Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Leal, Mariana Ferreira; Haynes, Ben P.; Schuster, Eugene; Yeo, Belinda; Afentakis, Maria; Zabaglo, Lila; Martins, Vera; Buus, Richard; Dodson, Andrew; Cheang, Maggie C.U.; Smith, Ian; Martin, Lesley-Ann; Dowsett, Mitch

doi:10.1158/1078-0432.ccr-19-1129

Cited by 18 publications

(12 citation statements)

References 44 publications

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“…First, there may an intrinsic subpopulation of cells in some ER+ tumors that have active NFB, expand rapidly in response to tamoxifen treatment, and contribute to de novo resistance. A similar selection mechanism was recently proposed for aromatase inhibitor tolerance/resistance, where an enrichment of cells bearing ESR1 mutations could rapidly be detected in tumors of women treated with aromatase inhibitors (38).…”

Section: Discussionmentioning

confidence: 75%

The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor–Positive Breast Cancers

Kastrati

Joosten

Semina

et al. 2020

Molecular Cancer Research

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The purpose of this study was to identify critical pathways promoting survival of tamoxifen-tolerant, estrogen receptor  positive (ER+) breast cancer cells, which contribute to therapy resistance and disease recurrence. Gene expression profiling and pathway analysis was performed in ER+ breast tumors of patients before and after neo-adjuvant tamoxifen treatment and demonstrated activation of the NFκB pathway and an enrichment of EMT/stemness features.Exposure of ER+ breast cancer cell lines to tamoxifen, in vitro and in vivo, gives rise to a tamoxifen-tolerant population with similar NFκB activity and EMT/stemness characteristics.Small molecule inhibitors and CRISPR/Cas9 knock out were used to assess the role of the nuclear factor κB (NFκB) pathway and demonstrated that survival of tamoxifen-tolerant cells requires NFκB activity. Moreover, this pathway was essential for tumor recurrence following tamoxifen withdrawal. These findings establish that elevated NFκB activity is observed in breast cancer cell lines under selective pressure with tamoxifen in vitro and in vivo, as well as in patient tumors treated with neo-adjuvant tamoxifen therapy. This pathway is essential for survival and regrowth of tamoxifen-tolerant cells, and, as such, NFκB inhibition offers a promising approach to prevent recurrence of ER+ tumors following tamoxifen exposure.Implications: Understanding initial changes that enable survival of tamoxifen-tolerant cells, as mediated by NFκB pathway, may translate into therapeutic interventions to prevent resistance and relapse, which remain major causes of breast cancer lethality.

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Section: Discussionmentioning

confidence: 75%

The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor–Positive Breast Cancers

Kastrati

Joosten

Semina

et al. 2020

Molecular Cancer Research

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“…Approximately 20–40% of patients who have received aromatase inhibition (AI) for MBC have ESR1 mutations, with prevalence varying by sites of metastatic disease [ 2 , 5 – 7 , 12 – 14 ]. In contrast, ESR1 mutation prevalence is only 4–5% in recurrent breast cancer after prior adjuvant AI (including recurrence while on adjuvant AI) [ 12 , 14 , 15 ], 1.5–7% after neoadjuvant AI [ 16 , 17 ], and less than 1% in ET-naïve MBC [ 7 , 10 , 14 ]. Thus, ESR1 mutations in HR-positive breast cancer occur almost exclusively after AI in the metastatic setting.…”

Section: Background and Overviewmentioning

confidence: 99%

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

et al. 2021

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In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.

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“…Although rare in primary breast tumors, mutations in the ESR1 LBD (ER mut ) occur in up to 40% of metastatic lesions, a finding that is consistent with their selection by conditions of extreme estrogen deprivation (24,25,(27)(28)(29)(30)(31). Two of the most common mutations, Y537S and D538G (ER Y537S and ER D538G ), account for roughly 70% of all ESR1 mutations identified in patients with metastatic breast cancer (24,25,(27)(28)(29)(30)(31). In addition to constitutively activating transcription, these mutations also exhibit distinct neomorphic activities that likely contribute to disease progression (32,33).…”

Section: Introductionmentioning

confidence: 79%

“…Whereas the mechanisms underlying resistance to endocrine therapies are varied and complex, it is now clear that gain-of-function point mutations within the ligand-binding domain (LBD) of ESR1 that permit it to exhibit constitutive transcriptional activity can confer resistance to aromatase inhibitors (24)(25)(26). Although rare in primary breast tumors, mutations in the ESR1 LBD (ER mut ) occur in up to 40% of metastatic lesions, a finding that is consistent with their selection by conditions of extreme estrogen deprivation (24,25,(27)(28)(29)(30)(31). Two of the most common mutations, Y537S and D538G (ER Y537S and ER D538G ), account for roughly 70% of all ESR1 mutations identified in patients with metastatic breast cancer (24,25,(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 98%

“…In addition to constitutively activating transcription, these mutations also exhibit distinct neomorphic activities that likely contribute to disease progression (32,33). Notwithstanding these important differences, most attention has been focused on how these disease-associated mutations reduce the ER-binding affinity of some clinically important antagonists, an activity that may limit their therapeutic utility (24,25,(27)(28)(29)(30)(31). The development of most SERDs was initiated before the prevalence of ER muts was fully appreciated, and it is now apparent that, as with fulvestrant, the affinity of ER muts for even the most contemporary SERDs is substantially reduced ($one order of magnitude; refs.…”

Section: Introductionmentioning

confidence: 99%

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The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor

Andreano

Baker

Park

et al. 2020

Molecular Cancer Therapeutics

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The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice although their durability in metastatic disease is limited by activating point mutations within the ligand-binding domain of ESR1 that permit ligand-independent activation of the receptor. It has been suggested that the most commonly occurring ESR1 mutations would likely compromise the clinical activity of selective estrogen receptor downregulators and selective estrogen receptor modulators (SERMs) when used as second-line therapies. It was unclear, however, how these mutations, which are likely coexpressed in cells with ER WT , may impact response to ER ligands in a clinically meaningful manner. To address this issue, we dissected the molecular mechanism(s) underlying ESR1-mutant pharmacology in models relevant to metastatic disease. These studies revealed that the response of ESR1 mutations to ligands was dictated primarily by the relative coexpression of ER WT in cells. Specifically, dysregulated pharmacology was only evident in cells in which the mutants were overexpressed relative to ligand-activated ER WT ; a finding that highlights the role of allelism in determining ER-mutant pharmacology. Importantly, we demonstrated that the antagonist activity of the SERM, lasofoxifene, was not impacted by mutant status; a finding that has led to its clinical evaluation as a treatment for patients with advanced ER-positive breast cancer whose tumors harbor ESR1 mutations.

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Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Cited by 18 publications

References 44 publications

The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor–Positive Breast Cancers

The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor–Positive Breast Cancers

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor

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