Chapter 75: Breast Cancer Subtypes Identified by Gene Expression Profiles and Molecular Markers

INTRODUCTION

In 2000, the era of genomic medicine in breast cancer was introduced when Perou et al¹ identified the “molecular portraits” of breast cancer. By analyzing the gene expression patterns of 8102 genes from 65 breast tumors, these authors identified four broad groups of tumors: (i) estrogen receptor (ER) positive/luminal-like, (ii) basal-like, (iii) ErbB-2 positive, and (iv) normal breast. These subtypes appeared biologically distinct as evidenced by their distinct genetic makeups and clinically distinct as evidenced by significant differences in outcome across the four groups. These initial subtypes have since been further refined by a number of groups, including The Cancer Genome Atlas Network,² and a consensus has emerged that there are four important subtypes, often referred to as luminal A, luminal B, HER2/neu positive, and basal-like, each with distinct features and clinical behavior.

The classification of breast cancer according to molecular subtypes has created a new paradigm for understanding and treating this disease. This new paradigm has opened the door to more personalized treatment and has identified opportunities for novel areas of investigation and clinical trials. This chapter will outline the characteristics of the different molecular subtypes of breast cancer and the clinical implications of each subtype with regard to treatment and prognosis.

CHARACTERISTICS OF THE TUMOR SUBTYPES

Biological Characteristics

The luminal A subtype is the most common breast cancer subtype. Luminal A tumors are ER positive, progesterone receptor (PR) positive, and HER2/neu negative. They are characterized by low histologic grade and good prognosis. Luminal A tumors have low expression of Ki-67 and are most likely to retain activity of major tumor suppressors RB1 and TP53.^2-4

Luminal B tumors have a higher grade and higher Ki-67 expression than luminal A tumors and are associated with a worse prognosis. These tumors are typically ER and/or PR positive and HER2/neu negative. The frequency of TP53 mutations is higher in the luminal B subtype than in the luminal A subtype.^2-4

Basal-like tumors, which account for 10% to 20% of breast cancers, are often referred to as triple-negative breast cancers (TNBCs) because they are typically negative for ER, PR, and HER2/neu expression. Basal-like tumors have a high frequency of TP53 mutations (80%) as well as RB1 and BRCA1 mutations. Basal-like tumors are characterized by high Ki-67 expression, high histologic grade, and a poorer prognosis compared to the luminal subtypes.^2-4

The HER2/neu-positive subtype, which accounts for 15% to 20% of breast cancer cases, is divided into two subgroups: tumors that express ER genes and tumors that do not express ER genes. The HER2/neu-positive subtype is characterized by overexpression of HER2/neu and HER2/neu-associated genes, high Ki-67 expression, high histologic grade, and a poor prognosis. HER2/neu-positive tumors have higher expression of TP53 than do luminal-HER2/neu-positive tumors, which have higher expression of ...