ADCs in Metastatic Breast Cancer: Sequencing, HER2-Low/Ultralow, and Managing ILD in Resource-Limited Settings
Authors: Dr. Herdee Gloriane C. Luna,
Institution: National Kidney and Transplant Institute Philippines, Quezon City
Introduction
Antibody-drug conjugates (ADCs) have changed the treatment of HR+/HER2-negative metastatic breast cancer. About 65% of these tumours are HER2-low and 25% are HER2-ultralow, so most patients are now biologically eligible for trastuzumab deruxtecan (T-DXd). In DESTINY-Breast06, T-DXd given before chemotherapy improved median PFS to 13.2 versus 8.1 months in HER2-low disease (HR 0.62), with consistent benefit in ultralow disease. Because the 0 versus 0-with-membrane-staining call now changes treatment, reproducible HER2 immunohistochemistry is essential.
Methods
In chemo-pretreated disease, T-DXd (DESTINY-Breast04) and sacituzumab govitecan (TROPiCS-02) show overall survival benefit. Datopotamab deruxtecan improves PFS but not OS, and sacituzumab tirumotecan shows large PFS gains with immature survival data. ASCENT-07, in chemo-naive patients, did not meet its blinded-review PFS endpoint for sacituzumab govitecan. Cross-trial comparisons remain hypothesis-generating because the populations differ.
Results
Sequencing is the central open question. All three approved ADCs carry topoisomerase-I payloads, which raises concern about cross-resistance. Preclinical work suggests resistance is only partly payload-driven, involving efflux transporters, antigen loss, lysosomal handling and DNA repair. Real-world data show that a second ADC performs worse than the first. After T-DXd, a topoisomerase-I ADC gives about 2.5 months of real-world PFS, while chemotherapy with a different mechanism gives about 6 months. Interval chemotherapy between ADCs is not supported by clear evidence. Prospective trials (TRADE-DXd, SERIES) should clarify this. Toxicity management is equally important. Interstitial lung disease occurs in roughly 11–12% of T-DXd-treated patients, with occasional fatal cases. Early detection, prompt interruption and grade-based corticosteroids are key, and selected grade 1 patients may be rechallenged.
Conclusion
In resource-limited settings, priorities include validated HER2 testing, protecting T-DXd for appropriate patients, and using evidence-based chemotherapy when ADCs are unavailable. Where tuberculosis is endemic, ILD must be distinguished from infection, so teams need pragmatic pathways built on oximetry, chest X-ray, tele-consultation and patient education.