An updated, complex systems model developed by a multidisciplinary expert panel that summarizes the current state of knowledge regarding the interaction between 4 domains of risk factors for breast cancer — biological, behavioral, social, and physical —was described in an article published in Cancer Epidemiology, Biomarkers & Prevention.1

Although it has long been recognized that multiple causal factors underlie breast cancer development, the focus has typically been on those variables that are proximal to the time of disease diagnosis. However, the authors of this article stated that “more may be learned about [breast cancer] etiology and prevention if we expand our attention to the complexity of causal pathways contributing in a more global sense,” and include “an understanding of the upstream determinants of these proximate risk factors.”

Toward that end, and with the objective of “[helping] to inform population- and individual-level prevention strategies and [reveal] gaps in existing literature where more research is needed on mechanisms or pathways to carcinogenesis,” the Paradigm II Complex Conceptual model of invasive breast cancer etiology, applicable to both pre- and postmenopausal women, was developed based on a previous version of the model that was limited to postmenopausal women.1,2  

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Specifically, the updated model is a conceptual framework described by the authors as incorporating “96 relationships linking the biological, behavior, social, and physical domains, demonstrating the complexity of breast cancer causation.” These relationships include proximate risk factors known to directly affect breast cancer incidence; associations between direct and indirect risk factors, such as education and physical activity; and upstream determinants such as income. Furthermore, genetic and biological pathways, as well as information on endocrine-disrupting chemicals were included in the model.

Of note, the interactions between these relationships (as well as the strength of quality of the evidence supporting them), and the direction of the associations, can be directly visualized through an interactive, online version of the model.3

“Taken together, the article and the online dynamic framework aim to educate and facilitate debate and discussion around risk factors and prevention strategies and to highlight areas where further research may substantially enhance our understanding of

breast cancer prevention and control,” the authors noted in their concluding remarks.


  1. Hiatt RA, Engmann NJ, Balke K, et al. A complex systems model of breast cancer etiology: The Paradigm II Conceptual Model. Cancer Epidemiol Biomarkers Prev [published online July 8, 2020].  doi: 10.1158/1055-9965.EPI-20-0016
  2. Hiatt RA, Porco TC, Fengchen L, et al. A multilevel model of postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers Prev. 2014;23:2078-2092.
  3. California Breast Cancer Research Program. A model of breast cancer causation. Accessed July 13, 2020.