Background: Previous studies have validated the ability of a 12-gene expression assay to predict risk of distant recurrence (DR) in women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) early stage breast cancer. Here, we employed a mathematical approach to estimate an expected absolute chemotherapy benefit based on the 12-gene expression test results. Methods: Data was included for patients who had clinical testing with the 12-gene expression assay in the US (Myriad Genetic Laboratories Inc., Salt Lake City, Utah) or Germany (Myriad GmbH, Munich, Germany). FFPE breast resections of treatment-naïve ER+, HER2- breast tissue were tested to generate a combined molecular and clinical score (EPclin score). For the entire group, the relative chemotherapy benefit was assumed to be 30% based on meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group. This was used to calculate the expected absolute chemotherapy benefit across the EPclin score continuum. This was first done in a conservative scenario where chemotherapy benefit was assumed to be independent of EPclin score (no interaction). The degree of interaction between expected chemotherapy benefit and the EPclin score was then systematically increased until the maximum possible EPclin score was associated with the maximum chemotherapy benefit. The mean absolute benefit was calculated for patients at high risk (EPclin ≥3.3) or low risk (EPclin < 3.3) of distant recurrence. Results: Overall, 2,205 ER+, HER2- breast resections (303 tested in USA, 1902 tested in Germany) were included here [1286 samples (58%) with low EPclin scores; 919 (42%) with high EPclin scores]. The mean absolute benefit ranged from 1.5% to 1.8% (mean 10-year risk of DR 4.6% to 4.3%) for patients with low risk EPclin scores compared to 5.3% to 7.3% (mean 10-year risk of DR 14.7% to 12.8%) for patients with high risk EPclin scores. Conclusions: In this analysis, the 12-gene expression assay was able to predict absolute benefit from adjuvant chemotherapy in women with ER+, HER2- early stage breast cancer, regardless of which EPclin score cohorts accrued maximal relative treatment benefit.