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

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.

Keywords: breast neoplasm; endocrine response; first-2-year relapse; model development; prognosis.

Figure 1

Association between 2-year invasive disease-free survival and gene expressions of ESR1 (A), PGR (B), BCL2 (C), GSTM1 (D), CD68 (E), and BAG1 (F). IDFS, invasive disease-free survival.

Figure 2

Association of F2P Score with 2-year invasive disease-free survival. IDFS, invasive disease-free survival.

Figure 3

Association of continuous F2P Score with 2-year invasive disease-free survival across treatment subgroups. The subgroup analysis regarding the ovarian suppression was performed in premenopausal women. AI, aromatase inhibitor; CI, confidence interval; TAM, tamoxifen.

Figure 4

Landmark analysis of the association of F2P Score with different outcomes. (A) invasive disease-free survival; (B) overall survival; (C) distant disease-free survival; (D) distant relapse-free survival.