Anne S. Quante

Barrett's esophagus is the established precursor of gastroesophageal adenocarcinoma, yet most cases are diagnosed outside surveillance. The study investigated demographic, life-style, and genetic contributions to disease stage and progression Barrett's esophagus. Data from 870 participants in the prospective, multicenter BarrettNET registry (10-year follow-up period) were analyzed. Epidemiological data (smoking, alcohol, physical activity, diet, BMI, reflux symptoms) were collected via standardized questionnaires; dietary quality was assessed with a validated nutrition score. Multivariable logistic regression identified factors associated with advanced disease at diagnosis (non-dysplastic disease versus dysplasia or cancer); progression was evaluated using Firth penalized logistic regression. In a genotyped subgroup (739 participants), weighted polygenic risk scores from 41 variants were included as a sensitivity analysis. Among 598 patients with non-dysplastic disease, 116 with dysplasia, and 156 with cancer, older age (OR 1.03, 95% CI 1.01–1.04), male sex (OR 1.92, 95% CI 1.28–2.90), and smoking (OR 1.64, 95% CI 1.15–2.35) were associated with advanced disease. Of 21 participants who progressed during follow-up, older age (OR 1.06, 95% CI 1.02–1.11) and smoking (OR 4.31, 95% CI 1.62–11.47) were associated with progression, whereas reflux symptoms were associated with lower odds (OR 0.36, 95% CI 0.15–0.84; apparent AUC 0.825). Dietary factors and polygenic risk scores showed no independent association with either outcome and did not improve prediction. Age, male sex, and smoking predicted advanced disease and progression in Barrett's esophagus, while currently available polygenic risk scores added little predictive value, supporting lifestyle-based approaches to risk stratification.

Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10−8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10−3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10−10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10−8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10−9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci.

The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has successfully implemented risk-adapted breast cancer surveillance for women at high breast cancer risk in Germany. Women with a family history of breast and ovarian cancer but without pathogenic germline variants in recognized breast cancer risk genes are recommended annual breast imaging if their predicted 10-year breast cancer risk is 5% or higher, using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk model, as outlined in the current GC-HBOC guideline. However, women who initially do not meet this risk threshold may do so later, even if there is no new cancer in their family. To determine when this threshold is crossed, one could annually repeat BOADICEA calculations using an aging pedigree: the “prediction by aging pedigree” (AP) approach. Alternatively, we propose a simplified and more practical “'conditional probability” (CP) approach, which calculates future risks based on the initial BOADICEA assessment. Using data from 6,661 women registered with GC-HBOC, both methods were compared. Initially, 74% of women, ages 30 to 48 years, had a 10-year breast cancer risk below 5%, but 53% exceeded this threshold at an older age based on the AP approach. Among the women with an initial risk below the threshold, the CP approach revealed that 99% of women exceeded the 5% threshold at the same or an earlier age compared with the AP approach (88% of cases were within the same year or 1 year earlier). The CP approach has been implemented as a user-friendly web application. Prevention Relevance: The German Consortium for Hereditary Breast Cancer recommends annual breast imaging for women if their 10-year breast cancer risk is 5% or higher. Women who initially do not meet this risk threshold may do so later. We propose a simple method to determine future risks based on initial risk assessments.

In Germany, it is currently recommended that women start mammographic breast cancer screening at age 50. However, recently updated guidelines state that for women younger than 50 and older than 70 years of age, screening decisions should be based on individual risk. International clinical guidelines recommend starting screening when a woman's 5-year risk of breast cancer exceeds 1.7%. We thus compared the performance of the current age-based screening practice with an alternative risk-adapted approach using data from a German population representative survey. We found that 10,498,000 German women ages 50–69 years are eligible for mammographic screening based on age alone. Applying the 5-year risk threshold of 1.7% to individual breast cancer risk estimated from a model that considers a woman's reproductive and personal characteristics, 39,000 German women ages 40–49 years would additionally be eligible. Among those women, the number needed to screen to detect one breast cancer case, NNS, was 282, which was close to the NNS = 292 among all 50- to 69-year-old women. In contrast, NNS = 703 for the 113,000 German women ages 50–69 years old with 5-year breast cancer risk <0.8%, the median 5-year breast cancer risk for German women ages 45–49 years, which we used as a low-risk threshold. For these low-risk women, longer screening intervals might be considered to avoid unnecessary diagnostic procedures. In conclusion, we show that risk-adapted mammographic screening could benefit German women ages 40–49 years who are at elevated breast cancer risk and reduce cost and burden among low-risk women ages 50–69 years.Prevention Relevance:We show that a risk-based approach to mammography screening for German women can help detect breast cancer in women ages 40–49 years with increased risk and reduce screening costs and burdens for low-risk women ages 50–69 years. However, before recommending a particular implementation of a risk-based mammographic screening approach, further investigations of models and thresholds used are needed.

Endoscopic screening for Barrett's esophagus as the major precursor lesion for esophageal adenocarcinoma is mostly offered to patients with symptoms of gastroesophageal reflux disease (GERD). However, other epidemiologic risk factors might affect the development of Barrett's esophagus and esophageal adenocarcinoma. Therefore, efforts to improve the efficiency of screening to find the Barrett's esophagus population “at risk” compared with the normal population are needed. In a cross-sectional analysis, we compared 587 patients with Barrett's esophagus from the multicenter German BarrettNET registry to 1976 healthy subjects from the population-based German KORA cohort, with and without GERD symptoms. Data on demographic and lifestyle factors, including age, gender, smoking, alcohol consumption, body mass index, physical activity, and symptoms were collected in a standardized epidemiologic survey. Increased age, male gender, smoking, heavy alcohol consumption, low physical activity, low health status, and GERD symptoms were significantly associated with Barrett's esophagus. Surprisingly, among patients stratified for GERD symptoms, these associations did not change. Demographic, lifestyle, and clinical factors as well as GERD symptoms were associated with Barrett's esophagus development in Germany, suggesting that a combination of risk factors could be useful in developing individualized screening efforts for patients with Barrett's esophagus and GERD in Germany.

In Germany, it is currently recommended that women start mammographic breast cancer screening at age 50. However, recently updated guidelines state that for women younger than 50 and older than 70 years of age, screening decisions should be based on individual risk. International clinical guidelines recommend starting screening when a woman's 5-year risk of breast cancer exceeds 1.7%. We thus compared the performance of the current age-based screening practice with an alternative risk-adapted approach using data from a German population representative survey. We found that 10,498,000 German women ages 50–69 years are eligible for mammographic screening based on age alone. Applying the 5-year risk threshold of 1.7% to individual breast cancer risk estimated from a model that considers a woman's reproductive and personal characteristics, 39,000 German women ages 40–49 years would additionally be eligible. Among those women, the number needed to screen to detect one breast cancer case, NNS, was 282, which was close to the NNS = 292 among all 50- to 69-year-old women. In contrast, NNS = 703 for the 113,000 German women ages 50–69 years old with 5-year breast cancer risk <0.8%, the median 5-year breast cancer risk for German women ages 45–49 years, which we used as a low-risk threshold. For these low-risk women, longer screening intervals might be considered to avoid unnecessary diagnostic procedures. In conclusion, we show that risk-adapted mammographic screening could benefit German women ages 40–49 years who are at elevated breast cancer risk and reduce cost and burden among low-risk women ages 50–69 years.Prevention Relevance:We show that a risk-based approach to mammography screening for German women can help detect breast cancer in women ages 40–49 years with increased risk and reduce screening costs and burdens for low-risk women ages 50–69 years. However, before recommending a particular implementation of a risk-based mammographic screening approach, further investigations of models and thresholds used are needed.

Endoscopic screening for Barrett's esophagus as the major precursor lesion for esophageal adenocarcinoma is mostly offered to patients with symptoms of gastroesophageal reflux disease (GERD). However, other epidemiologic risk factors might affect the development of Barrett's esophagus and esophageal adenocarcinoma. Therefore, efforts to improve the efficiency of screening to find the Barrett's esophagus population “at risk” compared with the normal population are needed. In a cross-sectional analysis, we compared 587 patients with Barrett's esophagus from the multicenter German BarrettNET registry to 1976 healthy subjects from the population-based German KORA cohort, with and without GERD symptoms. Data on demographic and lifestyle factors, including age, gender, smoking, alcohol consumption, body mass index, physical activity, and symptoms were collected in a standardized epidemiologic survey. Increased age, male gender, smoking, heavy alcohol consumption, low physical activity, low health status, and GERD symptoms were significantly associated with Barrett's esophagus. Surprisingly, among patients stratified for GERD symptoms, these associations did not change. Demographic, lifestyle, and clinical factors as well as GERD symptoms were associated with Barrett's esophagus development in Germany, suggesting that a combination of risk factors could be useful in developing individualized screening efforts for patients with Barrett's esophagus and GERD in Germany.