Strategic Treatment Sequencing: Optimizing Patient Outcomes

In treating mTNBC, timely initiation of therapy is critical, especially given the aggressive nature of the disease. This urgency makes efficient biomarker testing essential. For patients with suspected PD-L1–positive tumors, PD-L1 status—measured via the combined positive score—should ideally be available early on through reflex testing at diagnosis. This ensures that clinicians can make informed treatment decisions without unnecessary delays, particularly when immunotherapy is a potential component of the first-line regimen.

As ADCs such as sacituzumab govitecan and datopotamab deruxtecan move into the first-line setting, new questions arise regarding treatment sequencing. If patients receive an ADC early, determining the optimal second-line therapy becomes more complex. For example, in tumors with HER2-low expression, another ADC such as trastuzumab deruxtecan might be considered, but the possibility of cross-resistance between ADCs with similar mechanisms—especially those containing topoisomerase I inhibitors—has become a concern. Emerging real-world data suggest that patients pretreated with sacituzumab govitecan may experience reduced benefit from subsequent ADCs such as trastuzumab deruxtecan, with shorter progression-free survival noted in these cases.

Currently, definitive sequencing strategies remain under investigation, and head-to-head comparisons of ADCs are lacking. However, data indicate that switching to traditional chemotherapy agents—such as taxanes, eribulin, or platinum-based regimens—may provide a more effective alternative between ADC treatments. Trials such as TRADE-DXd are exploring these sequencing questions prospectively, aiming to clarify whether ADCs can be effectively used back-to-back or whether alternating with chemotherapy provides better outcomes. Until more robust data emerge, clinicians must balance real-world evidence with clinical judgment to navigate postprogression treatment pathways in mTNBC, with careful consideration of resistance patterns and treatment mechanisms.