Integrative analysis of pre-treatment RNA expression signatures and recurrent genomic alterations: 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 for 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.

Methods

We analyzed 220 patients from the WSG-ADAPT trial with early-stage, estrogen receptor-positive, HER2-negative breast cancer, who received three weeks of preoperative endocrine therapy with TAM or AI. Pre-treatment tumor samples were profiled using the NanoString BC360 panel, and post-treatment samples 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 pro-tumorigenic immune-(IFN-γ, Inflammatory Chemokines, Macrophages and Treg) and proliferation-related (BC Proliferation, Genomic Risk, and homologous recombination deficiency (HRD)) signature scores. In the AI group, signatures associated with reduced disease-free survival included BC p53 (hazard ratio [HR] with 95% confidence interval [CI] = 2.74 [1.08-6.94]), Genomic Risk (HR = 2.5 [1.07-5.83]), HRD (HR = 2.44 [1.12-5.29]) and Hypoxia (HR = 2.12 [1.17-3.87]). High expression of PD-1 (HR = 0.44 [0.21-0.94]) and PGR (HR = 0.24 [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.

Trial registration

WSG-ADAPT, NCT01779206 , Registered 2013-01-25, retrospectively registered.

Highlights

• Mutations in tumor protein p53 linked to endocrine therapy resistance in luminal breast cancer.

• Non-responders have higher pre-treatment immune activity and cell proliferation signals in tumors.

• Poor survival is associated with signatures of mutant p53, genomic risk, repair deficiency and hypoxia in tumors.

• High levels of programmed cell death protein 1 and progesterone receptor predict better outcomes.

• Combining clinical, transcriptomic, and genetic data may improve personalized therapy decisions.