Deciphering Morphological Spectrum, Stemness and PI3K/AKT/PTEN/MAPK Pathway Alterations in Metaplastic Breast Carcinoma

Metaplastic breast carcinoma (MBC) is a heterogenous group of invasive breast cancer with distinct morphological patterns and negativity for hormone receptors and HER2. The pathogenesis of MBC is unknown but tumour cells exhibit epithelial-mesenchymal transition and breast cancer stem cell-like characteristics. Genomic characterisation of these tumours can lead to identification of targetable mutations which may help in improving the overall treatment outcome. Sixty-seven retrospective cases of MBC were sub-classified morphologically. Cytoplasmic expression of ALDH1 was evaluated using IHC to estimate the stemness. Alteration in PI3K/AKT/PTEN/MAPK pathway was studied using next generation sequencing (n = 47). Histological subtypes were squamous cell carcinoma (n = 25), Metaplastic carcinoma with heterologous mesenchymal differentiation (n = 19), spindle cell carcinoma (n = 19), Fibromatosis like metaplastic carcinoma (n = 3), and Mixed metaplastic carcinoma (n = 1). ALDH1 was positive in 31.3% cases. PI3K was the most frequently altered gene followed by PTEN, TP53 and MAPK1 gene. PI3K alterations were more frequent in Spindle cell carcinoma and squamous carcinoma This study identified high frequency of stem cell marker and targetable genetic alterations in the PI3K signalling pathway. Thus, Inhibitors of the PI3K signalling pathway are ideal candidates for targeted therapy for MBC irrespective of histological subtype.