Resistance to therapy in estrogen receptor positive and human epidermal growth factor 2 positive breast cancers: progress with latest therapeutic strategies

Abstract

In this article, we focus on the subtype of estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-positive breast cancer (BC). Preclinical and clinical data indicate a complex molecular bidirectional crosstalk between the ER and HER2 pathways. This crosstalk probably constitutes one of the key mechanisms of drug resistance in this subclass of BC. Delaying or even reversing drug resistance seems possible by targeting pathways implicated in this crosstalk. High-risk patients currently receive anti-HER2 therapy, chemotherapy and endocrine therapy in the adjuvant setting. In metastatic cases, most patients receive a combination of anti-HER2 therapy and chemotherapy. Only selected patients presenting more indolent disease are candidates for combinations of anti-HER2 therapy and endocrine therapy. However, relative improvements in progression-free survival by chemotherapy-based regimens are usually lower in ER-positive patients than the ER-negative and HER2-positive subgroup. Consequently, new approaches aiming to overcome endocrine therapy resistance by adding targeted therapies to endocrine therapy based regimens are currently explored. In addition, dual blockade of HER2 or the combination of trastuzumab and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOP) inhibitors targeting the downstream pathway are strategies to overcome resistance to trastuzumab. This may lead in the near future to the less frequent use of chemotherapy-based treatment options in ER-positive, HER2-positive BC.

Identification of differentially expressed profiles of lncRNAs and mRNAs in ER-negative and HER-2 positive breast cancer

“…Moreover, ER-negative (ER-) BC exhibited dismal survival rates due to the highly aggressive and metastatic behavior. However, how ER leads to uncontrolled cell proliferation of breast cancer is yet to be fully understood [27,28]. Moreover, few studies have focused on the dysregulation of lncRNAs in the ER-negative subtype breast cancer.…”

Metastatic breast cancer: Endocrine therapy landscape reshaped

“…The presence of hyperactive growth factor pathways increases ER transcriptional activities in a ligand-independent pattern, i.e., even in the presence of estrogen antagonism. [ 55 56 ]…”

Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes

“…5c , purple), indicating that the performance of EL-NB and EL-B in C+T set relates to the molecular profile determining the response to the presence of trastuzumab in the treatment regimens. Moreover, since trastuzumab has been reported to be substantially less effective in oestrogen receptor (ER)-positive breast cancer 31 , 32 , it is important to note that the ER status of all cases enrolled in our study showed no correlation with the benefit from trastuzumab-containing therapy (Supplementary Fig. 5D , Supplementary Data 4 ).…”