Selecting HER2 or TROP2 Directed ADCs in HER2 Low and Hormone Receptor Positive Breast Cancer

This section addresses the growing need to choose between trastuzumab deruxtecan and datopotamab deruxtecan in HER2 low and hormone receptor positive breast cancer. The experts explain that both agents show activity in this setting, which has created a new decision point for clinicians. Dr Tarantino emphasizes that traditional HER2 scoring was developed for therapies that depend on HER2 signaling, not for ADCs that rely on internalization and payload delivery. As a result, the distinction between HER2 zero, HER2 low, and HER2 ultralow may not fully reflect the likelihood of benefit.

Dr Mouabbi discusses early efforts to quantify HER2 protein expression numerically rather than categorically. He explains that more precise measurement may improve patient selection and reduce the risk of excluding patients who could respond. The speakers caution that HER2 zero status is not always consistent between pathologists and that variability across tumor samples can complicate decision making.

They then describe the relevance of TROP2 expression. Although high TROP2 expression appears associated with stronger benefit in some analyses, no standardized scoring system exists for routine use. Because TROP2 is widely expressed in hormone receptor positive disease, the experts favor an inclusive approach when selecting patients for datopotamab deruxtecan.

The discussion also reviews safety considerations. Trastuzumab deruxtecan requires close monitoring for interstitial lung disease, while datopotamab deruxtecan requires attention to mucosal and ocular symptoms. These toxicity distinctions can guide selection based on patient comorbidities and tolerance.

The experts conclude that the choice between HER2 and TROP2 directed ADCs will continue to evolve as quantitative biomarker techniques develop. For now, they emphasize a patient centered approach that incorporates prior treatment history, expression profiles, and safety considerations to select the most appropriate therapy.