ESR1 mutation

Novel oral SERDs may represent a paradigm shift in managing PD after 1 L therapy, showing potential to improve PFS in selected patients.

Mutational analysis and molecular docking identified potential metal interaction sites within ESRRB's ligand-binding domain. Together, these results suggest calcium acts as a natural ligand for ESRRB and cadmium, which mimics calcium, activate ESRRB to mediate cell stemness and pluripotency.

Increased cancer risk, insulin resistance, and infertility all originate from defective estrogen signaling.

Giredestrant and camizestrant induced significant bradycardia in wild-type zebrafish embryos, whereas fulvestrant and amcenestrant (SERDs that do not induce bradycardia in patients) did not alter heart rate. Mutations in gper, esr2a, and esr2b did not confer resistance to SERD-induced bradycardia, whereas esr1 mutant embryos were protected. These findings demonstrate that SERD-associated bradycardia is mediated through Esr1 signaling, supporting an on-target adverse effect.

ESR1 mutations, while rare overall in treatment-naïve EC, are more prevalent in NSMP LGEC, potentially affecting AI efficacy. ESR1 status should be considered in selecting hormonotherapy and as a stratification factor in AI trials.

P1/2, N=196, Recruiting, Forward Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting

PARP trapping by olaparib treatment with or without endocrine therapy resulted in a significant increase of co-localized DNA-bound PARP1 and ER protein in ESR1 mutant cells, indicating ER-PARP1 co-regulation in ESR1 mutant breast cancer. Long-term treatment with endocrine therapy plus the CDK4/6 inhibitor abemaciclib led to the emergence of a Y537S ESR1 mutation in a cell line, which exhibited dysregulation of replication stress response, enhanced DNA damage response, and synergistic responses to inhibitors of these pathways. PARP inhibition also synergized with clinically relevant endocrine therapy in ESR1 mutant models, reducing tumor growth both ex vivo and in vivo. Together, these results identify replication stress and DNA damage responses as key dysregulated pathways in ESR1 mutant breast cancer with significant clinical potential for PARP inhibition in this metastatic breast cancer subset.

In 20 % of breast cancer patients with LM, genetic alterations in the CSF were discordant from the primary tumor and/or systemic metastases. These genetic alterations involved in particular the PTEN-PI3K-AKT pathway in TN breast cancer. No ESR1 mutation limited to CSF only was found in HR+/HER2-breast cancer. Divergence of genetic alterations in LM from breast cancer must be considered for optimization of future target treatment strategy.

Moreover, SLC25A15 knockout robustly reduced the ability of ESR1-mutated cells to establish LM in vivo. These findings highlight SLC25A15-mediated dysregulation of the UC as a critical driver of BC hepatic metastasis and identify SLC25A15 as a potential therapeutic target for disrupting metastatic spread of BC to the liver.

Current research focuses on overcoming endocrine resistance via combination therapies targeting mutations in ESR1, the gene encoding ERα, non-genomic signaling pathways, and the tumor microenvironment, which may advance precision medicine in breast cancer. This article summarizes recent advances in ERα-targeting inhibitors and their therapeutic implications, to provide potential precision therapeutic strategies for breast cancer patients with ER positive.

OPERA-01 (NCT06016738) is a phase III study designed to evaluate the safety and efficacy of palazestrant monotherapy compared to SOC ET in patients with ER+, HER2- locally advanced or metastatic breast cancer, regardless of ESR1 mutation status, whose disease advanced following treatment with at least one ET in combination with a CDK4/6i.Clinical Trial Registration: Clinicaltrials.gov NCT06016738. Registered 17 August 2023.