The addition of CDK4/6 inhibitors to endocrine therapy has changed the standard of care for patients with high-risk, early-stage estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer by reducing the risk of recurrence. However, one patient subgroup continues to present a clinical dilemma. In current practice, patients with low genomic risk but high anatomic risk receive adjuvant chemotherapy because of large tumors or significant lymph node involvement, even though their tumors may have lower-risk biology.