Background: The MammaPrint (MP) risk of distant recurrence signature identifies hormone receptor-positive (HR+), HER2-negative early-stage breast cancer (EBC) patients (pts) with increased or decreased chemosensitivity and chemotherapy (CT) benefit. The MINDACT trial demonstrated excellent outcomes for MP Low Risk tumors without CT, and previous studies show MP High Risk tumors exhibit higher sensitivity and benefit with CT. There remains an unmet clinical need for identifying biomarkers to inform specific regimen planning for pts who qualify for CT. Here, the association of MP index and 3-year (yr) Recurrence-Free Interval (RFI) was evaluated in pts with HR+HER2-, genomically High Risk Luminal B-Type EBC treated with taxane and cyclophosphamide (TC) vs anthracycline + TC (AC-T). Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III breast cancer pts who received MP testing, with or without BluePrint (BP) molecular subtyping, and consented to full transcriptome and clinical data collection. Pts with HR+HER2- MP High Risk and BP Luminal B-Type tumors who received chemotherapy with 3-yr follow-up data (N = 614) were included. High Risk tumors were further classified into High 1 (H1; 0.000 to -0.569) or High 2 (H2; -0.570 to -1.000). Differences in 3-year RFI, defined as time from diagnosis to a local-regional recurrence, distant recurrence, or breast cancer specific death per STEEP 2.0 criteria, between H1 and H2 tumors were evaluated by Kaplan-Meier analysis and log-rank test, stratified by CT regimen. Results: Patients had similar age, menopausal status, race, and lymph node status between H2 vs H1 tumors. H2 tumors were more likely Grade 3, compared to H1 tumors. 86% of tumors were classified as H1 Luminal B-Type (N = 530) and 14% were classified as H2 Luminal B-Type (N = 84). AC-T treated tumors had non-significant differences in 3-yr RFI between H1 Luminal B-Type (95.3% [95% CI, 91.8-98.8]; N = 184) and H2 Luminal B-Type (97.7% [95% CI, 93.4-100.0]; N = 44). In contrast, pts with H2 Luminal B-Type (N = 40) tumors treated with TC demonstrated a significantly worse RFI of 86.4% (95% CI, 74.2-100.0) compared with 97.1% (95% CI, 95.1-99.2) in pts with H1 Luminal B-Type (N = 346) tumors, with an absolute difference of 10.7% (p = 0.0076). Conclusions: These data show that among pts with Luminal B-Type tumors, MP H2 have significantly worse 3-yr RFI than pts with MP H1 tumors when treated with TC. This further supports ongoing research demonstrating the significant benefits of anthracycline-based CT for treating H2 Luminal B-Type tumors. Conversely, MP H1 tumors do not appear to benefit from the addition of anthracycline to CT regimen. These FLEX data add to the growing evidence identifying MammaPrint as a comprehensive genomic signature regarding both prognosis as well as selection of systemic therapy for HR+HER2- EBC pts. Clinical trial information: NCT03053193.