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Introduction
Breast cancer (BC) is the most common malignancy and the leading cause of cancer death in women worldwide. Approximately 75% of BCs are hormone receptor positive (HR+), HER2-negative (HER2-); systemic therapy with endocrine agents represents the mainstay of treatment both in the early and advanced stages of disease (1,2).
Considering the efficacy and the favorable safety profile of endocrine-directed agents, sequential lines of endocrine therapy (ET) should be the preferred treatment strategy in the advanced setting, except in the case of immediate life-threatening disease or rapid visceral recurrence during adjuvant ET (3,4).
Despite the effectiveness of ET in HR+ advanced BC, disease progression occurs in the majority of patients due to primary or acquired ET resistance.
In the last two decades, loss of estrogen receptor (ER) expression, ER mutations, alterations in co-regulatory proteins, and the upregulation of different signal transduction pathways have been identified as mechanisms leading to ET failure (5).
Among these mechanisms of resistance, cross-talk between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mTOR axis and ER signaling plays a key role in BC proliferation and progression and confers endocrine insensitivity to ET.
Preclinical and clinical studies have shown that co-targeting downstream elements of this pathway using mammalian target of rapamycin (mTOR) inhibitors may synergistically increase the antitumoral activity of ET and overcome anti-hormone therapy resistance in BCs (6–8).
Everolimus (Eve) is a mTOR inhibitor which induces apoptosis by blocking S6K1 and 4E-BP1 activation and inhibits cell growth, proliferation, and G1-S transition. Eve in combination with Exemestane (Exe), a steroidal aromatase inhibitor (SAI), was approved in 2012 based on the results of the pivotal BOLERO-2 trial. In this study, dual-blockade significantly improved progression-free survival (PFS), as compared with Exe alone, in non-steroidal AI (NSAI)-pretreated post-menopausal patients affected by HR+/HER2-MBC, while maintaining health-related quality of life (HRQoL) (9–11).
Over the past two years, a new class of drugs, namely, CDK4/6 inhibitors, in combination with letrozole or fulvestrant as first or second-line therapy, respectively, has increasingly been used in the treatment of luminal MBC disease. Despite the impressive results from recently published studies reporting a significant PFS benefit with CDK4-6 inhibitors (palbociclib, ribociclib, abemaciclib) in combination with ET compared with ET alone, overall survival (OS) data are still awaited and the optimal sequence of ET,...