Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches
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ABSTRACT:
SUBMITTER: Raheem F
PROVIDER: S-EPMC10671474 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:The importance and role of the estrogen receptor (ER) pathway have been well-recognized in both breast cancer development and progression. The treatment of choice in women with estrogen receptor-positive metastatic breast cancer (ER+ mBC) is classically divided into a variety of endocrine therapies, with three of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (AI), and selective estrogen receptor degraders (SERD). However, resistance develops in 30-50% of patients treated with these endocrine therapies due to a sophisticated and at times redundant interference at the molecular level between the ER, growth factors, and downstream cell-signaling pathways. Tumor response is heightened with adjunctive therapy that includes an mTORC1 inhibitor (everolimus), CDK4/6 inhibitors (palbociclib/ribociclib/abemaciclib), and an α isoform-specific PI3K inhibitor (alpelisib). Each of these inhibitors elicits potent anti-proliferative benefits; however, they fail to induce tumor cell death. Consequently, disease progression almost invariably occurs. Evasion of apoptosis is a hallmark of cancer. The p53 and BCL2 represent two important nodes of the apoptosis signaling pathway. Venetoclax, a potent and selective BCL2 inhibitor, synergizes with hormonal therapy in ER+ breast cancer models and is active in clinical trials. Similarly, an MDM2 inhibitor, AMG-232, which induces p53 is active in early clinical trials of both liquid and advanced solid tumor patients. In our ER+ BC cohort (Avera Cancer Institute, Sioux Falls, SD), we observed more than 70% of wild type TP53 and over 10% amplification of MDM2 and MDM4 as comparable with the TCGA data set. We summarized current treatment options, the molecular mechanisms that predispose to endocrine resistance, and a future pro-apoptotic treatment strategy for ER+ mBC patients. Our review presents critical analyses of the therapeutic options for the clinical management of ER+ Metastatic Breast Cancer in the light of a hypothesis targeting the induction of apoptosis in p53 wild type tumors. We reviewed not only the FDA approved current treatment approaches but also presented a discourse addressing the possibilities for novel combination strategy that can induce tumor cell apoptosis, a critical cellular mechanism delaying/denying tumor progression. Our review is unique as it presents patient data in support of our hypothesis.
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Project description:About 75% of all breast cancers are estrogen receptor (ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens (such as tamoxifen and fulvestrant) and aromatase inhibitors (such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy (acquired resistance) and a proportion of patients may fail to respond to initial therapy (de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectively overcome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.
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Project description:BackgroundResistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.MethodsTo study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant.ResultsWe found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival.ConclusionsThese data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.
| S-EPMC7893923 | biostudies-literature
Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
2018-10-19 | GSE121411 | GEO
Project description:Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients.
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Project description:The majority of breast cancers present with estrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2)-negative features and might benefit from endocrine therapy. Although endocrine therapy has notably evolved during the last decades, the invariable appearance of endocrine resistance, either primary or secondary, remains an important issue in this type of tumor. The improvement of our understanding of the cancer genome has identified some promising targets that might be responsible or linked to endocrine resistance, including alterations affecting main signaling pathways like PI3K/Akt/mTOR and CCND1/CDK4-6 as well as the identification of new ESR1 somatic mutations, leading to an array of new targeted therapies that might circumvent or prevent endocrine resistance. In this review, we have summarized the main targeted therapies that are currently being tested in ER+ breast cancer, the rationale behind them, and the new agents and combinational treatments to come.
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