Limits of substitution and context-dependent selective omission of Oncotype DX recurrence score testing

The Oncotype DX 21-gene recurrence score (RS) is widely used to guide adjuvant chemotherapy decisions in early-stage estrogen receptor-positive, HER2-negative breast cancer. However, its high cost and frequent discordance with conventional clinicopathologic risk assessment raise questions regarding whether RS can be substituted by other indicators or selectively omitted in specific clinical settings. In this narrative review, we examined whether RS can be reliably predicted or replaced by clinicopathologic or pathology-derived factors, and whether there are patient groups in whom RS testing has limited impact on treatment decision-making. A comprehensive literature search and structured screening process identified 54 studies that treated RS as an outcome variable, together with additional reports addressing selective testing strategies. Across diverse analytical approaches, RS could not be consistently substituted by existing indicators. Although modest correlations were observed, substantial case-level discordance persisted, particularly within the intermediate RS range, where predictive performance deteriorated near clinically relevant decision thresholds. In contrast, RS testing appeared less influential in treatment decisions for patients with clearly defined low- or high-risk clinicopathologic profiles or favorable special histologic subtypes. Overall, current evidence indicates that RS cannot be reliably replaced by other indicators, while its clinical value varies by context, suggesting that a selective rather than uniform application of RS testing may be reasonable in some settings.