Purpose: In the adjuvant treatment of estrogen receptor (ER)^positive breast cancer, additional markers are needed to identify women at high risk for recurrence. Experimental Design: We examined the association between the ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL-17BR) expression and the clinical outcomes of relapse and survival in women with ER-positive breast cancer enrolled onto a North Central Cancer Treatment Group adjuvant tamoxifen trial . Results: Tumor blocks were obtained from 211of 256 eligible patients, and quantitative reverse transcription-PCR profiles for HOXB13 and IL-17BR were obtained from 206 patients. The cut point for the two-gene log 2(expression ratio) that best discriminated clinical outcome (recurrence and survival) was selected and identified women with significantly worse relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS), independent of standard prognostic markers. The cut point differed as a function of nodal status [node negative (59th percentile) versus node positive (90th percentile)]. In the node-positive cohort (n = 86), the HOXB13/IL-17BR ratio was not associated with relapse or survival. In contrast, in the nodenegative cohort (n = 130), a high HOXB13/IL-17BR ratio was associated with significantly worse RFS [hazard ratio (HR), 1.98; P = 0.031], DFS (HR, 2.03; P = 0.015), and OS (HR, 2.4; P = 0.014), independent of standard prognostic markers. Conclusion: A high HOXB13/IL-17BR expression ratio is associated with increased relapse and death in patients with resected node-negative, ER-positive breast cancer treated with tamoxifen and may identify patients in whom alternative therapies should be studied.In the adjuvant treatment of estrogen receptor (ER) -positive breast cancer, hormonal therapy reduces the risk of breast cancer recurrence and decreases mortality. Tamoxifen, one of the most commonly used medications in the adjuvant treatment of ERpositive breast cancer, is a selective ER modulator that competes with estrogen for binding to the ER. When administered to women with surgically treated ER-positive breast cancer, tamoxifen reduces the risk of recurrence and death when taken for 5 years (1).The ER and progesterone receptor are the most important tumor markers that predict response to tamoxifen (2). However, because a significant proportion of ER-positive breast cancers fail to respond or eventually develop resistance to tamoxifen, additional prognostic markers, including tumor size, tumor grade, and nodal status, are commonly used by physicians to make treatment decisions. Clinical studies have shown, however, that even in ''good-prognosis'' tumors (e.g., estrogen positive, lymph node negative), up to 20% of women will experience recurrence despite 5 years of adjuvant tamoxifen therapy (3, 4). These findings indicate the need for additional markers that will identify women at high risk for recurrence.Recent studies have shown that the gene expression signature of a tumor is a means to predict recurrence ...