Sequencing ADCs and Managing Cumulative Toxicity

This segment addresses one of the most complex and evolving challenges in modern breast oncology: how to optimally sequence ADCs. Emerging real-world data suggest that the greatest clinical benefit is typically achieved with the first ADC used, highlighting the importance of selecting the most effective agent for the given disease setting upfront. For example, in HER2-low metastatic disease, many clinicians prioritize T-DXd based on the strength of available evidence.

A key question is whether traditional chemotherapy should be used between ADCs to minimize potential cross-resistance. Current retrospective data suggest limited benefit from this strategy, and many clinicians are increasingly comfortable sequencing ADCs back-to-back, particularly when targets differ or when clinical circumstances warrant rapid disease control. However, treatment decisions remain highly individualized, incorporating patient tolerance, preferences, and cumulative toxicity.

Toxicity profiles vary meaningfully across ADC classes and targets. HER2-directed agents carry higher risks of interstitial lung disease and require cardiac monitoring, while TROP-2–directed therapies are more commonly associated with hematologic or gastrointestinal effects. Even agents with similar targets may differ substantially due to linker and payload design.

Long-term tolerability is an important consideration, particularly fatigue, nausea, and cumulative treatment burden. Dose reductions, treatment breaks, and supportive care interventions are often necessary, and some patients may maintain durable responses even after extended treatment interruptions.

Overall, ADC sequencing remains an area of active investigation, with prospective trials needed to guide evidence-based strategies while clinicians balance efficacy with long-term quality of life.