Integrative analysis of RNA expression signatures and recurrent genomic alterations before treatment: link to menopausal status, short-term endocrine therapy response and disease-free survival in luminal breast cancer.

BACKGROUND: Endocrine therapy with tamoxifen (TAM) or aromatase inhibitors (AI) is an effective treatment of patients with estrogen receptor-positive, HER2-negative luminal breast cancer. However, many patients do not respond to this therapy, leading to disease recurrence. This study aimed to identify baseline clinical, molecular, and genetic features associated with menopause status, primary endocrine therapy resistance and long-term outcomes in luminal breast cancer. PATIENTS AND METHODS: We analyzed 220 patients from the WSG-ADAPT trial with early-stage, estrogen receptor-positive, HER2-negative breast cancer, who received 3 weeks of preoperative endocrine therapy with TAM or AI. Tumor samples obtained before treatment were profiled using the NanoString BC360 panel, and samples obtained after treatment were analyzed for recurrent genomic alterations by next-generation panel sequencing. A subset of the TCGA-BRCA cohort was used for external validation. Univariate Cox regression analyses were used for prognosis analysis. RESULTS: The NanoString signatures were clustered into three stable blocks: A (reactive microenvironment and stemness), B (immune) and C (proliferation and genomic risk). Non-responders more frequently harbored TP53 mutations, which were linked to significantly elevated protumorigenic immune- (interferon-γ, inflammatory chemokines, macrophages and regulatory T cells) and proliferation-related [breast cancer proliferation, genomic risk, and homologous recombination deficiency (HRD)] signature scores. In the AI group, signatures associated with reduced disease-free survival included breast cancer p53 [hazard ratio (HR) 2.74, 95% confidence interval (CI) 1.08-6.94]; genomic risk (HR 2.5, 95% CI 1.07-5.83); HRD (HR 2.44, 95% CI 1.12-5.29) and hypoxia (HR 2.12, 95% CI 1.17-3.87). High expression of programmed cell death protein 1 (HR 0.44, 95% CI 0.21-0.94) and progesterone receptor (HR 0.24, 95% CI 0.07-0.81) indicated better outcomes, respectively. These associations were validated using external data. CONCLUSIONS: Endocrine resistance in luminal breast cancer is characterized by elevated immune signatures, increased proliferation, and specific genomic alterations. The integration of clinical information, gene expression patterns, and genetic data enhances patient stratification and potentially informs treatment decisions. These findings support the use of integrative analyses to guide personalized endocrine therapy and improve outcomes.