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

Carey K. Anders, David S. Hsu, Gloria Broadwater, Chaitanya R. Acharya, John A. Foekens, Yi Zhang, Yixin Wang, P. Kelly Marcom, Jeffrey R. Marks, Phillip G. Febbo, Joseph R. Nevins, Anil Potti, Kimberly L. Blackwell

From the Division of Medical Oncology, Department of Medicine, and Institute for Genome Sciences and Policy, Duke University; Cancer Center Biostatistics, Duke University Medical Center, Durham, NC; Veridex Inc, Johnson and Johnson, San Diego, CA; and Erasmus Medical Center, Rotterdam, the Netherlands

Corresponding author: Carey K. Anders, MD, Duke University Medical Center, Box 3841, 3829 Duke South, Red Zone, Durham, NC 27710; e-mail: ander118{at}mc.duke.edu

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 ER 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.

Supported by National Institutes of Health Grant No. CA093245-05 (C.K.A.) from the National Cancer Institute.

Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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