Mammographic Density and Screening Sensitivity, Breast Cancer Incidence and Associated Risk Factors in Danish Breast Cancer Screening

Background: Attention in the 2000s on the importance of mammographic density led us to study screening sensitivity, breast cancer incidence, and associations with risk factors by mammographic density in Danish breast cancer screening programs. Here, we summarise our approaches and findings. Methods: Dichotomized density codes: fatty, equal to BI-RADS density code 1 and part of 2, and other mixed/dense data from the 1990s—were available from two counties, and BI-RADS density codes from one region were available from 2012/13. Density data were linked with data on vital status, incident breast cancer, and potential risk factors. We calculated screening sensitivity by combining data on screen-detected and interval cancers. We used cohorts to study high density as a predictor of breast cancer risk; cross-sectional data to study the association between life style factors and density, adjusting for age and body mass index (BMI); and time trends to study the prevalence of high density across birth cohorts. Results: Sensitivity decreased with increasing density from 78% in women with BI-RADS 1 to 47% in those with BI-RADS 4. For women with mixed/dense compared with those with fatty breasts, the rate ratio of incident breast cancer was 2.45 (95% CI 2.14–2.81). The percentage of women with mixed/dense breasts decreased with age, but at a higher rate the later the women were born. Among users of postmenopausal hormone therapy, the percentage of women with mixed/dense breasts was higher than in non-users, but the patterns across birth cohorts were similar. The occurrence of mixed/dense breast at screening age decreased by a z-score unit of BMI at age 13—odds ratio (OR) 0.56 (95% CI 0.53–0.58)—and so did breast cancer risk and hazard ratio (HR) 0.92 (95% CI 0.84–1.00), but it changed to HR 1.01 (95% CI 0.93–1.11) when controlled for density. Age and BMI adjusted associations between life style factors and density were largely close to unity; physical activity OR 1.06 (95% CI 0.93–1.21); alcohol consumption OR 1.01 (95% CI 0.81–1.27); air pollution OR 0.96 (95% 0.93–1.01) per 20 μg/m3; and traffic noise OR 0.94 (95% CI 0.86–1.03) per 10 dB. Weak negative associations were seen for diabetes OR 0.61 (95% CI 0.40–0.92) and cigarette smoking OR 0.86 (95% CI 0.75–0.99), and a positive association was found with hormone therapy OR 1.24 (95% 1.14–1.35). Conclusion: Our data indicate that breast tissue in middle-aged women is highly dependent on childhood body constitution while adult life-style plays a modest role, underlying the need for a long-term perspective in primary prevention of breast cancer

Diabetes, diabetes treatment, and mammographic density in Danish Diet, Cancer, and Health cohort

PURPOSE: We examined whether diabetes and diabetes treatment are associated with MD in a cohort study of Danish women above age of 50 years. METHODS: Study cohort consisted of 5,644 women (4,500 postmenopausal) who participated in the Danish Diet, Cancer, and Health cohort (1993–1997) and subsequently attended mammographic screening in Copenhagen (1993–2001). We used MD assessed at the first screening after the cohort entry, defined as mixed/dense or fatty. Diabetes diagnoses and diabetes treatments (diet, insulin, or oral antidiabetic agents) were self-reported at the time of recruitment (1993–1997). The association between MD and diabetes was analyzed by logistic regression adjusted for potential confounders. Effect modification by menopausal status and body mass index (BMI) was performed by introducing an interaction term into the model and tested by Wald test. RESULTS: Of 5,644 women with mean age of 56 years, 137 (2.4%) had diabetes and 3,180 (56.3%) had mixed/dense breasts. Having diabetes was significantly inversely associated with having mixed/dense breasts, in both, the crude model (odds ratio; 95% confidence interval: 0.33; 0.23–0.48), and after adjustment for adiposity and other risk factors (0.61; 0.40–0.92). Similar inverse associations were observed for 44 women who controlled diabetes by diet only and did not receive any medication (0.56; 0.27–1.14), and 62 who took oral antidiabetic agents only for diabetes (0.59; 0.32–1.09), while women taking insulin had increased odds of mixed/dense breasts (2.08; 0.68–6.35). There was no effect modification of these associations by menopausal status or BMI. CONCLUSIONS: Having diabetes controlled by diet or oral antidiabetic agents is associated with a decrease in MD, whereas taking insulin is associated with an increase in MD

Inter-observer agreement according to three methods of evaluating mammographic density and parenchymal pattern in a case control study:impact on relative risk of breast cancer

BACKGROUND: Mammographic breast density and parenchymal patterns are well-established risk factors for breast cancer. We aimed to report inter-observer agreement on three different subjective ways of assessing mammographic density and parenchymal pattern, and secondarily to examine what potential impact reproducibility has on relative risk estimates of breast cancer. METHODS: This retrospective case–control study included 122 cases and 262 age- and time matched controls (765 breasts) based on a 2007 screening cohort of 14,736 women with negative screening mammograms from Bispebjerg Hospital, Copenhagen. Digitised randomized film-based mammograms were classified independently by two readers according to two radiological visual classifications (BI-RADS and Tabár) and a computerized interactive threshold technique measuring area-based percent mammographic density (denoted PMD). Kappa statistics, Intraclass Correlation Coefficient (ICC) (equivalent to weighted kappa), Pearson’s linear correlation coefficient and limits-of-agreement analysis were used to evaluate inter-observer agreement. High/low-risk agreement was also determined by defining the following categories as high-risk: BI-RADS’s D3 and D4, Tabár’s PIV and PV and the upper two quartiles (within density range) of PMD. The relative risk of breast cancer was estimated using logistic regression to calculate odds ratios (ORs) adjusted for age, which were compared between the two readers. RESULTS: Substantial inter-observer agreement was seen for BI-RADS and Tabár (κ=0.68 and 0.64) and agreement was almost perfect when ICC was calculated for the ordinal BI-RADS scale (ICC=0.88) and the continuous PMD measure (ICC=0.93). The two readers judged 5% (PMD), 10% (Tabár) and 13% (BI-RADS) of the women to different high/low-risk categories, respectively. Inter-reader variability showed different impact on the relative risk of breast cancer estimated by the two readers on a multiple-category scale, however, not on a high/low-risk scale. Tabár’s pattern IV demonstrated the highest ORs of all density patterns investigated. CONCLUSIONS: Our study shows the Tabár classification has comparable inter-observer reproducibility with well tested density methods, and confirms the association between Tabár’s PIV and breast cancer. In spite of comparable high inter-observer agreement for all three methods, impact on ORs for breast cancer seems to differ according to the density scale used. Automated computerized techniques are needed to fully overcome the impact of subjectivity

Incidence and Mortality in Upper Gastrointestinal Cancer After Negative Endoscopy for Gastroesophageal Reflux Disease

BACKGROUND AND AIMS: Gastroesophageal reflux disease (GERD) is associated with an increased risk of cancer of the upper gastrointestinal tract. This study aimed to assess whether and to what extent a negative upper endoscopy in patients with GERD is associated with decreased incidence and mortality in upper gastrointestinal cancer (ie, esophageal, gastric, or duodenal cancer). METHODS: We conducted a population-based cohort study of all patients with newly diagnosed GERD between July 1, 1979 and December 31, 2018 in Denmark, Finland, Norway, and Sweden. The exposure, negative upper endoscopy, was examined as a time-varying exposure, where participants contributed unexposed person-time from GERD diagnosis until screened and exposed person-time from the negative upper endoscopy. The incidence and mortality in upper gastrointestinal cancer were assessed using parametric flexible models, providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 1,062,740 patients with GERD (median age 58 years; 52% were women) followed for a mean of 7.0 person-years, 5324 (0.5%) developed upper gastrointestinal cancer and 4465 (0.4%) died from such cancer. Patients who had a negative upper endoscopy had a 55% decreased risk of upper gastrointestinal cancer compared with those who did not undergo endoscopy (HR, 0.45; 95% CI, 0.43-0.48), a decrease that was more pronounced during more recent years (HR, 0.34; 95% CI, 0.30-0.38 from 2008 onward), and was otherwise stable across sex and age groups. The corresponding reduction in upper gastrointestinal mortality among patients with upper endoscopy was 61% (adjusted HR, 0.39; 95% CI, 0.37-0.42). The risk reduction after a negative upper endoscopy in incidence and mortality lasted for 5 and at least 10 years, respectively. CONCLUSIONS: Negative upper endoscopy is associated with strong and long-lasting decreases in incidence and mortality in upper gastrointestinal cancer in patients with GERD.Peer reviewe