Resistance to Trastuzumab in Clinical Her2 Breast Cancer: Possible Relation to Molecular Subtype and Cancer Stem Cells

Abstract

Molecular breast cancer (BC) subtypes and cancer stem cells (CSCs) can determine sensitivity to trastuzumab. A better predictivevalue of clinical human epidermal growth factor receptor2 (cHER2) BC can be provided, by incorporating CSCs heterogeneityinto clinical decisions. The study aimed at investigating involvement of transition of CSCs biology and the molecular subtype indevelopment of trastuzumab resistance in HER2 BC, recommending the use of trastuzumab combinations/modifications able tosuppress CSCs and overcome trastuzumab resistance. The study was conducted on 40 BC patients age range 27-63 years, 20served as control group and 20 as metastatic (predicted resistance) group. Clinicopathological analysis included HER2, ER andPR status, chemotherapy regimen and number of herceptin cycles. Histological analysis included, molecular subtype markers(HER2 and cytokeratin (CK) 5/6), CSCs marker CD44 and morphometric studies. Quantitative polymerase chain reaction (qPCR)was performed. In the metastatic group significant decrease in the area% of HER2 positive (+ve) immunoexpression (IE),significant increase in the area% of CK5/6 IE and CD44 +ve cells was detected. qPCR values of HER2 gene confirmed asignificant decrease. It was concluded that resistance to trastuzumab in the metastatic group of HER2 BC is related to basal likesubtype and overexpression of CD44 +ve CSCs. This nictitates IHC assessment of molecular subtype and type of CSCs to allowthe choice of most appropriate treatment regimen giving best expected prognosis.