Cytokeratin KRT8/18 expression differentiates distinct subtypes of grade 3 invasive ductal carcinoma of the breast

Invasive ductal carcinomas of the breast (IDC) are routinely assessed on hematoxylin and eosin stained paraffin sections, with limited use of immunohistochemistry (IHC). Most IDC are regarded as a single diagnostic entity, IDC of no special type (IDC-NST), which is subdivided further only by grading. However, recent research suggests that there is high clinical relevance in differentiating IDC subtypes. Here, we ascertain whether tumor histology alone can predict basal or luminal cell phenotype in high-grade IDC-NST, and whether IHC and molecular characteristics are associated with the observed morphologies. A total of 29 grade 3 IDC-NST samples were studied, 10 tumors from a selected pilot cohort A and 19 tumors from an unselected validation cohort B. Along with histopathological assessment, the expression of ESR1, PGR, ERBB2 (HER-2), the basal/myoepithelial marker TP73L (p63), cytokeratins 5/6 (KRT5/6) and 14 (KRT14), and the luminal-specific cytokeratins 8/18 (KRT 8/18) and 19 (KRT19) was assessed by IHC. Hierarchical cluster analysis of clinicopathological variables and, separately, microarray expression profiles showed that the phenotypically distinctive basaloid and luminal tumors of cohort A fell into two main groups, defined by heterogeneous or uniformly positive expression of KRT8/18. The 38 genes differentially expressed between these two classes included ERBB2, KRT8, and six other genes previously associated with ERBB2-positive or luminal phenotypes. Tumor histology was not predictive for validation cohort B, but quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed two molecularly defined clusters that again aligned with the KRT8/18 staining phenotypes. Metaphase comparative genomic hybridization revealed 10q, 16q, and 20q copy-number imbalances that associated recurrently with KRT8/18 staining patterns.