Radiation exposure and screening yield by digital breast tomosynthesis compared to mammography: results of the TOSYMA Trial breast density related.

OBJECTIVES: The randomized TOmosynthesis plus SYnthesized MAmmography (TOSYMA) screening trial has shown that digital breast tomosynthesis plus synthesized mammography (DBT + SM) is superior to digital mammography (DM) in invasive breast cancer detection varying with breast density. On the other hand, the overall average glandular dose (AGD) of DBT is higher than that of DM. Comparing the DBT + SM and DM trial arm, we analyzed here the mean AGD and their determinants per breast density category and related them to the respective invasive cancer detection rates (iCDR). METHODS: TOSYMA screened 99,689 women aged 50 to 69 years. Compression force, resulting breast thickness, the calculated AGD obtained from each mammography device, and previously published iCDR were used for comparisons across breast density categories in the two trial arms. RESULTS: There were 196,622 exposures of 49,227 women (DBT + SM) and 197,037 exposures of 49,132 women (DM) available for analyses. Mean breast thicknesses declined from breast density category A (fatty) to D (extremely dense) in both trial arms. However, while the mean AGD in the DBT + SM arm declined concomitantly from category A (2.41 mGy) to D (1.89 mGy), it remained almost unchanged in the DM arm (1.46 and 1.51 mGy, respectively). In relative terms, the AGD elevation in the DBT + SM arm (64.4% (A), by 44.5% (B), 27.8% (C), and 26.0% (D)) was lowest in dense breasts where, however, the highest iCDR were observed. CONCLUSION: Women with dense breasts may specifically benefit from DBT + SM screening as high cancer detection is achieved with only moderate AGD elevations. CLINICAL RELEVANCE STATEMENT: TOSYMA suggests a favorable constellation for screening with digital breast tomosynthesis plus synthesized mammography (DBT + SM) in dense breasts when weighing average glandular dose elevation against raised invasive breast cancer detection rates. There is potential for density-, i.e., risk-adapted population-wide breast cancer screening with DBT + SM. KEY POINTS: Breast thickness declines with visually increasing density in digital mammography (DM) and digital breast tomosynthesis (DBT). Average glandular doses of DBT decrease with increasing density; digital mammography shows lower and more constant values. With the smallest average glandular dose difference in dense breasts, DBT plus SM had the highest difference in invasive breast cancer detection rates.

Isolating the effect of confounding from the observed survival benefit of screening participants - a methodological approach illustrated by data from the German mammography screening programme.

BACKGROUND: Mammography screening programmes (MSP) aim to reduce breast cancer mortality by shifting diagnoses to earlier stages. However, it is difficult to evaluate the effectiveness of current MSP because analyses can only rely on observational data, comparing women who participate in screening with women who do not. These comparisons are subject to several biases: one of the most important is self-selection into the MSP, which introduces confounding and is difficult to control for. Here, we propose an approach to quantify confounding based on breast cancer survival analyses using readily available routine data sources. METHODS: Using data from the Cancer Registry of North Rhine-Westphalia, Germany, we estimate the relative contribution of confounding to the observed survival benefit of participants of the German MSP. This is accomplished by comparing non-participants, participants with screen-detected and participants with interval breast cancers for the endpoints "death from breast cancer" and "death from all causes other than breast cancer" - the latter being assumed to be unrelated to any MSP effect. By using different contrasts, we eliminate the effects of stage shift, lead and length time bias. The association of breast cancer detection mode with survival is analysed using Cox models in 68,230 women, aged 50-69 years, with breast cancer diagnosed in 2006-2014 and followed up until 2018. RESULTS: The hazard of dying from breast cancer was lower in participants with screen-detected cancer than in non-participants (HR = 0.21, 95% CI: 0.20-0.22), but biased by lead and length time bias, and confounding. When comparing participants with interval cancers and non-participants, the survival advantage was considerably smaller (HR = 0.62, 95% CI: 0.58-0.66), due to the elimination of stage shift and lead time bias. Finally, considering only mortality from causes other than breast cancer in the latter comparison, length time bias was minimised, but a survival advantage was still present (HR = 0.63, 95% CI: 0.56-0.70), which we attribute to confounding. CONCLUSIONS: This study shows that, in addition to stage shift, lead and length time bias, confounding is an essential component when comparing the survival of MSP participants and non-participants. We further show that the confounding effect can be quantified without explicit knowledge of potential confounders by using a negative control outcome.

Digital Breast Tomosynthesis versus Digital Mammography for Detection of Early-Stage Cancers Stratified by Grade: A TOSYMA Subanalysis.

Background Breast cancer screening with digital breast tomosynthesis (DBT) plus synthesized mammography (SM) increases invasive tumor detection compared with digital mammography (DM). However, it is not known how the prognostic characteristics of the cancers detected with the two screening approaches differ. Purpose To compare invasive breast cancers detected with DBT plus SM (test arm) versus DM (control arm) screening with regard to tumor stage, histologic grade, patient age, and breast density. Materials and Methods This exploratory subanalysis of the Tomosynthesis plus Synthesized Mammography (TOSYMA) study, which is a multicenter randomized controlled trial embedded in the German mammography screening program, recruited women aged 50-70 years from July 2018 to December 2020. It compared invasive cancer detection rates (iCDRs), rate differences, and odds ratios (ORs) between the arms stratified by Union for International Cancer Control (UICC) stage (I vs II-IV), histologic grade (1 vs 2 or 3), age group (50-59 vs 60-70 years), and Breast Imaging Reporting and Data System categories of breast density (A or B vs C or D). Results In total, 49 462 (median age, 57 years [IQR, 53-62 years]) and 49 669 (median age, 57 years [IQR, 53-62 years]) participants were allocated to DBT plus SM and DM screening, respectively. The iCDR of stage I tumors with DBT plus SM was 51.6 per 10 000 women (255 of 49 462) and with DM it was 30.0 per 10 000 women (149 of 49 669). DBT plus SM depicted more stage I tumors with grade 2 or 3 (166 of 49 462, 33.7 per 10 000 women) than DM (106 of 49 669, 21.3 per 10 000 women; rate difference, +12.3 per 10 000 women [95% CI: 0.3, 24.9]; OR, 1.6 [95% CI: 0.9, 2.7]). DBT plus SM achieved the highest iCDR of stage I tumors with grade 2 or 3 among women aged 60-70 years with dense breasts (41 of 7364, 55.4 per 10 000 women; rate difference, +21.6 per 10 000 women [95% CI: -21.1, 64.3]; OR, 1.6 [95% CI: 0.6, 4.5]). Conclusion DBT plus SM screening appears to lead to higher detection of early-stage invasive breast cancers of grade 2 or 3 than DM screening, with the highest rate among women aged 60-70 years with dense breasts. Clinical trial registration no. NCT03377036 © RSNA, 2023 See also the editorial by Ha and Chang in this issue.

Association of lipid-lowering drugs and antidiabetic drugs with age-related macular degeneration: a meta-analysis in Europeans.

BACKGROUND/AIMS: To investigate the association of commonly used systemic medications with prevalent age-related macular degeneration (AMD) in the general population. METHODS: We included 38 694 adults from 14 population-based and hospital-based studies from the European Eye Epidemiology consortium. We examined associations between the use of systemic medications and any prevalent AMD as well as any late AMD using multivariable logistic regression modelling per study and pooled results using random effects meta-analysis. RESULTS: Between studies, mean age ranged from 61.5±7.1 to 82.6±3.8 years and prevalence ranged from 12.1% to 64.5% and from 0.5% to 35.5% for any and late AMD, respectively. In the meta-analysis of fully adjusted multivariable models, lipid-lowering drugs (LLD) and antidiabetic drugs were associated with lower prevalent any AMD (OR 0.85, 95% CI=0.79 to 0.91 and OR 0.78, 95% CI=0.66 to 0.91). We found no association with late AMD or with any other medication. CONCLUSION: Our study indicates a potential beneficial effect of LLD and antidiabetic drug use on prevalence of AMD across multiple European cohorts. Our findings support the importance of metabolic processes in the multifactorial aetiology of AMD.

Breast Density and Breast Cancer Screening with Digital Breast Tomosynthesis: A TOSYMA Trial Subanalysis.

Background Digital breast tomosynthesis (DBT) plus synthesized mammography (SM) reduces the diagnostic pitfalls of tissue superimposition, which is a limitation of digital mammography (DM). Purpose To compare the invasive breast cancer detection rate (iCDR) of DBT plus SM versus DM screening for different breast density categories. Materials and Methods An exploratory subanalysis of the TOmosynthesis plus SYnthesized MAmmography (TOSYMA) study, a randomized, controlled, multicenter, parallel-group trial recruited within the German mammography screening program from July 2018 to December 2020. Women aged 50-69 years were randomly assigned (1:1) to DBT plus SM or DM screening examination. Breast density categories A-D were visually assessed according to the Breast Imaging Reporting and Data System Atlas. Exploratory analyses were performed of the iCDR in both study arms and stratified by breast density, and odds ratios and 95% CIs were determined. Results A total of 49 762 women allocated to DBT plus SM and 49 796 allocated to DM (median age, 57 years [IQR, 53-62 years]) were included. In the DM arm, the iCDR was 3.6 per 1000 screening examinations in category A (almost entirely fatty) (16 of 4475 screenings), 4.3 in category B (102 of 23 534 screenings), 6.1 in category C (116 of 19 051 screenings), and 2.3 in category D (extremely dense breasts) (six of 2629 screenings). The iCDR in the DBT plus SM arm was 2.7 per 1000 screening examinations in category A (12 of 4439 screenings), 6.9 in category B (154 of 22 328 screenings), 8.3 in category C (156 of 18 772 screenings), and 8.1 in category D (32 of 3940 screenings). The odds ratio for DM versus DBT plus SM in category D was 3.8 (95% CI: 1.5, 11.1). The invasive cancers detected with DBT plus SM were most often grade 2 tumors; in category C, it was 58% (91 of 156 invasive cancers), and in category D, it was 47% (15 of 32 invasive cancers). Conclusion The TOmosynthesis plus SYnthesized MAmmography trial revealed higher invasive cancer detection rates with digital breast tomosynthesis plus synthesized mammography than digital mammography in dense breasts, relatively and absolutely most marked among women with extremely dense breasts. ClinicalTrials.gov registration no.: NCT03377036 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Moy in this issue.

Effectiveness of Mammography Screening on Breast Cancer Mortality - A Study Protocol for Emulation of Target Trials Using German Health Claims Data.

Background: The efficacy of mammography screening in reducing breast cancer mortality has been demonstrated in randomized trials. However, treatment options - and hence prognosis - for advanced tumor stages as well as mammography techniques have considerably improved since completion of these trials. Consequently, the effectiveness of mammography screening under current conditions is unclear and controversial. The German mammography screening program (MSP), an organized population-based screening program, was gradually introduced between 2005 and 2008 and achieved nation-wide coverage in 2009. Objective: We describe in detail a study protocol for investigating the effectiveness of the German MSP in reducing breast cancer mortality in women aged 50 to 69 years based on health claims data. Specifically, the proposed study aims at estimating per-protocol effects of several screening strategies on cumulative breast cancer mortality. The first analysis will be conducted once 10-year follow-up data are available. Methods and Analysis: We will use claims data from five statutory health insurance providers in Germany, covering approximately 37.6 million individuals. To estimate the effectiveness of the MSP, hypothetical target trials will be emulated across time, an approach that has been demonstrated to minimize design-related biases. Specifically, the primary contrast will be in terms of the cumulative breast cancer mortality comparing the screening strategies of "never screen" versus "regular screening as intended by the MSP". Ethics and Dissemination: In Germany, the utilization of data from health insurances for scientific research is regulated by the Code of Social Law. All involved health insurance providers as well as the responsible authorities approved the use of the health claims data for this study. The Ethics Committee of the University of Bremen determined that studies based on claims data are exempt from institutional review. The findings of the proposed study will be published in peer-reviewed journals.

Digital breast tomosynthesis plus synthesised mammography versus digital screening mammography for the detection of invasive breast cancer (TOSYMA): a multicentre, open-label, randomised, controlled, superiority trial.

BACKGROUND: Two dimensional (2D) full-field digital mammography is the current standard of breast cancer screening. Digital breast tomosynthesis generates pseudo-three dimensional datasets of the breast from which synthesised 2D (s2D) mammograms can be reconstructed. This innovative approach reduces the likelihood of overlapping breast tissues that can conceal features of malignancy. We aimed to compare digital breast tomosynthesis plus s2D mammography with digital screening mammography for the detection of invasive breast cancer. METHODS: TOSYMA was a randomised, open-label, superiority trial done at 17 screening units in two federal states of Germany. Eligible participants were women aged 50-69 years who had been invited to participate in a population-wide, quality-controlled mammography screening programme. Women were randomly assigned (1:1) to digital breast tomosynthesis plus s2D mammography or digital mammography alone using block randomisation (block size of 32), stratified by site. The primary endpoints were the detection rate of invasive breast cancer and invasive interval cancer rate at 24 months, analysed in the modified full analysis set, which included all randomly assigned participants who underwent either type of screening examination. Ten examinations, corresponding to a second study participation, were excluded. Analyses were done according to the intention-to-treat principle. Interval cancer rates will be reported in the follow-up study. Safety was assessed in the as-treated population, which included all participants who were randomly assigned. This trial is registered with ClinicalTrials.gov, NCT03377036, and is closed to accrual. FINDINGS: Between July 5, 2018, and Dec 30, 2020, 99 689 women were randomly assigned to digital breast tomosynthesis plus s2D mammography (n=49 804) or digital mammography (n=49 830). Invasive breast cancers were detected in 354 of 49 715 women with evaluable primary endpoint data in the digital breast tomosynthesis plus s2D group (detection rate 7·1 cases per 1000 women screened) and in 240 of 49 762 women in the digital mammography group (4·8 cases per 1000 women screened; odds ratio 1·48 [95% CI 1·25-1·75]; p<0·0001). Adverse events and device deficiencies were rare (six adverse events in each group; 23 device deficiencies in the digital breast tomosynthesis plus s2D group vs five device deficiencies in the digital mammography group) and no serious adverse events were reported. INTERPRETATION: The results from this study indicate that the detection rate for invasive breast cancer was significantly higher with digital breast tomosynthesis plus s2D mammography than digital mammography alone. Evaluation of interval cancer rates in the follow-up study will further help to investigate incremental long-term benefits of digital breast tomosynthesis screening. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation).

The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium.

PURPOSE: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. DESIGN: Pooled analysis of 4 case-control and 6 cohort studies. PARTICIPANTS: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. METHODS: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan-Meier analyses in population-based cohorts. MAIN OUTCOME MEASURES: Age-related macular degeneration features and stage. RESULTS: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4-13.3), and of mixed late AMD was 12.2 (95% CI, 7.3-20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0-11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 µm (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen ≥ 125 µm (OR, 2.1; 95% CI, 1.5-3.0), up to an OR of 7.2 (95% CI, 3.8-13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2-5.4); risks of other characteristics were not different. CONCLUSIONS: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.

Are there sustained psychological impacts in women diagnosed with in-situ or early invasive breast cancers?

Purpose: The detection of a ductal carcinoma in-situ (DCIS) or an early invasive breast cancer (EIBC), particularly by population-wide mammography-screening-programs, is controversial as an unknown proportion of these cases may be due to overdiagnosis. We investigated whether women with such potentially overdiagnosed breast cancers suffer from sustained adverse psycho-social consequences. Methods: Standardized questionnaires were mailed to 900 survivors, diagnosed with either DCIS or EIBC, requesting self-reports on quality of life using EORTC Quality of Life Questionnaire C-30. Levels of anxiety and depression were assessed using the HADS questionnaires. Item score values in the study group were compared to reference data obtained from normative studies in the German female reference population. Results: The 577 women who returned completed questionnaires had a mean age of 65.1 years, 387 (67%) had been diagnosed by mammography screening. Median time since diagnosis was 5.9 years. There were no substantial differences between the study sample and the reference population for most of the items. While most score values were even slightly more favorable in the study group, the scores for cognitive function were moderately lower, especially among younger patients. Score values for anxiety were generally higher among younger women (50 to 59 years) from the study group, while depression scores were lower irrespective of age. Conclusions: This study indicates that the diagnosis of DCIS or EIBC, which is predominantly a result of screening, does not seem to induce sustained, adverse psychological impacts in affected women when compared with the respective general female population. Only anxiety levels remained elevated among younger women.

Decision aid and cost compensation influence uptake of PSA-based early detection without affecting decisional conflict: a cluster randomised trial.

International guidelines recommend to inform men about the benefits and harms of prostate specific antigen (PSA) based early detection of prostate cancer. This study investigates the influence of a transactional decision aid (DA) or cost compensation (CC) for a PSA test on the decisional behaviour of men. Prospective, cluster-randomised trial to compare two interventions in a 2 × 2 factorial design: DA versus counselling as usual, and CC versus noCC for PSA-testing. 90 cluster-randomised physicians in the administrative district of Muenster, Germany recruited 962 participants aged 55-69 yrs. in 2018. Primary endpoint: the influence of the DA and CC on the decisional conflict. Secondary endpoints: factors which altered the involvement of the men regarding their decision to take a PSA-test. The primary endpoint was analysed by a multivariate regression model. The choice to take the PSA test was increased by CC and reduced by the DA, the latter also reduced PSA uptake in men who were offered CC. The DA led to an increase of the median knowledge about early detection, changed willingness to perform a PSA test without increasing the level of shared decision, giving participants a stronger feeling of having made the decision by themselves. The DA did not alter the decisional conflict, as it was very low in all study groups. DA reduced and CC increased the PSA uptake. The DA seemed to have a greater impact on the participants than CC, as it led to fewer PSA tests even if CC was granted.Trial registration: German Clinical Trial Register (Deutsches Register Klinischer Studien DRKS00007687). Registered: 06/05/2015. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007687 .

Genetic Risk, Lifestyle, and Age-Related Macular Degeneration in Europe: The EYE-RISK Consortium.

PURPOSE: Age-related macular degeneration (AMD) is a common multifactorial disease in the elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation remains challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes. DESIGN: Pooled analysis of cross-sectional data from the European Eye Epidemiology Consortium. PARTICIPANTS: Seventeen thousand one hundred seventy-four individuals 45 years of age or older participating in 6 population-based cohort studies, 2 clinic-based studies, and 1 case-control study. METHODS: Age-related macular degeneration was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized. Minor allele frequencies and population-attributable fraction (PAF) were calculated. A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional ß values; a lifestyle score was constructed based on smoking and diet. MAIN OUTCOME MEASURES: Intermediate and late AMD. RESULTS: The risk variants with the largest difference between late AMD patients and control participants and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Combining all genetic variants, the total genetic risk score ranged from -3.50 to 4.63 and increased with AMD severity. Of the late AMD patients, 1581 of 1777 (89%) showed a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS, 90% of patients with late disease), but risk in 3 pathways was most frequent (35% of patients with late disease). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least 2-fold. CONCLUSIONS: Genetic risk variants contribute to late AMD in most patients. However, lifestyle factors have a strong influence on the outcome of genetic risk and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in most late AMD patients but are mostly combined with risks in other pathways.

The Mode of Detection Is Not Associated with Quality of Life in Women with Breast Cancer.

INTRODUCTION: Apart from saving lives, mammography screening programs (MSP) are expected to reduce negative side effects of treatment by detecting cancer earlier, when it is more responsive to less aggressive treatment. This study compared quality of life (QoL) among women with breast cancers that were detected either by screening mammography, as interval cancers, or clinically among women not participating in the MSP. METHODS: Retrospective study of first-ever invasive breast cancers detected among MSP-eligible women aged 50-69 years between 2006 and 2012 in Münster, Germany. EORTC QLQ-C30 and -BR23 questionnaires were mailed to 1,399 cases still alive in 2015 (response rate 64.1%). RESULTS: Women's responses were obtained on average 6.1 years after diagnosis. Mean crude and age-adjusted scores for overall QoL, breast and body image (BBI), and five functional scales (FS) were comparable between groups of detection mode. Clearly lower adjusted means for most scores were observed in women with interval cancers, if time since diagnosis was less than 5 years. Cases younger than 60 years showed lower values for some FS, particularly among interval and screen-detected cases. DISCUSSION/CONCLUSION: In summary, cases with breast cancer showed health-related score values that were similar to the general population of the same age. There was also no indication that mode of detection markedly influenced these scores. However, after adjusting for tumor stage and other influential factors, screening participants appeared more susceptible to score declines after a diagnosis of cancer than non-participants.

Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration: The EYE-RISK Consortium.

PURPOSE: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. DESIGN: Case-control association analysis of metabolomics data. PARTICIPANTS: Five European cohorts consisting of 2267 AMD patients and 4266 control participants. METHODS: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression. MAIN OUTCOME MEASURES: Metabolites associated with AMD. RESULTS: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. CONCLUSIONS: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD.

Incidence of advanced-stage breast cancer in regular participants of a mammography screening program: a prospective register-based study.

BACKGROUND: The European Guidelines for breast cancer screening suggest that the impact of population-based mammography screening programmes (MSP) may be assessed using the relative reduction in the incidence of advanced breast cancer (ABC, that is, stage UICC II and higher) as a surrogate indicator of screening effectiveness. METHODS: This prospective, population register-based study contained individual data of 1,200,246 women (aged 50-69 years) who attended the initial prevalence screening between 2005 and 2009. Of them, 498,029 women returned for the regular (i.e., within 24 months) first subsequent, and 208,561 for the regular second subsequent incidence screenings. The incidence rate of ABC was calculated for the 24-months period following, but not including, the initial screening by incorporating all interval ABCs and all ABCs detected at the regular first incidence screening; the ABC rate for the second 24-months period was determined in the same way, including ABCs detected in the interval after the first and, respectively, at the second incidence screening. The relative reduction in the ABC incidence was derived by comparing the age-standardized rates in these two periods with an age-standardized reference incidence rate, observed in the target population before the MSP implementation. The strengths and weaknesses of this particular study design were contrasted with a recently published checklist of main methodological problems affecting studies of the effect of MSP on ABC incidence. RESULTS: The age-standardized ABC incidence rate was 291.6 per 100,000 women for the 24-months period subsequent to the initial screening, and 275.0/100,000 for the 24-months period following the first subsequent screening. Compared to the 2-year incidence of 349.4/100,000 before the start of the MSP, this amounted to a relative reduction of 16.5 and 21.3%, respectively, in the incidence of ABC among regular MSP participants. CONCLUSIONS: The design employed in this study avoids some of the substantial methodological limitations that compromised previous observational studies. Nevertheless, specific limitations prevail that demand a cautious interpretation of the results. Therefore, the study findings, indicating a reduction in ABC for regular MSP participants, need to be followed with respect to potential impacts on breast cancer mortality rates.

Stratification of Breast Cancer Risk in Terms of the Influence of Age and Mammographic density. / Stratifizierung des Brustkrebsrisikos hinsichtlich der Einflüsse von Alter und mammografischer Dichte.

PURPOSE: Analysis of the influence of the singular risk factors age and breast density on the 2-year incidence of breast cancer among participants in the German mammography screening program. MATERIALS AND METHODS: The multicenter study includes 111 456 subsequent round digital mammographic screening examinations from four screening units with prospective visual categorization of breast density. Based on detection in screening and during the 2-year interval after negative screening participation (interval cancers), 2-year breast cancer incidences (2 YBCI) (‰) were calculated in the 5-year age groups (5 YAG) of the target group 50-69 years and in the BI-RADS density categories ACR 1-4. Multivariate statistical evaluations were carried out using logistic regression models. RESULTS: With an increase in the 5 YAG, the 2 YBCI increased by 5.0 ‰, 6.7 ‰, 8.5 ‰ to 9.7 ‰, and was significantly different among 55-59, 60-64 and 65-69-year-old women compared to the youngest reference group 50-54 years (odds ratio (OR): 1.34; 1.68; and 1.93; p-value < 0.0001). With an increase in density categories 1-4, the 2 YBCI increased from 2.6 ‰, to 5.8 ‰, 9.6 ‰, and 9.7 ‰. The 2 YBCI differed significantly in breast density categories 2, 3, 4 from reference group 1 (OR: 2.17; 3.65; and 3.76; p-value < 0.0001). Only within the two main breast density groups 2 (frequency 44.3 %) and 3 (44.7 %), a significant increase in the 2 YBCI was observed across the 5 YAG (category 2: 3.7-8.9 ‰; category 3: 5.8-11.7 ‰; p-value < 0.001 each). The 2 YBCI was above the median of 7.5 ‰ in women with breast density category 2 and aged 65-69 years, as well as in women with breast density categories 3 and 4 aged 55-69 years. A 2 YBCI below the median was seen in women between 50-54 years regardless of breast density, as well as women in category 1 in all age groups. CONCLUSION: Within the main breast density categories 2 and 3 (almost 90 % of participants), incidences increase with age to double. A consistently low incidence is found regardless of breast density at a young screening age and in women with the lowest breast density. KEY POINTS: · The risk of breast cancer is modified by age in density categories.. · Women aged 50-54 years have a low risk in all density categories.. · Women in category ACR 1 of any age group have a low risk.. CITATION FORMAT: · Weigel S, Heindel W, Dietz C et al. Stratifizierung des Brustkrebsrisikos hinsichtlich der Einflüsse von Alter und mammografischer Dichte. Fortschr Röntgenstr 2020; 192: 678 - 685.

Secure Linking of Data from Population-Based Cancer Registries with Healthcare Data to Evaluate Screening Programs.

BACKGROUND: The evaluation of population-based screening programs, like the German Mammography Screening Program (MSP), requires collection and linking data from population-based cancer registries and other sources of the healthcare system on a case- specific level. To link such sensitive data, we developed a method that is compliant with German data protection regulations and does not require written individual consent. METHODS: Our method combines a probabilistic record linkage on encrypted identifying data with 'blinded anonymisation'. It ensures that all data either are encrypted or have a defined and measurable degree of anonymity. The data sources use a software to transform plain-text identifying data into a set of irreversibly encrypted person cryptograms, while the evaluation attributes are aggregated in multiple stages and are reversibly encrypted. A pseudonymisation service encrypts the person cryptograms into record assignment numbers and a downstream data-collecting centre uses them to perform the probabilistic record linkage. The blinded anonymisation solves the problem of quasi-identifiers within the evaluation data. It allows selecting a specific set of the encrypted aggregations to produce data export with ensured k-anonymity, without any plain-text information. These data are finally transferred to an evaluation centre where they are decrypted and analysed. Our approach allows creating several such generalisations, with different resulting suppression rates allowing dynamic balance information depth with privacy protection and also highlights how this affects data analysability. RESULTS: German data protection authorities approved our concept for the evaluation of the impact of the German MSP on breast cancer mortality. We implemented a prototype and tested it with 1.5 million simulated records, containing realistically distributed identifying data, calculated different generalisations and the respective suppression rates. Here, we also discuss limitations for large data sets in the cancer registry domain, as well as approaches for further improvements like l-diversity and how to reduce the amount of manual post-processing. CONCLUSION: Our approach enables secure linking of data from population-based cancer registries and other sources of the healthcare system. Despite some limitations, it enables evaluation of the German MSP program and can be generalised to be applicable to other projects.

Implementation of an algorithm for the identification of breast cancer deaths in German health insurance claims data: a validation study based on a record linkage with administrative mortality data.

OBJECTIVE: To adapt a Canadian algorithm for the identification of female cases of breast cancer (BC) deaths to German health insurance claims data and to test and validate the algorithm by comparing results with official cause of death (CoD) data on the individual and the population level. DESIGN: Validation study, secondary data, medical claims. SETTING: Claims data of two statutory health insurance providers (SHIs) for inpatient and outpatient care, CoD added via record linkage with epidemiological cancer registry (ECR).ParticipantsAll women insured with the two SHIs and who deceased in the period 2006-2013, were residents of North Rhine Westphalia (NRW) and were linked with ECR data: n=22 413. MAIN OUTCOME MEASURES: Based on inpatient and outpatient diagnoses in the year before death, six algorithms were derived and the accordance of the algorithm-based CoD with the official CoD was evaluated calculating specificity, sensitivity, negative and positive predictive values (NPV, PPV). Furthermore, algorithm-based age-specific BC mortality rates covering several calendar years were calculated for the entire insured female population and compared with official national rates. RESULTS: Our final algorithm, derived from the NRW subsample, comprised codes indicating the presence of BC, metastases, a terminal illness phase and the absence of codes for other tumours. Overall, specificity, sensitivity, NPV and PPV of this algorithm were 97.4%, 91.3%, 98.9% and 81.7%, respectively. In the age range 40-80 years, sensitivity and PPV slightly decreased with increasing age. Algorithm-based age-specific BC mortality rates agreed well with official rates except for the age group 85 years and older. CONCLUSIONS: The algorithm-based identification of BC deaths in German claims data is feasible and valid, except for higher ages. The algorithm to ascertain BC mortality rates in an epidemiological study seems applicable when information on the official CoD is not available in the original database.

Development and Prospective Randomized Evaluation of a Decision Aid for Prostate-specific Antigen-based Early Detection of Prostate Cancer in Men Aged Between 55 and 69Yr: The PSAInForm Trial.

For men interested in early detection of prostate cancer, the potential impact on decisional conflict of a decision aid with or without cost compensation for the prostate-specific antigen test will be investigated.