Young Age at Diagnosis Correlates With Worse Prognosis and Defines a Subset of Breast Cancers With Shared Patterns of Gene Expression

TLDR

Breast cancer in young women is associated with poorer survival and more adverse clinicopathologic features, but the underlying biology remains undefined. The authors compared age‑specific cohorts (≤45 vs ≥65) of 784 early‑stage breast cancers using clinically annotated microarray data, applying univariate and multivariate analyses of prognosis, clinicopathologic variables, mRNA expression, single‑gene analysis, and gene set enrichment analysis. Young women’s tumors exhibited lower estrogen receptor positivity, larger size, higher HER‑2/EGFR expression, higher grade, and a trend toward worse disease‑free survival, with genomic profiling revealing distinct gene sets and lower hormone receptor expression, and age, low ERβ, and high EGFR mRNA predicting inferior DFS.

Abstract

Purpose Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined. Patients and Methods Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: ≤ 45 years, n = 200; older: ≥ 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed. Results Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERα mRNA (P < .0001), ERβ (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERβ and higher EGFR mRNA expression were significant predictors of inferior DFS. Conclusion This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.