort study, data from 37 185 women screened with DBT and SM and from 61 742 women screened with DM as part of a population-based screening program in 2014 and 2015 were included. Early performance measures, including recall rate due to abnormal mammographic findings, rate of screen-detected breast cancer, positive predictive value of recall, positive predictive value of needle biopsy, histopathologic type, tumor size, tumor grade, lymph node involvement, hormonal status, Ki-67 level, and human epidermal growth factor receptor 2 status were compared in women who underwent DBT and SM screening and in those who underwent DM screening by using χ2 tests, two-sample unpaired t tests, and tests of proportions. Results Recall rates were 3.4% for DBT and SM screening and 3.3% for DM screening (P = .563). DBT and SM screening showed a significantly higher rate of screen-detected cancer compared with DM screening (9.4 vs 6.1 cancers per 1000 patients screened, respectively; P < .001). The rate of detection of tumors 10 mm or smaller was 3.2 per 1000 patients screened with DBT and SM and 1.8 per 1000 patients screened with DM (P < .001), and the rate of grade 1 tumors was 3.3 per 1000 patients screened with DBT and SM versus 1.4 per 1000 patients screened with DM (P < .001). On the basis of immunohistochemical analyses, rates of lymph node involvement and tumor subtypes did not differ between women who underwent DBT and SM screening and those who underwent DM screening. Conclusion DBT and SM screening increased the detection rate of histologically favorable tumors compared with that attained with DM screening. © RSNA, 2018 Online supplemental material is available for this article.

Gene expression profiles of breast biopsies from healthy women identify a group with claudin-low features.

BACKGROUND: Increased understanding of the variability in normal breast biology will enable us to identify mechanisms of breast cancer initiation and the origin of different subtypes, and to better predict breast cancer risk. METHODS: Gene expression patterns in breast biopsies from 79 healthy women referred to breast diagnostic centers in Norway were explored by unsupervised hierarchical clustering and supervised analyses, such as gene set enrichment analysis and gene ontology analysis and comparison with previously published genelists and independent datasets. RESULTS: Unsupervised hierarchical clustering identified two separate clusters of normal breast tissue based on gene-expression profiling, regardless of clustering algorithm and gene filtering used. Comparison of the expression profile of the two clusters with several published gene lists describing breast cells revealed that the samples in cluster 1 share characteristics with stromal cells and stem cells, and to a certain degree with mesenchymal cells and myoepithelial cells. The samples in cluster 1 also share many features with the newly identified claudin-low breast cancer intrinsic subtype, which also shows characteristics of stromal and stem cells. More women belonging to cluster 1 have a family history of breast cancer and there is a slight overrepresentation of nulliparous women in cluster 1. Similar findings were seen in a separate dataset consisting of histologically normal tissue from both breasts harboring breast cancer and from mammoplasty reductions. CONCLUSION: This is the first study to explore the variability of gene expression patterns in whole biopsies from normal breasts and identified distinct subtypes of normal breast tissue. Further studies are needed to determine the specific cell contribution to the variation in the biology of normal breasts, how the clusters identified relate to breast cancer risk and their possible link to the origin of the different molecular subtypes of breast cancer.

Expression levels of uridine 5'-diphospho-glucuronosyltransferase genes in breast tissue from healthy women are associated with mammographic density.

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 a linear regression model was 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 amongst 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.