Breast cancer is a multifaceted disease comprising of distinct biological subtypes with diverse natural history, presenting a varied spectrum of clinical, pathologic and molecular features with different prognostic and therapeutic implications.1
Recent attention has been directed singularly at molecular classifications of breast cancer.1,2
Currently, routine clinical management of breast cancer incorporates specific molecular markers; namely ER-estrogen receptor, PR-progesterone receptor, HER2-human epidermal growth factor receptor 2 gene, that have been proven to provide therapeutic, predictive and prognostic value.3
Global gene expression profiles (GEP) has led to the identification of five molecular breast cancer subtypes (), of which only four have been well defined while the fifth being “normal mammary stromal cells like” is poorly defined.
Types of invasive breast carcinomas based on gene expression profiling (GEP).
The hormonal positive group (ER and/or PR positive) of tumors are clustered into a large group named ‘luminal class’ which is further sub-divided into Luminal A and Luminal B depending on presence or absence of HER2 positivity. The hormonal negative group of tumors is comprised of
- HER-2+ type: Tumors with gene characteristics of HER2 amplification
- Basal type: Tumors with gene expression that is similar to normal basal/myoepithelial cells
- Normal breast stromal cells like tumors that lack hormonal group, HER2 amplification and basal-like expression profile which are similar to normal mammary stromal cells.3,4
Breast cancers ER/PR−, HER2− phenotype are classified as triple negative/basal-like tumors3
and have poor prognosis and therapy response.5
Although an ER negative/PR negative/HER-2 negative (ER-/PR-/HER-2-) or “triple negative” immunophenotype is considered sufficient to identify basal-like tumors, increasing evidence shows that “basal-like” and “triple negative” are not synonymous. A more complete definition should include expression of basal cytokeratins (CK5/6, 14, 17) and/or over-expression of human epidermal growth factor receptor 1 (HER-1).6
This is further supported by recent evidence suggesting that triple negative breast carcinomas represent a more heterogeneous group than basal-like tumors.7
The aggressive behavior of these triple negative breast tumors is due to the co-expression of basal markers.8
Basal cytokeratins (CK) represent a large number of high molecular weight (HMW) cytokeratins mainly seen in the basal cell layers of stratified epithelium.9
In the human breast, these cytokeratins are also expressed in the basally-located myo-epithelial cell layer and in a small proportion of luminal epithelial cells of the glands.10
Breast tumors characterized by CK5, CK14 and CK17 expression are classified as basal phenotype. As these markers were seen in the basal layers, “basalness” was often interpreted as a sign of a myo-epithelial origin which created confusion. However it has been observed that not only grade 3 invasive ductal carcinomas (NOS), but also other histological breast cancer subgroups, such as metaplastic and medullary carcinomas, with or without associated BRCA1 mutations also expressed CK5/6, a basal marker.11
In contrast to all other breast cancer subgroups, metaplastic subgroups harbor EGFR-amplifications,11
more commonly than other types of breast cancer.12
Thus, breast carcinomas have been deemed basal when they express HMW-cytokeratin even in a single malignant cell.12
“Basal phenotypes” of breast carcinomas are usually ER, PR and HER-2 neu negative and have been consistently associated with expression of epidermal growth factor receptor (EGFR), c-kit, p53, and p63.13
Basal breast cancer requires a set of diagnostic markers, and has been defined differently in different studies.12
In 2009, Rakha and Ellis,3,14
recommended 4 basal markers, namely C5/6, CK14, CK17 and EGFR of which at-least 2 should be positive to be termed as Basal-like breast cancer.
The present study has been undertaken to:
- Evaluate the expression of two basal markers (CK5/6 and EGFR) among triple negative breast cancers and high grade infiltrating duct carcinomas.
- Study whether triple negative phenotype (IHC profile) can be a surrogate marker (profile) for basal phenotype.
- Correlate the expression of basal markers with disease free survivals among triple negative phenotype and high grade infiltrating duct carcinomas.