A Novel Prognostic Scoring System Integrating Gene Expressions and Clinicopathological Characteristics to Predict Very Early Relapse in Node-Negative Estrogen Receptor-Positive/HER2-Negative Breast Cancer.

Caijin Lin,Xiaochun Fei,Weiguo Chen,Xiaosong Chen,Lin Lin,Li Zhu,Jianrong He,Ou Huang,Yafen Li,Kunwei Shen,Jiayi Wu

doi:10.3389/fonc.2020.01335

Caijin Lin, Xiaochun Fei + Show 9 more

Open Access

https://doi.org/10.3389/fonc.2020.01335

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Abstract

Background: Despite low aggressiveness in tumor biology and high responsiveness to endocrine therapy, subgroups of patients with estrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer relapse early in the first two years after initiation of endocrine therapy, indicating potential endocrine resistance. Accordingly, we attempted to establish a scoring system to inform the first-2-year prognosis (F2P Score).Methods: Patients with node-negative ER+/HER2- breast cancer and complete data of gene expressions in a 21-gene panel were retrospectively retrieved from Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB). The F2P Score was established based on the clinical and genomic variables associated with the first-2-year relapse after shrinkage correction and validated using the bootstrap resampling method. Model performance was quantified by Harrell's concordance-index (C-index) and Bayesian information criteria (BIC).Results: The F2P Score was established by integrating the clinical (age and tumor size) and genomic (ESR1, PGR, BCL2, CD68, GSTM1, and BAG1) variables with a C-index of 0.71 and BIC of 397.46. Bootstrap C-index was 0.72 (95% CI, 0.62–0.81) and BIC was 396.75 (95% CI, 252.37–541.13). A higher score indicated an increased likelihood of a first-2-year relapse, when used as continuous (HR, 2.94; 95% CI, 1.87–4.61) or categorical (HR, 3.68; 95% CI, 1.70–8.00) predictors in multivariate analysis. Both continuous and categorical F2P Score also remained prognostic for overall survival and other endpoints. No significant interaction was observed between the F2P Score and treatment subgroups. Additionally, the F2P Score outperformed the IHC4, clinical treatment score and 21-gene test in predicting first-2-year relapse.Conclusion: The F2P Score reported herein, integrating the clinicopathological and genomic variables, may inform prognosis and endocrine responsiveness. After the benefits and risks have been considered, treatment escalation may be an alternative strategy for patients with a higher score.

Highlights

Estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2–) breast cancer constitutes ∼70% of malignant breast neoplasms [1, 2]
It is of great importance to develop a prognostic approach for relapse in the first two years, since treatment escalation is required for patients classified as high risk of very early relapse who are potentially endocrine-resistant
Thirty in 66 (45.5%) invasive disease-free survival (IDFS) events and 10 in 21 (47.6%) distant relapses were observed for the first two years, and the annual rates were 1.39 and 0.47%, respectively. When compared to those without first-2-year relapse, worse prognosis was observed for patients who relapsed on the first two years, with a 5-year overall survival (OS) of 98.8% and 70.6%, respectively (Figure S1)

Summary

Introduction

Estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2–) breast cancer constitutes ∼70% of malignant breast neoplasms [1, 2]. Some headway has been made concerning the underlying mechanisms of endocrine resistance, including the mutations in the ligand-binding domain of ESR1, the downregulation of progesterone receptor (PR) by hyperactive crosstalk between ER and growth factor signaling pathways, and the imbalance between the non-apoptotic and pro-apoptotic functions of BCL2 family [8,9,10,11,12] These studies reinforce the idea that molecular biomarkers alone cannot yield accurate predictions for endocrine sensitivity and the likelihood of early relapse. Despite low aggressiveness in tumor biology and high responsiveness to endocrine therapy, subgroups of patients with estrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer relapse early in the first two years after initiation of endocrine therapy, indicating potential endocrine resistance. We attempted to establish a scoring system to inform the first-2-year prognosis (F2P Score)

Methods

Results

Conclusion