Refining risk stratification in HR-positive/HER2-negative early breast cancer: how to select patients for treatment escalation?

Purpose Despite advances in adjuvant therapeutic strategies, many patients with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) experience disease recurrence, even many years after primary surgery. The aim of this review is: (i) to point out the current clinical, pathological, and genomic features that contribute to define the risk of recurrence in HR-positive EBC, (ii) to explore the potential role of liquid biopsy-based assays for refining risk assessment, and (iii) to discuss future perspectives and innovative strategies to optimize risk stratification and select patients for treatment escalation. Methods We searched PubMed, EMBASE and Scopus to review the current evidence about risk stratification in patients with HR-positive EBC, and to identify studies deemed to have the highest scientific value. Results Risk stratification of HR-positive/HER2-negative relies on traditional clinicopathological features (age, menopausal status, tumor size, nodal status, tumor grading, HR expression level, and proliferation markers), along with newly developed genomic scores, which accurately predict risk of recurrence and survival. Multiparametric scores including both clinicopathological and genomic variables have the highest prognostication power, even if comparative studies have not defined which one should be preferred. In parallel, liquid biopsy-based showed to be a valuable tool to identify high risk patients. Conclusion The most appropriate definition of "high" and "low" risk HR-positive EBC is still unclear. Accordingly, treatment escalation/de-escalation depending on recurrence risk remains challenging. Implementation of new tools for risk stratification, such as liquid biopsy-based assays, as well as development of novel treatment strategies are strongly warranted.