ESR1 mutation

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.

The use of drug therapies such as imlunestrant that specifically target ESR1 mutations in advanced breast cancer cases reflects the incorporation of genetic biomarkers into routine clinical decision making...The further development of HRD and the viral onco-genes have widened the options available for a biomarker-based therapy. This chapter will provide an in-depth explanation of an Introduction to Cancer Biomarkers and new research developments.

ctDNA effectively detected ESR1 and PIK3CA mutations relevant to targeted therapies, while failed to identify a subset of patients with ESR1 amplification, as well as other CNVs potentially mediating CDK4/6 inhibitor resistance. TP53 mutations observed at high frequency in ctDNA without tissue confirmation may reflect clonal hematopoiesis and its prognostic significance requires careful interpretation. As liquid biopsy is valuable for disease and treatment monitoring, understanding its strengths and limitations is essential. Tissue CGP remains a complementary tool for establishing baseline tumor profiles and enhancing CNV detection in comprehensive molecular characterization.

The May 1 approval of vepdegestrant, the first PROTAC drug to earn regulatory clearance, establishes targeted protein degradation as a clinically validated therapeutic modality. For patients with ESR1-mutant advanced breast cancer, it offers a new therapeutic option after standard hormone-based regimens have failed. And for the broader field, it is proof of concept for a pipeline of protein-destroying drugs that now numbers in the dozens.