Degree of Early Estrogen Response Predict Survival after Endocrine Therapy in Primary and Metastatic ER-Positive Breast Cancer

SIMPLE SUMMARY: Over 70% of breast cancer patients in the US have estrogen receptor (ER)-positive tumors. A better predictive biomarker of endocrine therapy would be useful to improve patient compliance. We found that estrogen response early score generated by a GSEA algorithm was significantly associated with immune cell infiltrations, patient survival, and endocrine therapy response in ER-positive breast cancer. Furthermore, the score may be a useful tool to predict response to endocrine therapy in both primary and metastatic breast cancer compared to ER gene expression. This study demonstrates that the estrogen response early score may be a useful prognostic and predicative biomarker in patients with either primary or metastatic breast cancer. ABSTRACT: Endocrine therapy is the gold-standard treatment for ER-positive/HER2-negative breast cancer. Although its clear benefit, patient compliance is poor (50–80%) due to its long administration period and adverse effects. Therefore, a predictive biomarker that can predict whether endocrine therapy is truly beneficial may improve patient compliance. In this study, we use estrogen response early gene sets of gene set enrichment assay algorithm as the score. We hypothesize that the score could predict the response to endocrine therapy and survival of breast cancer patients. A total of 6549 breast cancer from multiple patient cohorts were analyzed. The score was highest in ER-positive/HER2-negative compared to the other subtypes. Earlier AJCC stage, as well as lower Nottingham pathological grade, were associated with a high score. Low score tumors enriched only allograft rejection gene set, and was significantly infiltrated with immune cells, and high cytolytic activity score. A low score was significantly associated with a worse response to endocrine therapy and worse survival in both primary and metastatic breast cancer patients. The hazard ratio was double that of ESR1 expression. In conclusion, the estrogen response early score predicts response to endocrine therapy and is associated with survival in primary and metastatic breast cancer.