Breast Cancer: Multiple Subtypes within a Tumor?

Abstract

Breast cancer is a heterogeneous disease, and stratification of tumors is paramount to achieve better clinical outcomes. While it is common to stratify and treat breast tumors as a single entity, insights from studies on intratumoral heterogeneity and cancer stem cells raise the possibility that multiple breast cancer subtypes may coexist within a tumor. A role for plasticity in driving dynamic conversions between breast cancer subtypes is proposed, and the clinical implications include a need for combinatorial therapeutic strategies that account for the discrete disease entities and their plasticity. Accordingly, the advent of single-cell technologies will be crucial in enabling the diagnosis and stratification of distinct disease subtypes down to the cellular level.

Keywords: breast cancer; cancer stem cells; intratumoral heterogeneity; plasticity.

Figure 1. Association between differentiation states of the mammary gland hierarchy and intrinsic breast cancer subtypes

Depiction of differentiation states within the normal mammary gland hierarchy during embryonic development as well as in the postnatal mammary gland. Corresponding intrinsic breast cancer subtypes which are most closely associated with each state are illustrated (on the right).

Figure 2, Key Figure. Multiple breast cancer subtypes within a tumor and its therapeutic implications

Illustrated are individual tumors (Tumors A–D) with cells occupying varying levels of the differentiation hierarchy within a tumor. Distinct differentiation states are illustrated in separate colors. Based on the presumption that each differentiation state is associated most closely with a particular breast cancer intrinsic subtype, this would imply that multiple breast cancer subtypes can co-exist in a tumor. As such, combinatorial therapeutic approaches which account for each disease subtype present may be required for improved efficacy of treatment.

Figure 3. Integrated model of clonal evolution along with hierarchical heterogeneity

An illustration of intra-tumoral genetic heterogeneity as a result of clonal evolution (Each circle with varying color represents a different genetic subclone). In addition to the clonal diversity, each subclone may exhibit plasticity across a spectrum of differentiation states (Note: hierarchy and differentiation states are illustrated below each subclone, and subclones may exhibit plasticity across a different range of differentiation states).This integrated model illustrates the potential interplay between clonal evolution and hierarchical heterogeneity, where genetic sub-clones may have cells that span varying spectra of the differentiation hierarchy.