Clinical and Pathologic Characteristics of Triple Negative Breast Cancer (TNBC)

TNBCs:
- Present with rapid growth
- Are more likely to be diagnosed clinically rather than mammographically than ER-positive cancers
- Are more likely to be diagnosed as interval cancers between mammograms:
  - However, intrinsic differences in the density of breast tissue among women diagnosed with TNBC may also explain these differences in presentation
Pathologic characteristics:
TNBC are usually:
- High grade
The most common histology is:
- Infiltrating ductal carcinoma:
  - Although a rare histologic subtype:
    - Medullary carcinoma:
      - Is generally triple negative
TNBCs can exhibit geographic necrosis, a pushing border of invasion, and a stromal lymphocytic response (Table)

Immunophenotypic and pathologic features of triple negative breast cancer

An uncommon subgroup of TNBCs:
- Is defined histopathologically as metaplastic:
  - However, this is a diverse group of cancer types ranging from squamous to stromal in nature
By definition:
- TNBC lacks immunohistochemical (IHC) expression of the:
  - ER, PR, and HER2
- Since these three biomarkers represent the only known approved targets for breast cancer treatment:
  - Considerable effort has been made to better understand other biologic forces driving TNBC
Molecular classification of TNBC:
- The triple-negative clinical phenotype:
- Mostly comprises the basal-like molecular subtype:
  - Although triple-negative and basal breast cancers are not synonymous and there is substantial heterogeneity within TNBCs:
- As examples, in one study of utilizing DNA and RNA profiling of TNBCs:
  - Four stable subtypes were identified:
    - Luminal androgen receptor
    - Mesenchymal
    - Basal-like immunosuppressed
    - Basal-like immune-activated
- In another study, 172 triple-negative tumors based on IHC staining were correlated with gene expression profiles that defined the basal subtype:
  - Only 71% of TNBCs were assigned the basal subtype
- In a converse analysis (where subtype was identified and correlated with IHC staining) of 160 tumors:
  - 77% of basal tumors were triple negative by IHC
- Other evidence from copy number variation and mutational analyses has also suggested wide variability and breadth of clonal spectra in TNBC
Basal breast cancer:
- Is characterized by the genomic expression of the “basal cluster,”:
  - A unique cluster of genes that includes the epidermal growth factor receptor (EGFR, also called HER1), basal cytokeratins 5/6, c-Kit, the proliferation cluster, and low expression of the hormone receptor- and HER2-related genes
- Separate subtypes of TNBC have been characterized by gene expression, including:
  - Two basal-like subtypes (BL1 and BL2)
  - Immunomodulatory
  - Mesenchymal
  - Mesenchymal stem-like
  - Luminal androgen subtypes
  - Additional subtypes that have been characterized include:
    - Claudin-low
    - Interferon-rich subtypes
Gene expression analysis:
- Has also revealed that the tumor suppressor gene p53 (TP53) and several DNA repair genes:
  - Particularly the breast cancer susceptibility genes (BRCA):
    - Are either mutated or aberrantly expressed in TNBC
      - These molecular features may have implications for chemotherapy sensitivity to platinum and other directly DNA-damaging agents
Taken together, these studies have produced mixed results with varying conclusions among the different investigators:
- None has reached the level of providing clinical considerations at present