Breast cancer complexity: implications of intratumoral heterogeneity in clinical management

Abstract

Generation of intratumoral phenotypic and genetic heterogeneity has been attributed to clonal evolution and cancer stem cells that together give rise to a tumor with complex ecosystems. Each ecosystem contains various tumor cell subpopulations and stromal entities, which, depending upon their composition, can influence survival, therapy responses, and global growth of the tumor. Despite recent advances in breast cancer management, the disease has not been completely eradicated as tumors recur despite initial response to treatment. In this review, using data from clinically relevant breast cancer models, we show that the fates of tumor stem cells/progenitor cells in the individual tumor ecosystems comprising a tumor are predetermined to follow a limited (unipotent) and/or unlimited (multipotent) path of differentiation which create conditions for active generation and maintenance of heterogeneity. The resultant dynamic systems respond differently to treatments, thus disrupting the delicate stability maintained in the heterogeneous tumor. This raises the question whether it is better then to preserve stability by preventing takeover by otherwise dormant ecosystems in the tumor following therapy. The ultimate strategy for personalized therapy would require serial assessments of the patient's tumor for biomarker validation during the entire course of treatment that is combined with their three-dimensional mapping to the tumor architecture and landscape.

Keywords: Breast cancer; Clinical models; Heterogeneity; Stem cells; Tumor ecosystem.

Figure 1

Model for origination of breast cancer heterogeneity. In route (1), CSC/TICs/progenitors differentiate into breast cancer histotypes of a specific lineage (e.g., hyperplasia, a specific DCIS subtype, etc.), signifying limited or restricted differentiation potential, whereas in route (2), multiple histotypes are generated from CSCs/TICs/progenitors suggesting multipotency. The unipotent and multipotent CSCs/progenitors may represent distinct subsets; alternatively, the CSCs/TICs may produce precursor cells that possess the ability to give rise to one or more histotypes (a, b, c). The histotype composition of a breast tumor or “heterogeneity” would depend upon the renewal and differentiation rates and routes taken by the CSCs/TICs/progenitors, and alterations impacted by clonal evolution and expansions of the differentiated derivatives.

Figure 2

Tile map of a breast cancer section showing histologic homogeneity within a heterogeneous tumor milieu. Note the preservation of orderly ecosystems as defined by areas composed of individual histologic subtypes, (a) hyperplasia, (b) DCIS, and (c) invasive cancer within a complex and heterogeneous tumor milieu, implicating their origination from separate progenitors. Also note the heterogeneity in the stromal microenvironments surrounding each ecosystem (denoted by arrow) that implicate their roles in generation/maintenance of tumor heterogeneity.

Figure 3

Tumors are comprised of heterogeneous ecosystems that have variable therapy sensitivities and the potential to influence growth, survival and therapy responses of neighboring tumor cells through cell-microenvironment mediated interactions. (1) Pathologic complete response, a surrogate endpoint that is predictive of long term disease-free survival, is associated with complete or near complete resolution of the lesion and potentially its heterogeneous landscape. (2) Partial response defined as a ≥30% decrease in tumor size could either result in the residual tumor remaining dormant or stable, or eventually progressing depending upon the compositions and activities of the residual tumor. (3) An increase or no change in tumor size is defined as a “no response” outcome where the most vulnerable tumor subpopulations are eliminated with potential enrichment of the tumor with ecosystems that are more or less heterogeneous and containing therapy resistant variants. In scenarios (2) and (3), the tumors could either attain a state of tumor homeostasis (stable disease) or imbalance (disease progression) depending upon the nature of reestablished tumor ecosystems.