Tumor Heterogeneity in Breast Cancer

Abstract

Breast cancer is a heterogeneous disease and differs greatly among different patients (intertumor heterogeneity) and even within each individual tumor (intratumor heterogeneity). Clinical and morphologic intertumor heterogeneity is reflected by staging systems and histopathologic classification of breast cancer. Heterogeneity in the expression of established prognostic and predictive biomarkers, hormone receptors, and human epidermal growth factor receptor 2 oncoprotein is the basis for targeted treatment. Molecular classifications are indicators of genetic tumor heterogeneity, which is probed with multigene assays and can lead to improved stratification into low- and high-risk groups for personalized therapy. Intratumor heterogeneity occurs at the morphologic, genomic, transcriptomic, and proteomic levels, creating diagnostic and therapeutic challenges. Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Despite the improved knowledge of the complex genetic and phenotypic features underpinning tumor heterogeneity, there has been only limited advancement in diagnostic, prognostic, or predictive strategies for breast cancer. The current guidelines for reporting of biomarkers aim to maximize patient eligibility for targeted therapy, but do not take into account intratumor heterogeneity. The molecular classification of breast cancer is not implemented in routine clinical practice. Additional studies and in-depth analysis are required to understand the clinical significance of rapidly accumulating data. This review highlights inter- and intratumor heterogeneity of breast carcinoma with special emphasis on pathologic findings, and provides insights into the clinical significance of molecular and cellular mechanisms of heterogeneity.

Keywords: biomarkers; breast cancer; genetic markers; histopathology; tumor heterogeneity.

Figure 1

Histopathologic heterogeneity of breast cancer: invasive mammary carcinoma with mixed morphology (A), composed of basaloid areas with osteoid production (B) and ductal not otherwise specified (C) components. Lymph node metastasis showing a diffuse pattern of tumor growth (D). Magnification: 100× (A), 200× (B–D); Hematoxylin-eosin staining.

Figure 2

Biomarker heterogeneity of breast cancer: mucinous carcinoma (A) with variable expression of estrogen receptor from no immunoreactivity to nuclear staining with weak to strong intensity (B); invasive ductal carcinoma (C) with areas of 3+ (positive) and 1+ (negative) membranous staining for human epidermal growth factor receptor 2 (D). Magnification: 200× (A–D); hematoxylin-eosin staining (A,C) and immunohistochemistry (B,D).