Controversies and Opportunities in the Clinical Daily Use of the 21-Gene Assay for Prognostication and Prediction of Chemotherapy Benefit in HR+/HER2-Early Breast Cancer

Simple Summary In breast cancer oncology, great progress has been made towards a more personalised approach. In particular, the introduction of genomic signature testing has helped physicians select the best adjuvant treatment for hormone-receptor-positive, human epidermal growth factor receptor-2-negative early breast cancer. Although Oncotype DX is recognised worldwide as the preferred genomic test, there are still some areas of uncertainty and opportunity. The aim of this review is to discuss the most challenging and urgent issues related to its daily use, providing insights for better integration and wider application in clinical practice. Several multigene assays have been developed to help clinicians in defining adjuvant treatment for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative early breast cancer. Despite the 21-gene assay having been available for decades, it has only recently been included in the healthcare systems of several countries. Clinical optimisation of the test remains of critical interest to achieve a greater impact of genomic information in HR+/HER2- early breast cancer. Although current guidelines recommend the use of the 21-gene assay in early breast cancer at intermediate risk of relapse, the implication of the Recurrence Score (RS) in some grey areas still remains uncertain. Our aim is to critically discuss the role of RS in peculiar circumstances. In particular, we focus on the complex integration of genomic data with clinicopathological factors; the potential clinical impact of RS in node-positive premenopausal women and in the neoadjuvant setting; the significance of RS in special histologies and in male patients; and the management and time-optimisation of test ordering. In the absence of robust evidence in these areas, we provide perspectives for improving the use of the 21-gene assay in the decision-making process and guide adjuvant treatment decisions even in challenging cases.