ESR1 mutation

Herein, we developed drug-conjugated Tam-NHC-gold(I) complexes that can target breast cancer cells by the binding of tamoxifen (Tam) to the G protein-coupled estrogen receptor (GPER) present on cell membranes...Moreover, 7b exhibited potent antiproliferative activity on both wild-type and mutant MCF-7Y537S in xenograft mouse models with low toxicity. This study verified that 7b may offer a new approach for the treatment of endocrine-resistant breast cancer.

High-resolution lineage tracing and multi-omic studies demonstrate that CDK4/6i resistance is shaped by clonal selection and adaptive remodeling of cell states, with the ESR1 mutation status and the specific inhibitor acting as key determinants of evolutionary trajectories. These findings suggest that both variables should be considered when designing sequential and combination treatment strategies to overcome CDK4/6i resistance.

Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance... Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor-positive, HER2-negative metastatic breast cancer...Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120... Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2- mBC.

These results demonstrate that both dPCR and NGS-based liquid biopsy workflows can be successfully implemented for ESR1 mutation testing in routine clinical practice using locally validated assays. This multicentre verification study provides practical guidance on assay verification, DNA input requirements, and key analytical parameters required to ensure reliable ESR1 mutation detection across different European laboratories. Robust analytical verification of ESR1 testing may improve diagnostic reliability and support personalized treatment strategies for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

P=N/A, N=0, Available, Genentech, Inc.

PROTACs, especially ER degraders, suggest a potential strategy for addressing endocrine resistance in advanced ER + breast cancer, as reflected in encouraging preliminary clinical data. This integrated analysis highlights the rapid translation of this technology while underscoring the critical need to expand target scope, address inherent resistance mechanisms, and broaden applications to other breast cancer subtypes. Our article synthesizes current knowledge and trial landscape, thereby providing a consolidated foundation to inform future research and clinical development of PROTACs in breast cancer.

Routine assessment of ESR1 mutations using liquid biopsy should be integrated into clinical practice to enable dynamic, molecularly guided treatment optimization. The expanding arsenal of ER-targeted therapies supports personalized sequencing strategies that move beyond rigid temporal cutoffs and improve outcomes in ET resistant disease.

The regulatory approval of elacestrant for ESR1-mutant disease and randomized trial data showing progression-free survival (PFS) benefit from ctDNA-guided endocrine switching (PADA-1, SERENA-6) position ESR1 genotyping as a dynamic biomarker with direct therapeutic implications...The convergence of structural mechanisms, liquid biopsy technology, and biomarker-driven drug development provides a framework for precision oncology in endocrine-resistant breast cancer. While these advances are substantial, important challenges remain, including the lack of mature overall survival (OS) data from interception trials, cost and accessibility barriers to serial ctDNA monitoring in diverse global healthcare settings, the unresolved question of optimal therapeutic sequencing in patients with concurrent ESR1 and PI3K pathway alterations, and the need to distinguish clinically actionable low-variant allele frequency (VAF) ESR1 calls from background noise in liquid biopsies.

In early-stage breast cancer, converging evidence across subtypes shows that ctDNA-defined minimal residual disease (MRD) robustly identifies patients at high risk of recurrence. Collectively, these findings position ctDNA as a potential biomarker for dynamic treatment adaptation, supporting the next phase of precision oncology focused on MRD-guided escalation, de-escalation, and therapeutic interception across the breast cancer continuum.

Concurrent ESR1 mutations and methylation were identified in six cases, suggesting combined genetic and epigenetic mechanisms of endocrine resistance. Overall, CTC-derived genomic DNA showed higher sensitivity for detecting ESR1 mutations than plasma ctDNA, supporting the potential value of CTC analysis for characterizing endocrine resistance in advanced BC.

Here, we integrate multi-omic profiling, spanning bulk and single-cell transcriptome, chromatin architecture (Hi-C), and the cistrome, to systematically compare the mechanisms involved in adaptive resistance to selective estrogen receptor modulators (SERMs, e.g., tamoxifen) and degraders (SERDs, e.g., fulvestrant), and the mechanism driven by constitutive ESR1 mutation, to characterize how mode of ERα perturbation influences lineage identity and epithelial-mesenchymal state. Together, these findings indicate that endocrine resistance does not converge on a single molecular endpoint but instead reflects drug-specific adaptive states defined by ER signaling context, lineage identity, and chromatin architecture. Our study establishes the basal-pEMT axis as a coordinated, epigenetically encoded module of SERM-induced plasticity and reframes endocrine resistance as a multidimensional evolutionary process shaped by therapeutic mechanisms of action.

Oral SERDs are reshaping the management of ESR1-mutant disease, with agents such as elacestrant and imlunestrant emerging as standard second-line options. However, primary resistance to SERD monotherapy remains substantial, highlighting the need for combination strategies. Future directions include ctDNA-guided approaches and expansion into earlier treatment settings.