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Thyroid disease is a frequent comorbidity in women with breast cancer, and many require thyroid hormone replacement therapy (THRT). We postulated that THRT has a deleterious clinical effect mechanistically through hormonal interactions, nuclear receptor cross-talk, and upregulation of high-risk breast cancer genes. Observational studies of patients with lymph node-negative (LN ) breast cancer ( = 820 and = 16 were performed to test interactions between THRT and clinical, histologic, outcome, and treatment variables. Differences betwe