Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer

Reinert, Tomás; Gonçalves, Rodrigo; Bines, José

doi:10.1007/s11864-018-0542-0

Cited by 28 publications

(26 citation statements)

References 51 publications

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“…CCND1 amplification has been shown to be a predictor of poor prognosis in ER+ breast carcinoma patients in multiple studies [20–22]. ESR1 mutations can potentially lead to hormonal therapy resistance for HR+ patients [23]. ZNF703 overexpression has been shown to have resistance to tamoxifen through activation of the Akt/mTOR signaling pathway in a study using luminal B‐type breast cancer cell lines [24].…”

Section: Discussionmentioning

confidence: 99%

Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer

Huang¹,

Li²,

Haberberger³

et al. 2020

The Oncologist

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Background We examined the current biomarker landscape in breast cancer when programmed death‐ligand 1 (PD‐L1) testing is integrated with comprehensive genomic profiling (CGP). Material and Methods We analyzed data from samples of 312 consecutive patients with breast carcinoma tested with both CGP and PD‐L1 (SP142) immunohistochemistry (IHC) during routine clinical care. These samples were stratified into hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2−; n = 159), HER2‐positive (n = 32), and triple‐negative breast cancer (TNBC) cohorts (n = 121). Results We found that in the TNBC cohort, 43% (52/121) were immunocyte PD‐L1–positive, and in the HR+/HER2− cohort, 30% (48/159) had PIK3CA companion diagnostics mutations, and hence were potentially eligible for atezolizumab plus nab‐paclitaxel or alpelisib plus fulvestrant, respectively. Of the remaining 212 patients, 10.4% (22/212) had a BRCA1/2 mutation, which, if confirmed by germline testing, would allow olaparib plus talazoparib therapy. Of the remaining 190 patients, 169 (88.9%) were positive for another therapy‐associated marker or a marker that would potentially qualify the patient for a clinical trial. In addition, we examined the relationship between immunocyte PD‐L1 positivity and different tumor mutation burden (TMB) cutoffs and found that when a TMB cutoff of ≥9 mutations per Mb was applied (cutoff determined based on prior publication), 11.6% (14/121) patients were TMB ≥9 mutations/Mb and of these, TMB ≥9 mutations per Mb, 71.4% (10/14) were also positive for PD‐L1 IHC. Conclusion Our integrated PD‐L1 and CGP methodology identified 32% of the tested patients as potentially eligible for at least one of the two new Food and Drug Administration approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker‐guided potential therapeutic options. Implications for Practice This integrated programmed death‐ligand 1 immunohistochemistry and comprehensive genomic profiling methodology identified 32% of the tested patients as eligible for at least one of the two new Food and Drug Administration‐approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker‐guided potential therapeutic options. These findings suggest new research opportunities to evaluate the predictive utility of other commonly seen PIK3CA mutations in hormone receptor‐positive breast cancers and to standardize tumor mutation burden cutoffs to evaluate its potentially predictive role in triple‐negative breast cancer.

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Section: Discussionmentioning

confidence: 99%

Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer

Huang¹,

Li²,

Haberberger³

et al. 2020

The Oncologist

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“…Given the essential roles of steroid hormones and their cognate NRs in development, homeostasis and metabolism, it is not surprising that dysregulation of their activities is directly responsible for a number of important human conditions (Huang et al 2010, Evans & Mangelsdorf 2014. For instance, the ER is a key driver of 70% of breast cancer subtypes that require estrogen hormones for progression, and different point mutations in the ER genes are linked to acquired resistance to commonly used estrogenblocking drugs such as tamoxifen (Kojetin et al 2008, Katzenellenbogen et al 2018, Nasrazadani et al 2018, Reinert et al 2018. Regarding oxosteroid receptors, single-residue mutations in GR and MR genes have mainly been associated to loss-of-function phenotypes (Zennaro & Fernandes-Rosa 2017).…”

Section: Dysregulation Of Steroid Receptors and Human Diseasementioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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“…In our study, we performed a drug-target network to explore that BUB1 were connected with AR, ESR1, AKT1, and FOXO3 under a scenario of genistein-target network. AR and ESR1 involved in the regulation of gene expression and affect cellular proliferation [30,31]. AKT1 mediated many processes including metabolism, proliferation, cell survival, growth and angiogenesis [32].…”

Section: Discussionmentioning

confidence: 99%

The potential drug for treatment in pancreatic adenocarcinoma: a bioinformatical study based on distinct drug databases

et al. 2020

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Background: The prediction of drug-target interaction from chemical and biological data can advance our search for potential drug, contributing to a therapeutic strategy for pancreatic adenocarcinoma (PAAD). We aim to identify hub genes of PAAD and search for potential drugs from distinct databases. The docking simulation is adopted to validate our findings from computable perspective. Methods: Differently expressed genes (DEGs) of PAAD were performed based on TCGA. With two Cytoscape plugins of CentiScaPe and MCODE, hub genes were analyzed and visualized by STRING analysis of Protein-protein Interaction (PPI). The hub genes were further selected with significant prognostic values. In addition, we examined the correlation between hub genes and immune infiltration in PAAD. Subsequently, we searched for the hub gene-targeted drugs in Connectivity map (Cmap) and cBioportal, which provided a large body of candidate drugs. The hub gene, which was covered in the above two databases, was estimated in Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Herbal Ingredients' Targets (HIT) database, which collected natural herbs and related ingredients. After obtaining molecular structures, the potential ingredient from TCMSP was applied for a docking simulation. We finalized a network connectivity of ingredient and its targets. Results: A total of 2616 DEGs of PAAD were identified, then we further determined and visualized 24 hub genes by a connectivity analysis of PPI. Based on prognostic value, we identified 5 hub genes including AURKA (p = 0.0059), CCNA2 (p = 0.0047), CXCL10 (p = 0.0044), ADAM10 (p = 0.00043), and BUB1 (p = 0.0033). We then estimated tumor immune correlation of these 5 hub genes, because the immune effector process was one major result of GO analysis. Subsequently, we continued to search for candidate drugs from Cmap and cBioportal database. BUB1, not covered in the above two databases, was estimated in TCMSP and HIT databases. Our results revealed that genistein was a potential drug of BUB1. Next, we generated two docking modes to validate drug-target interaction based on their 3D structures. We eventually constructed a network connectivity of BUB1 and its targets. Conclusions: All 5 hub genes that predicted poor prognosis had their potential drugs, especially our findings showed that genistein was predicted to target BUB1 based on TCMSP and docking simulation. This study provided a reasonable approach to extensively retrieve and initially validate putative therapeutic agents for PAAD. In future, these drug-target results should be investigated with solid data from practical experiments.

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Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer

Cited by 28 publications

References 51 publications

Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer

Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

The potential drug for treatment in pancreatic adenocarcinoma: a bioinformatical study based on distinct drug databases

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