Estrogen Receptor-Positive Breast Cancer: Exploiting Signaling Pathways Implicated in Endocrine Resistance

Abstract

Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-α is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal. Several classes of antiestrogenic agents are available for patients with early, advanced, or metastatic BC, including selective ER modulators, aromatase inhibitors, and a selective ER degrader. Clinical development is focused upon characterizing the efficacy and tolerability of inhibitors that target the phosphatidylinositol 3 kinase (PI3K)/akt murine thymoma viral oncogene (AKT)/mammalian target of rapamycin inhibitor (mTOR) signaling pathway or the cyclin-dependent kinase 4/6 (CDK4/6) cell cycle pathway in women with hormone receptor-positive, human epidermal growth receptor 2-negative BC who have demonstrated disease recurrence or progression. De novo and acquired resistance remain a major challenge for women with BC receiving antiestrogenic therapy. Therefore, sequential combination of targeted ET is preferred in these patients, and the ever-increasing understanding of resistance mechanisms may better inform the selection of future therapy. This review describes the intricate roles of the PI3K/AKT/mTOR and CDK4/6 pathways in intracellular signaling and the use of endocrine and endocrine-based combination therapy in BC.

Implications for practice: The foundational strategy for treating hormone receptor-positive, human epidermal growth receptor 2-negative, advanced breast cancer includes the use of endocrine therapy either alone or in combination with targeted agents. The use of combination therapy aims to downregulate cell-signaling pathways with the intent of minimizing cellular "crosstalk," which can otherwise result in continued tumorigenesis or progression through redundant pathways. This review provides the clinician with the molecular rationale and clinical evidence for these treatments and refers to evidence-based guidelines to inform the decision-making process.

Keywords: Aromatase inhibitor; CDK4/6 inhibitor; Endocrine therapy; Estrogen receptor degrader; mTOR inhibitor.

Figure 1.

Critical nuclear (classical) and nonnuclear (alternative) signaling pathways implicated in endocrine resistance and targets for drugs in development. Note: Upon ligand binding, the estrogen‐ER complex dimerizes and interacts with coregulator proteins and specific sequences of DNA and the estrogen response elements to promote the transcription of a wide range of genes that participate in the regulation of the cell cycle, DNA replication, cellular differentiation, apoptosis, and angiogenesis. Abbreviations: AKT, akt murine thymoma viral oncogene; CDK4/6, cyclin‐dependent kinase 4/6; E2, estradiol; E2F, E2F transcription factors; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERα, estrogen receptor‐α; HER1, human epidermal growth receptor 1; HER2, human epidermal growth receptor 2; HER3, human epidermal growth receptor 3; HER4, human epidermal growth receptor 4; IGFR, insulin‐like growth factor receptor; MAPK, mitogen‐activated protein kinase; MEK, mitogen‐activated ERK‐activating kinase; mTOR, mammalian target of rapamycin; P, phosphate; PI3K, phosphoinositide‐3‐kinase; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; Rb, retinoblastoma protein; RTK, receptor tyrosine kinase; SERD, selective estrogen receptor downregulator; SERM, selective estrogen receptor modulator. *Upon ligand binding, the estrogen‐ER complex dimerizes and interacts with coregulator proteins and specific sequences of DNA and the estrogen response elements (EREs) to promote the transcription of a wide range of genes that participate in the regulation of the cell cycle, DNA replication, cellular differentiation, apoptosis, and angiogenesis.

Figure 2.

Treatment algorithm for endocrine therapy for hormone receptor‐positive metastatic breast cancer. Treatment recommendations for premenopausal patients include ovarian suppression. In the setting of patients with no prior adjuvant endocrine therapy, tamoxifen may be considered for premenopausal women. (Adapted from Rugo et al. [5] with permission from the American Society of Clinical Oncology.) Note: Treatment alternatives include an AI with or without a CDK4/6 inhibitor or fulvestrant with or without a CKD4/6 inhibitor. Abbreviations: AI, aromatase inhibitor; CDK4/6, cyclin‐dependent kinase 4/6.