Abstract and Introduction
Abstract
Breast cancer is a heterogeneous disease, divisible into a variable number of clinical subtypes. A fundamental question is how many etiological classes underlie the clinical spectrum of breast cancer? An etiological subtype reflects a grouping with a common set of causes, whereas a clinical subtype represents a grouping with similar prognosis and/or prediction. Herein, we review the evidence for breast cancer etiological heterogeneity. We then evaluate the etiological evidence with mRNA profiling data. A bimodal age distribution at diagnosis with peak frequencies near ages 50 and 70 years is a fundamental characteristic of breast cancer for important tumor features, clinical characteristics, risk factor profiles, and molecular subtypes. The bimodal peak frequencies at diagnosis divide breast cancer overall into a "mixture" of two main components in varying proportions in different cancer populations. The first breast cancer tends to arise early in life with modal age-at-diagnosis near 50 years and generally behaves aggressively. The second breast cancer occurs later in life with modal age near 70 years and usually portends a more indolent clinical course. These epidemiological and molecular data are consistent with a two-component mixture model and compatible with a hierarchal view of breast cancers arising from two main cell types of origin. Notwithstanding the potential added value of more detailed categorizations for personalized breast cancer treatment, we suggest that the development of better criteria to identify the two proposed etiologic classes would advance breast cancer research and prevention.
Introduction
Clinically, breast cancer is widely recognized as a heterogeneous disease. In this commentary, we focus instead upon the etiological perspective of breast cancer heterogeneity. By etiological heterogeneity, we mean breast cancer subtypes (components, classes, or groupings) that share common sets of causes. This is distinct from a clinical subtype, which refers to tumors with common prognostic characteristics and/or predictive features (response to targeted-treatment).
As efforts proceed to improve the taxonomy of clinical breast cancer, a fundamental question persists; how many etiological subtypes actually exist? Clinical taxonomic systems have defined multiple classes in an effort to optimize therapeutic management. At its extreme, this approach translates into "precision" or "personalized" medicine, with a view that each person's tumor is unique.
We propose a more parsimonious view for breast cancer etiology, which we believe is consistent with a hierarchal view of breast cancer derived from two main cell types of origin. We show that any given breast cancer molecular or clinical category demonstrates a mixture of two stereotypical age-specific incidence patterns with bimodal peak frequencies near ages 50 years and 70 years. We hypothesize that the consistency of this pattern supports a two-component mixture model, where different molecular and/or clinical categorizations represent variable combinations of two etiological subtypes. In this model, it is the difference in the relative distributions of the two putative subtypes that endows any given breast cancer categorization with its distinguishable biological features.