ABSTRACT: BACKGROUND:The recommendation for chemotherapy in early-stage breast cancer patients has been refined by the 21-gene Recurrence Score. However, uncertainty remains whether patients in the Intermediate Risk category benefit from chemotherapy. METHODS:We analyzed female patients from the National Cancer Database from 2006 to 2012 who had pT1c-T2N0M0 breast cancer, were ER/PR-positive and HER2-negative, received endocrine therapy, and had a 21-gene Recurrence Score from 11 to 25. We performed univariate and multivariate logistic regression analyses to see what impacted chemotherapy receipt. We compared overall survival using Kaplan-Meier curves and the log-rank test. A multivariable Cox proportional hazards regression model was used to assess what variables impacted overall survival. RESULTS:Of 21,991 patients who met all inclusion and exclusion criteria, 4646 (21.1%) received chemotherapy and 17,345 (78.9%) did not. Chemotherapy was more often received by patients who were younger (adjusted odds ratios (aORs) compared to age < 40 years, 0.48 for 40s, 0.34 for 50s, 0.20 for 60s, 0.10 for 70s, and 0.07 for 80+), had private insurance vs Medicare (aOR = 1.37), were from metro vs urban counties (aOR = 1.15), and were treated in community cancer centers vs academic programs (aOR = 1.26), and those with tumors of higher grade (grade 2 vs 1, aOR = 1.72; grade 3 vs 1, aOR = 3.76), higher tumor stage (pT2 vs pT1c, aOR = 1.62), or presence of lymphovascular invasion (LVI) (aOR = 1.41). At a median follow-up of 46.4 months, there was no significant difference in overall survival between patients who received chemotherapy vs those who did not (5-year estimated overall survival, 97.4% vs 97.8%, p = 0.89). On multivariable analysis, worse overall survival was associated with Black race, treatment at a community program, Medicaid, high-grade tumors, pT2 vs pT1c, higher Charlson-Deyo score, and no radiotherapy. Utilization trends showed that chemotherapy receipt in these patients has been decreasing from 25.8% in 2010 to 18.4% in 2013 (p < 0.001). CONCLUSIONS:In these patients where the benefit of chemotherapy remains uncertain, current practices see chemotherapy more likely to be used in patients with younger age, higher pathologic T stage, higher grade tumors, and LVI. No apparent difference was seen in overall survival between those who received chemotherapy and those who did not.