Future potential targets of antibody-drug conjugates in breast cancer.

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required. Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7-H4. In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors.

Whether Human Epidermal growth factor Receptor 2 (HER2)-low status has prognostic significance in HR + /HER2- advanced Breast Cancer (aBC) patients treated with first-line Endocrine Therapy plus CDK 4/6 inhibitors remains unclear. In 428 patients evaluated, HER2-low status was independently associated with significantly worse PFS and OS when compared with HER2-0 status. Based on our findings, HER2-low status could become a new prognostic biomarker in this clinical setting.