Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast

Pure apocrine carcinoma of the breast is rare and has been defined by using a combination of morphologic (apocrine morphology in >90% of tumour cells) and immunohistochemical criteria (oestrogen receptor (ER) and progesterone receptor (PR) negative and androgen receptor (AR) positive). Recent advances in the molecular classification of breast tumours have uncovered a subset of breast tumours associated with high expression of androgen receptor mRNA including the so-called ‘luminal androgen receptor (LAR) tumours’ and ‘molecular apocrine tumours’ (MATs). Recognition of these tumour subsets has opened potential avenues for therapies exploiting the AR pathway in triple negative breast carcinoma (TNBC). In this second part of our two-part review, we focus on the definition of pure apocrine carcinoma, recent advances in understanding the molecular apocrine signature in breast carcinoma, its relationship to pure apocrine carcinoma defined at the level of light microscopy and immunohistochemistry (IHC) and the therapeutic implications of androgen expression in TNBC. We complete the article with a summary of the utility of IHC in stratifying apocrine lesions of the breast.

Classification of breast tumours into molecular apocrine, luminal and basal groups based on an explicit biological model

ABSTRACTThe gene expression profiles of human breast tumours fall into three main groups that have been called luminal, basal and either HER2-enriched or molecular apocrine. To escape from the circularity of descriptive classifications based purely on gene signatures I describe a biological classification based on a model of the mammary lineage. In this model I propose that the third group is a tumour derived from a mammary hormone-sensing cell that has undergone apocrine metaplasia. I first split tumours into hormone sensing and milk secreting cells based on the expression of transcription factors linked to cell identity (the luminal progenitor split), then split the hormone sensing group into luminal and apocrine groups based on oestrogen receptor activity (the luminal-apocrine split). I show that the luminal-apocrine-basal (LAB) approach can be applied to microarray data (186 tumours) from an EORTC trial and to RNA-seq data from TCGA (674 tumours), and compare results obtained with the LAB and PAM50 approaches. Unlike pure signature-based approaches, classification based on an explicit biological model has the advantage that it is both refutable and capable of meaningful improvement as biological understanding of mammary tumorigenesis improves.