Why Has Breast Cancer Screening Failed to Decrease the Incidence of de Novo Stage IV Disease?

Background: Despite screening mammography, the incidence of Stage IV breast cancer (BC) at diagnosis has not decreased over the past four decades. We previously found that many BCs are small due to favorable biology rather than early detection. This study compared the biology of Stage IV cancers with that of small cancers typically found by screening. Methods: Trends in the incidence of localized, regional, and distant female BC were compared using SEER*Stat. The National Cancer Database (NCDB) was then queried for invasive cancers from 2010 to 2015, and patient/disease variables were compared across stages. Biological variables including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2), grade, and lymphovascular invasion were sorted into 48 combinations, from which three biological subtypes emerged: indolent, intermediate, and aggressive. The distributions of the subtypes were compared across disease stages. Multivariable regression assessed the association between Stage IV disease and biology. Results: SEER*Stat confirmed that the incidence of distant BC increased between 1973 and 2015 (annual percent change [APC] = 0.46). NCDB data on roughly 993,000 individuals showed that Stage IV disease at presentation is more common in young, black, uninsured women with low income/education and large, biologically aggressive tumors. The distribution of tumor biology varied by stage, with Stage IV disease including 37.6% aggressive and 6.0% indolent tumors, versus sub-centimeter Stage I disease that included 5.1% aggressive and 40.6% indolent tumors (p < 0.001). The odds of Stage IV disease presentation more than tripled for patients with aggressive tumors (OR3.2, 95% CI 3.0-3.5). Conclusions: Stage I and Stage IV breast cancers represent very different populations of biologic tumor types. This may explain why the incidence of Stage IV cancer has not decreased with screening.