Background: Multi-gene tumor assays have provided clinically useful prognostic information for patients with HR receptor and node-positive breast cancer. The 21-gene RS was shown to be prognostic for patients treated with tamoxifen alone, and exploratory studies suggested that it may be predictive of benefit from chemotherapy. In retrospective analyses from S8814, patients with low RS appeared to get no benefit from adjuvant CAF chemotherapy, while those with higher RS did. These retrospective data require validation, especially since more modern chemotherapy might be more effective than the regimen used in S8814. In January 2011 SWOG activated a trial to test the efficacy of using modern chemotherapy regimens in node positive patients with low RS, whose prognosis is still moderately poor but may not benefit from adjuvant chemotherapy based on tumor biology predicted by the RS value. The trial is similar to the Tailor RX study, but focuses on a node-positive population with low and intermediate RS. Methods: Phase III randomized clinical trial of best endocrine therapy vs. best endocrine therapy and chemotherapy. Patients with 1 to 3 positive lymph nodes, HR-positive and HER2-negative invasive breast cancer with RS ≤ 25 are eligible for randomization. Approximately, 9,400 patients will be screened to randomize 4000, stratified by RS (0-13 vs. 14-25), menopausal status, and axillary surgery (sentinel node vs.full dissection). Patients will be informed of their RS. Trial is powered on finding a significant interaction of treatment assignment and the continuous RS value and subsequently deriving a cutpoint for using the assay to guide treatment decisions. Patients who consent to screening are required to consent to banking of the tumor tissue and blood for further studies. Patient Reported Outcomes will be collected pre, post screening and post-randomization. The study also has a cost-effectiveness analysis. Status: Open nationwide through participating NCI-funded cooperative groups. NCT01272037.