Background: Breast cancer is a heterogeneous disease, divisible into a variable number of clinical subtypes depending upon the analytical approach. A fundamental question is how many etiological subtypes underlie the spectrum of clinical breast tumors? A clinical subtype represents a grouping according to prognosis (outcome) or prediction (expected treatment response), whereas an etiological subtype reflects a common set of causes.

Methods: We initiated a systematic literature review to examine the historical, epidemiological, biostatistical, and molecular evidence for breast cancer etiology. Information sources included CANCERLIT, Index Medicus, and PubMed. Data resources included the Surveillance, Epidemiology, and End Results program.

Results: A bimodal age distribution at diagnosis was a fundamental characteristic of breast cancer for important tumor characteristics, risk factor profiles, molecular markers, and prognosis; suggestive of a ‘mixture’ of two main etiological subtypes in varying proportions in different populations. The first breast cancer tended to arise early in life with modal age-at-diagnosis near 50 years and generally behaved aggressively. The second breast cancer occurred later in life with modal age near 70 years, and usually portended a more indolent clinical course.

Conclusion: Epidemiological and molecular patterns suggest that breast cancer etiology reflects a bimodal breast cancer mixture model, possibly emerging from two stem cells of origin. Notwithstanding, the potential added value of more detailed categorizations and personalized approaches for the targeted treatment of breast cancer, we suggest that the development of criteria to better identify the two proposed main etiologic types would advance etiologic research and the prevention of breast cancer.

Citation Format: William F. Anderson, Philip S. Rosenberg, Aleix Prat, Charles M. Perou, Mark E. Sherman. How many epidemiological types of breast cancer: Two, three, four, or more. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 266. doi:10.1158/1538-7445.AM2014-266