TAM is an non-steroidal anti-estrogen with partial estrogen-agonist activity that is widely used in the treatment of ER+ BC (Figure 1).13,14 Although patients with ER- tumors do not typically respond to these treatments, studies have shown that between 5% and 10% of these patients still benefit from therapy with TAM.13,15,16 The response to TAM is often of limited duration, suggesting that patients treated with TAM develop resistance over time.17,18 However, the mechanism through which this resistance occurs remains unknown. Several studies in patients with BC in the metastatic phase have reported that although >50% of patients with ER+ BC respond to TAM therapy, 40% of patients receiving TAM as adjuvant therapy eventually relapse and die from their illness.17 Resistance is thus the main problem with endocrine therapy.
Although endocrine therapy with TAM has been highly successful, 20%–30% of patients develop therapeutic resistance.14,17,19 Several mechanisms have been suggested that can lead to the development of resistance to endocrine therapy and include genetic and epigenetic factors.20,21 Among the main mechanisms leading to TAM resistance are:
Mutations in the ESR1 gene have been associated with acquired resistance from prolonged exposure to endocrine therapy with anti-estrogens.22 The specific point mutations in ESR1 that are associated with resistance lead to the loss of ER expression and the development of resistance to treatment.23 Such modifications cause further proliferation and tumor progression in the absence of hormonal stimulation.23
One of the molecular mechanisms underlying the resistance to endocrine therapy involves polymorphisms in cytochrome P450 family 2 subfamily D member 6 (CYP2D6), a member of the cytochrome P450 family that converts TAM into active metabolites (4-hydroxy tamoxifen-4OH-TAM). Such polymorphisms lead to the expression of enzymes with different levels of activity that result in reduced responses to TAM.24 (Figure 2A)
Alterations in translation signals lead to increased expression and activity of the tyrosine kinase family receptors, such as human EGFR, insulin-like growth factor 1 receptor (IGFR), and G protein-coupled estrogen receptor (GPR30).25 These events result in aberrant activation of cyclic adenosine monophosphate/protein kinase A (cAMP/PKA), mitogen-activated protein kinase (MAPK/ERK), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways.26 Activation of these kinases leads to phosphorylation of ER and its co-activators such as collagen-binding A-domains of integrins (A1B1), mediator complex subunit 1 (MED1), or the coactivator-associated arginine methyltransferase 1 (CARM1), leading to the activation of proliferation and inhibition of apoptosis.27 (Figure 2B).
In endocrine resistance, expression of factors such as fork head box protein A1 (FOXA1) and PBX homeobox 1 (PBX1) is often altered, leading to the altered or aberrant expression of ER28 (Figure 2C). ER deregulation increases not only HER2-mediated signaling but also the activation of transcription factors such as SP1, AP-1, and nuclear factor kappa B (NFκB), which promotes the transcription of oncogenes.29
Other mechanisms that can lead to TAM resistance include the activation of alternative signaling pathways that prevent and/or exceed blocking of estrogen signaling induced by TAM. For example, mutations in the tumor suppressor protein, phosphatase and tensin homolog (PTEN), leads into uncontrolled transduction of the PI3K signal in ER+ tumors, leading to treatment resistance30,31 (Figure 2D). Alternatively, tumors can acquire TAM resistance through the regulation of AKT.32 Additionally, tumor cells can achieve resistance by decreasing the concentration of active TAM through the metabolism of an altered TAM.21 Furthermore, activation of PI3K/AKT pathway causes phosphorylation of demethyltransferase proteins [lysine demethylase 6B (KDM6B)] and methyltransferase proteins [similar to enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)], which modify histones; this epigenetic mechanism leads to the development of endocrine therapy resistance from the reactivation of genes (Figure 2D).
FUL is an ER+ regulator with low cytotoxicity that, contrary to TAM, acts as an antagonist by binding, blocking and degrading ER and inhibiting ER transcriptional activity33 (Figure 1). Therefore, its action is more powerful than that of TAM.34 FUL has recently been approved for use in combination with Piqray (alpelisib),35 which acts as a selective inhibitor of PI3K.36 The effectiveness of this combination therapy (FUL + Piqray) was determined in the SOLAR-1 trial, in which postmenopausal women and men with advanced or metastatic BC with ER+/PR+/HER2- and mutations in the PIK3CA gene who were treated with the combination showed significantly prolonged progression-free survival.37
AIs are one of the major treatment options for ER+ BC in postmenopausal patients. AIs stop estrogen production in postmenopausal women by blocking the aromatase enzyme, which converts androgen hormone to small amounts of estrogen. Anastrozole, exemestane and letrozole are AIs that are used in all clinical stages of BC worldwide (Figure 1). Anastrozole and letrozole are non-steroidal AIs, while exemestane is a steroidal AI.38 Although these three compounds have been shown to suppress overall plasma and tissue estrogens by >90%, some studies suggest that letrozole is the most potent of the nonsteroidal compounds.39
In metastatic BC, these AIs can be used sequentially and cause new responses in selected patients after resistance to the first treatment. For example, metastatic BC patients can benefit from a steroidal AI (exemestane) when they relapse after initial treatment with a non-steroidal AI (anastrozole or letrozole).39–41 However, information about the benefit of using a non-steroidal AI after a steroid AI is scarce. Based on the results in metastatic BC after progression with anastrozole or letrozole therapy, treatment with exemestane alone or in combination with an mTOR inhibitor such as everolimus has been recommended.38
The addition of CDK4/6 inhibitors to standard endocrine therapy has improved outcomes in first and last line therapy settings.12 CDK4/6 inhibitors are anticancer drugs that have been mainly investigated in the last decade. The anti-carcinogenic effect of CDK4/6 inhibitors is based on their ability to block the progression of the cell cycle from G1 phase to S phase through blocking the activity of the cyclin D-CDK4/6 holoenzyme, thus limiting the proliferation of sensitive tumor cells.42 Currently, three selective CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved by the Food and Drug Administration (FDA) for use in the treatment of ER+/HER2- BC43 (Figure 1). The use of these inhibitors in combination with AI as first-line therapy or with FUL as second-line therapy in ER+/HER2- metastatic BC has shown improved progression-free survival in Phase III trials.12,44,45 However, abemaciclib is the only inhibitor among the three CDK4/6 inhibitors that has received FDA approval as monotherapy in ER+/HER2- metastatic BC, indicating its high potential as a single agent.46,47
Several phase III trials, such as the PALOMA-3 trial (FUL + palbociclib/placebo),48 the MONARCH-2 trial (FUL + abemaciclib/placebo),44 and the MONALEESA-3 trial (FUL with or without ribociclib),49 have demonstrated the efficacy of the combination of FUL and CDK4/6 inhibitors. In the PALOMA-3 trial, the addition of palbociclib to FUL resulted in a prolongation of overall survival of 6.9 months among patients with advanced ER+/HER2- BC who showed disease progression after prior endocrine therapy.50 In the MONARCH-2 and MONALEESA-3 clinical trials, the combination of FUL with abemaciclib or ribociclib, respectively, resulted in an improvement in both progression-free survival and overall survival.50,51
Despite the benefits of CDK4/6 inhibitors, some adverse effects have been observed, including hematological toxicities, mainly neutropenia, and non-hematological toxicities such as fatigue, nausea, vomiting, stomatitis, alopecia, skin rash, diarrhea, decreased appetite, and infections. However, such toxicities are uncomplicated and manageable with dose interruption or reduction.52
Recent studies have also shown that CDK4/6 inhibitors have similar efficacy when combined with an AI in the first-line treatment of ER+ metastatic BC and are superior to monotherapy with FUL or AI, regardless of tumor characteristics.12 These findings confirm that CDK4/6 inhibitors improve survival outcomes for ER+ BC patients when incorporated with AI in both the first and last lines.47
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