Ailasequn resistance is mainly related to ESR1 mutations, and its mechanism involves changes in the estrogen receptor signaling pathway. Subsequent treatments need to be adjusted according to the mutation status. The following provides a detailed explanation from three aspects: resistance mechanisms, detection methods, and alternative treatment options.

Mechanism of resistance to ESR1 mutation

(1) Ligand binding domain mutations: Y537S and D538G mutations lead to changes in receptor conformation, reducing drug binding affinity.

(2) Constituent activation: Mutation causes the receptor to continuously activate downstream proliferation signaling pathways independent of estrogen.

(3) Epigenetic changes: Abnormal histone modifications result in sustained expression of target genes.

2. Drug resistance detection methods

(1) CtDNA testing: Dynamic monitoring of ESR1 mutation allele frequency changes through liquid biopsy.

(2) Organ biopsy: After drug resistance, it is necessary to re puncture to obtain the mutation spectrum and guide subsequent treatment selection.

3 follow-up treatment plans

(1) CDK4/6 inhibitor: Combined with pembrolizumab to overcome partial ESR1 mutation resistance.

(2) MTOR inhibitor: Everolimus combined with endocrine therapy is effective for D538G mutation.

(3) New SERDs, such as SAR439859, maintain activity against Y537S mutations.

4 Clinical Management Suggestions

(1) Immediate detection of ESR1 mutation status is necessary after progression to avoid continuing monotherapy.

(2) Discontinue treatment if grade 3 toxicity occurs, and continue medication at a reduced dose level after recovery.