Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy

Abstract

Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway. The strategy of combined hormone therapy with targeted agents has shown an improvement of progression-free survival (PFS) in several phase II or III trials, including three different classes of drugs: mTOR inhibitors, PI3K and CDK4/6 inhibitors. A recent phase III trial has shown that fulvestrant combined with a CDK 4/6 inhibitor doubles PFS in aromatase inhibitor-pretreated postmenopausal ER+ breast cancer. Other combinations are ongoing to disrupt the interaction between PI3K/AKT/mTOR and cyclin D/CDK4/6/Rb pathways. Despite these successful strategies, reliable and reproducible biomarkers are needed. Tumor genomics are dynamic over time, and blood-based biomarkers such as circulating tumor DNA represent a major hope to elucidate the adaptive mechanisms of endocrine resistance. The optimal combinations and biomarkers to guide this strategy need to be determined.

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

“…Recent preclinical studies suggested the potential utility of a 'triple association' of ET with both CDK 4/6 and mTOR or PI3K inhibitors [46]. Therefore, several early-stage clinical trials are currently exploring this new potential strategy [47].…”

Hydroquinone Exhibits In Vitro and In Vivo Anti-Cancer Activity in Cancer Cells and Mice

“…As the second point, Akt, a cell survival-regulatory enzyme, can be considered as target of HQ. Thus, it was previously confirmed that HQ is able to bind to Cys-310 residue in Akt and subsequently block the phosphorylation of Thr-308 in Akt [ 20 ], an essential step to activate nuclear factor (NF)-κB pathway and to manage cell survival [ 33 ], via activation of inhibitor of κB kinase (IKK) [ 34 , 35 , 36 ]. Since there is lack of a direct evidence on the involvement of Akt as the target of HQ in this study, further detailed experiments will be continued to verify this possibility.…”

Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer

“…HER2 may lead to tamoxifen resistance by activating estrogen receptor co-activator proteins [ 8 ]. P13K/AKT/mTOR signaling pathway activation plays a major role in the development of endocrine resistance and is a target of many therapies designed to overcome resistance [ 10 ]. There are also studies evaluating the role of the ESR1 mutation in acquired endocrine resistant breast cancer.…”

“…This leads to the transition from gap 1 (G1) to the DNA synthesis (S) phase of the cell cycle, ultimately leading to cell division [ 12 ]. Activation of the pathway leading to Rb phosphorylation has been associated with the development of endocrine resistance [ 10 ]. CDK 4/6 inhibitors block the phosphorylation of Rb, leading to cell cycle arrest, and can reverse endocrine resistance when used.…”