E2F cell cycle pathway score as a predictive biomarker of ER+/HER2- breast cancer response to neoadjuvant chemotherapy.

Abstract

e12593 Background: Although the survival rate of patients diagnosed with breast cancer has greatly improved over the last decades, the metastatic stage of the disease remains incurable. Estrogen receptor positive (ER+)/human receptor 2 negative (HER2-) breast cancers accounts for approximately 70% of metastatic breast cancers and, it is responsible for most of the deaths from the disease. Another issue of ER+/HER2- breast cancer is its poor response to neoadjuvant chemotherapy (NAC). Recently, several clinical trials have shown that endocrine therapy plus FDA-approved cyclin-dependent kinases (CDK) 4/6 inhibitors have improved the treatment response to patients with advanced ER+/HER2 breast. The CDK 4/6 is an important E2F-related factor. Therefore, we hypothesized that E2F pathway is predictive biomarker for treatment response of ER+/HER2- breast cancer. Methods: METABRIC dataset was used for training cohort. And TCGA breast cancer as well as four neoadjuvant therapeutic cohorts were used as validation cohort. The E2F pathway score was calculated by Gene Set Variant Analysis (GSVA). Results: Tumors with high E2F pathway score enriched cell proliferation and cell cycle pathway related gene sets (G2M, MYC v1, and v2, MITOTIC, MTORC1, PI3K AKT MTOR, and DNA repair; FDR < 0.001). The high E2F pathway score was significantly associated with TNBC and HER2+ (p < 0.001), which are known to be clinically aggressive, and advanced stage (p < 0.001) and high grade (p < 0.001). The score also correlated with copy mutation (r = 0.605, p < 0.01). The patients, who had early recurrence before 5 years, had significantly high score rather than non-recurrence patients (p < 0.001). Moreover, these results were validated in TCGA cohort. The high E2F pathway score group had a higher pCR rate than the low score group with ER+/HER2- breast cancer (p < 0.001). Interestingly, the tumors in high score group expressed higher CDK pathway related molecules compared to low score group. Conclusions: The E2F pathway score was found to be a predictive biomarker for neoadjuvant chemotherapy in ER+/HER2- breast cancer patients.