Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role

Abstract

Endocrine therapy (ET) is a pivotal strategy to manage early- and advanced-stage estrogen receptor-positive (ER+) breast cancer. In patients with metastatic breast cancer (MBC), progression of disease inevitably occurs due to the presence of acquired or intrinsic resistance mechanisms. ET resistance can be driven by ligand-independent, ER-mediated signaling that promotes tumor proliferation in the absence of hormone, or ER-independent oncogenic signaling that circumvents endocrine regulated transcription pathways. Estrogen receptor 1 (ESR1) mutations induce constitutive ER activity and upregulate ER-dependent gene transcription, provoking resistance to estrogen deprivation and aromatase inhibitor therapy. The role ESR1 mutations play in regulating response to other therapies, such as the selective estrogen receptor degrader (SERD) fulvestrant and the available CDK4/6 inhibitors, is less clear. Novel oral SERDs and other next-generation ETs are in clinical development for ER+ breast cancer as single agents and in combination with established targeted therapies. Recent results from the phase III EMERALD trial demonstrated improved outcomes with the oral SERD elacestrant compared to standard anti-estrogen therapies in ER+ MBC after prior progression on ET, and other agents have shown promise in both the laboratory and early-phase clinical trials. In this review, we will discuss the emerging data related to oral SERDs and other novel ET in managing ER+ breast cancer. As clinical data continue to mature on these next-generation ETs, important questions will emerge related to the optimal sequence of therapeutic options and the genomic and molecular landscape of resistance to these agents.

Keywords: SERD; breast cancer; endocrine therapy; estrogen; metastatic disease.

Figure 1.

Drivers of ET resistance can be broadly subdivided into two categories of (i) ER-dependent and (ii) ER-independent mechanisms. (a) Ligand binding domain Estrogen Receptor 1 (ESR1) mutations mediate ligand-independent ER signaling and promote ET resistance via constitutive ER activity, upregulated coactivator binding, and stability against proteolytic degradation; ER remains a viable therapeutic target in these tumors. ER-independent resistance may be mediated by several mechanisms including mutations or amplifications in growth factor-driven RTKs (HER2, EGFR, and FGFR), alterations in MAPK pathway components including KRAS, BRAF, MAP2K1, and NF1, and upregulation in PI3K/AKT pathway signaling, though notably, PIK3CA and AKT mutations have not been shown to provoke resistance in the clinical setting. These alterations serve to upregulate mitogenic and survival signaling and promote cell cycle progression and drug resistance. (b) At the cellular level, depicted are select pathways implicated in response and resistance to ET in ESR1-mut and ESR1-wt metastatic breast cancer. Note, while ER-dependent and ER-independent pathways are largely depicted separately for conceptualization, there is considerable intracellular crosstalk between these pathways. Purple factors are involved in estrogen-dependent signaling. Green factors facilitate estrogen-independent, ER-mediated signaling. Red, orange, and pink factors engage in ER crosstalk, and dysregulation in mitogenic signaling pathway components can contribute to ER-independent tumor growth and SERD resistance. AKT, protein kinase B; CDK, cyclin-dependent kinase; CoA, coactivator; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERE, estrogen response element; ERK, extracellular signal-regulated kinase; ESR1-mut, ESR1 mutant; ESR1-wt, ESR1 wild-type; ET, endocrine therapy; FGFR, fibroblast growth factor receptor; GF RTK, growth factor-driven receptor tyrosine kinase; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated protein kinase; MEK, meiotic chromosome-axis-associated kinase; mTOR, mammalian target of rapamycin; p, phosphate; PI3K, phosphoinositide 3-kinase; Rb, retinoblastoma; SERD, selective estrogen receptor degrader.

Figure 2.

The mechanisms of action of different ETs, simplified for conceptualization. (a) Estrogen binds the ER, a ligand-dependent transcription factor, promoting ER dimerization and translocation to the nucleus. The estrogen-bound ER dimer regulates gene expression that facilitates cell growth and survival. (b) The AIs block the aromatization of androgens to estrogen. (c) SERMs competitively bind ER and mediate a tissue-dependent anti-estrogen effect. (d) SERDs slow ER nuclear translocation, increase receptor turnover, and reduce transcription of ER-regulated genes. (e) PROTACs mediate an interaction between ER and the E3 ligase complex, facilitating ubiquitination of ER and subsequent proteasomal degradation; the PROTAC molecule is recycled in this process. (f) SERCAs covalently bind the C530 residue in the ER ligand-binding domain and promote a unique antagonist conformation that decreases ER-regulated gene transcription. (g) CERANs bind ER and potentiate their effect by inducing ER degradation and blocking transcriptional activity. AIs, aromatase inhibitors; CERANs, complete estrogen receptor antagonists; ER, estrogen receptor; ETs, endocrine therapies; PROTACs, proteolysis targeting chimers; SERCAs, selective estrogen receptor covalent antagonists; SERDs, selective estrogen receptor degraders; SERMs, selective estrogen receptor modulators.