Correlation between ESR1 mutation and PD-L1 expression in breast carcinoma: A narrative review

Estrogen receptor alpha (ESR1) mutations emerge in 20-50% of metastatic hormone receptor-positive breast cancers following endocrine therapy and confer constitutive, ligand-independent receptor signalling. Programmed death ligand 1 (PD-L1) serves as a critical immune checkpoint regulator in tumor immune evasion. The relationship between ESR1 mutations and PD-L1 expression represents an important area of investigation with potential therapeutic implications.

A literature review was conducted examining ESR1 mutation biology, PD-L1 expression patterns, immune microenvironment alterations, and mechanistic connections between these biomarkers in breast cancer.

ESR1 mutations, particularly D538G and Y537S variants, promote basal-like transformation associated with elevated basal cytokeratins and immune pathway activation. Metastatic lesions harbouring ESR1 mutations demonstrate significantly higher infiltration of regulatory T cells, macrophages, and specifically PD-L1-positive immune-suppressive macrophages compared to wild-type tumors. These mutations upregulate immunomodulatory proteins including androgen receptor, CHI3L1, and interferon-stimulated genes, creating an immunosuppressive microenvironment correlating with enhanced PD-L1 expression.

ESR1 mutations correlate with PD-L1 upregulation through basal-like transformation and immune microenvironment remodelling, creating both therapeutic challenges and opportunities. The identification of immunogenic ESR1-derived neoepitopes suggests potential for vaccine-based immunotherapy, while combined targeting of endocrine resistance and immune evasion mechanisms represents a promising therapeutic strategy for ESR1-mutant breast cancers. Timely immunotherapy in ESR1-mutated breast cancer may be critical, as early intervention is likely more effective than treating advanced disease. Hormone therapy can enhance anti-PD-1 efficacy, supporting combination strategies.