Background: A breast cancer (BC)-associated SNP is found in an enhancer region of the TOX3 gene, which encodes a nuclear protein expressed in ER⁺ mammary epithelial cells but with unknown biological function. As the disease-risk allele reduces TOX3 expression, we proposed that a decrease in TOX3 might favor a progenitor cell state that is more susceptible to tumorigenesis. However, in the context of BC, our data has implicated TOX3 as a tumor promoter. Indeed, high TOX3 gene expression is significantly associated with poor outcome among patients with luminal B (LumB) disease. The Oncotype DX assay predicts likelihood of distant recurrence in ER⁺ early stage BC, improving patient selection for adjuvant chemotherapy. However, LumB subtypes often have an intermediate recurrence score (RS), where the absolute benefit of chemotherapy is unclear. Thus, we investigated whether TOX3 expression might provide additional discriminatory power. Methods: Tumor specimens were obtained from Cedars-Sinai Medical Center in a retrospective study. Tissue microarrays of 200 histologically-defined LumB breast tumors (ER⁺Her2^-/+ Ki67 > 14%), half of which with associated Oncotype DX data, were stained with an anti-TOX3 monoclonal antibody, to correlate with RS and clinicopathologic outcomes. Results: TOX3 protein was expressed in a significant subset of LumB tumors. Using image analysis to create a histoscore, we found no correlation between TOX3 expression and RS. TOX3 expression was also not associated with frequency of Ki67⁺ cells, patient age, or tumor size. Further in-depth clinico-pathologic evaluation and prognosis data will be reported. Conclusions: Despite overall efficacy of adjuvant chemotherapy in early stage BC, many patients are exposed to the associated risks without deriving significant benefit. A number of lines of evidence suggest that TOX3 renders tumors more aggressive and metastatic. The lack of correlation of TOX3 expression and RS may suggest a facet of the biology of ER⁺ aggressive cancers that may not be addressed by the Oncotype DX assay. Thus, prospective studies examining recurrence risk and chemotherapy benefit may need to be expanded to integrate TOX3 expression as an adjunct novel biomarker to guide optimal personalized therapy for BC.