Background: The risk factors responsible for breast cancer have been well documented, but the roles of risk factors as initiators, causing the occurrence of screen-detected breast cancer, or promoters, responsible for the progression of the screen-detected to the clinically-detected breast cancer, have been scarcely evaluated. Methods: We used data from women in a cohort in Kopparberg (Dalarna), Sweden between 1977 and 2010. Conventional risk factors, breast density, and tumor-specific biomarkers are superimposed to the temporal course of the natural history of the disease. Results: The results show that older age at first full-term pregnancy, dense breast, and a family history of breast cancer increased the risk of entering the preclinical screen-detectable phase of breast cancer by 23%, 41%, and 89%, respectively. Overweight/obesity (body mass index ≥25 kg/m2) was a significant initiator (adjusted relative risk [aRR] 1.15; 95% confidence interval [CI], 0.99e1.33), but was inversely associated with the role of promoter (aRR 0.65; 95% CI, 0.51e0.82). Dense breast (aRR 1.46; 95% CI, 1.12 e1.91), triple-negative (aRR 2.07; 95% CI, 1.37e3.15), and Ki-67 positivity (aRR 1.66; 95% CI, 1.19e2.30) were statistically significant promoters. When the molecular biomarkers were considered collectively as one classification, the basal-like subtype was the most influential subtype on promoters (aRR 4.24; 95% CI, 2.56e7.02) compared with the Luminal A subtype. Discussion: We ascertained state-dependent covariates of initiators and promoters to classify the risk of the two-step progression of breast cancer. The results of the current study are useful for individuallytailored screening and personalized clinical surveillance of patients with breast cancer that was detected at an early stage.
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