The effect of the Flemish breast cancer screening program on breast cancer-specific mortality: A case-referent study.

BACKGROUND: Breast cancer screening programs were introduced in many countries worldwide following randomized controlled trials in the 1980s showing a reduction in breast cancer-specific mortality. However, their effectiveness remains debated and estimates vary. A breast cancer screening program was introduced in 2001 in Flanders, Belgium where high levels of opportunistic screening practices are observed. The effectiveness of this program was estimated by measuring its effect on breast cancer-specific mortality. METHODS: We performed a case-referent study to investigate the effect of participation in the Flemish population-based mammography screening program (PMSP) on breast cancer-specific mortality from 2005 to 2017. A multiple logistic regression model assessed the association between breast cancer-specific death and screening program participation status in the four years prior to (pseudo)diagnosis (yes/no), with adjustment for potential confounders (individual socio-economic position and calendar year of diagnosis) and stratified for age. In addition, we performed different sensitivity analyses. RESULTS: We identified 1571 cases and randomly selected 6284 referents. After adjustment, women who participated in PMSP had a 51 % lower risk of breast cancer-specific mortality compared to those who did not (adjusted odds ratio [aOR] =0.49, 95 % CI: 0.44-0.55). Sensitivity analyses did not markedly change the estimated associations. Correction for self-selection bias reduced the effect size, but the estimate remained significant. CONCLUSION: Our results indicate that in a context of high opportunistic screening rates, participation in breast cancer screening program substantially reduces breast cancer-specific mortality. For policy, these results should be balanced against the potential harms of screening, including overdiagnosis and overtreatment.

Effectiveness of Organized Mammography Screening for Different Breast Cancer Molecular Subtypes.

BACKGROUND: Screening program effectiveness is generally evaluated for breast cancer (BC) as one disease and without considering the regularity of participation, while this might have an impact on detection rate. OBJECTIVES: To evaluate the short-term effectiveness of a mammography screening program for the major molecular subtypes of invasive BC. METHODS: All women who participated in the screening program and were diagnosed with screen-detected or interval BC in Flanders were included in the study (2008-2018). Molecular subtypes considered were luminal and luminal-HER2-positive, human epidermal growth factor receptor 2-positive, and triple-negative BC (TNBC). The relationship between the BC stage at diagnosis (early (I-II) versus advanced (III-IV)) and the method of detection (screen-detected or interval) and the relationship between the method of detection and participation regularity (regular versus irregular) were evaluated by multi-variable logistic regression models. All models were performed for each molecular subtype and adjusted for age. RESULTS: Among the 12,318 included women, BC of luminal and luminal-HER2-positive subtypes accounted for 70.9% and 11.3%, respectively. Screen-detected BC was more likely to be diagnosed at early stages than interval BC with varied effect sizes for luminal, luminal-HER2-positive, and TNBC with OR:2.82 (95% CI: 2.45-3.25), OR:2.39 (95% CI: 1.77-3.24), and OR:2.29 (95% CI: 1.34-4.05), respectively. Regular participation was related to a higher likelihood of screening detection than irregular participation for luminal, luminal-HER2-positive, and TNBC with OR:1.21 (95% CI: 1.09-1.34), OR: 1.79 (95% CI: 1.38-2.33), and OR: 1.62 (95% CI: 1.10-2.41), respectively. CONCLUSIONS: Regular screening as compared to irregular screening is effective for all breast cancers except for the HER2 subtype.

Overdiagnosis of invasive breast cancer in population-based breast cancer screening: A short- and long-term perspective.

BACKGROUND: Overdiagnosis of invasive breast cancer (BC) is a contentious issue. OBJECTIVE: The aim of this paper is to estimate the overdiagnosis rate of invasive BC in an organised BC screening program and to evaluate the impact of age and follow-up time. METHODS: The micro-simulation model SiMRiSc was calibrated and validated for BC screening in Flanders, where women are screened biennially from age 50 to 69. Overdiagnosis rate was defined as the number of invasive BC that would not have been diagnosed in the absence of screening per 100,000 screened women during the screening period plus follow-up time (which was set at 5 years and varied from 2 to 15 years). Overdiagnosis rate was calculated overall and stratified by age. RESULTS: The overall overdiagnosis rate for women screened biennially from 50 to 69 was 20.1 (95%CI: 16.9-23.2) per 100,000 women screened at 5-year follow-up from stopping screening. Overdiagnosis at 5-year follow-up time was 12.9 (95%CI: 4.6-21.1) and 74.2 (95%CI: 50.9-97.5) per 100,000 women screened for women who started screening at age 50 and 68, respectively. At 2- and 15-year follow-up time, overdiagnosis rate was 98.5 (95%CI: 75.8-121.3) and 13.4 (95%CI: 4.9-21.9), respectively, for women starting at age 50, and 297.0 (95%CI: 264.5-329.4) and 34.2 (95%CI: 17.5-50.8), respectively, for those starting at age 68. CONCLUSIONS: Sufficient follow-up time (≥10 years) after screening stops is key to obtaining unbiased estimates of overdiagnosis. Overdiagnosis of invasive BC is a larger problem in older compared to younger women.

Simultaneous measurement of plasma concentrations of proinsulin and C-peptide and their ratio with a trefoil-type time-resolved fluorescence immunoassay.

BACKGROUND: When the concentrations of 2 or more substances are measured separately, their molar ratios are subject to the additive imprecisions of the different assays. We hypothesized that the cumulative error for concentration ratios of peptides containing a common sequence might be minimized by measuring the peptides simultaneously with a "trefoil-type" immunoassay. METHODS: As a model of this approach, we developed a dual-label time-resolved fluorescence immunoassay (TRFIA) to simultaneously measure proinsulin, C-peptide, and the proinsulin-C-peptide ratio (PI/C). A monoclonal antibody captures all C-peptide-containing molecules, and 2 differently labeled antibodies distinguish between proinsulin-like molecules and true C-peptide. RESULTS: The trefoil-type TRFIA was capable of measuring plasma C-peptide and proinsulin simultaneously without mutual interference at limits of quantification of 48 and 8125 pmol/L, and 2.1 and 197 pmol/L, respectively. Within-laboratory imprecision values for the trefoil-type TRFIA ranged between 8.4% and 12% for the hormone concentrations. Unlike the hormone results obtained with separate assays, imprecision did not increase when PI/C was calculated from trefoil assay results (P < 0.05). Peptide concentrations were highly correlated with results obtained in individual comparison assays (r(2) > or = 0.965; P < 0.0001). The total error for PI/C obtained with the trefoil-type TRFIA remained < or = 25% over a broader C-peptide range than with separate hormone assays (79-7200 pmol/L vs 590-4300 pmol/L C-peptide). Preliminary data indicate little or no interference by heterophile antibodies. CONCLUSIONS: The developed trefoil-type TRFIA is a reliable method for simultaneous measurement of proinsulin, C-peptide, and PI/C and provides proof of principle for the development of other trefoil-type multiple-label immunoassays.