Bystander effect (ADC)
When a released payload leaks out of the targeted cell and kills its neighbours, including cells that lack the target.
Requires a cleavable linker and membrane-permeable payload (DXd, MMAE, SN-38). Explains why T-DXd works in HER2-low tumours and why T-DM1 (non-permeable) does not. Also a source of toxicity to adjacent normal tissue.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.