HER2-low and HER2-ultralow
Tumours with a little HER2 (IHC 1+ or 2+ without amplification), or a trace (ultralow), which older HER2 drugs ignored but Enhertu can attack.
HER2-low: IHC 1+ or 2+/ISH-negative (~50% of breast cancers, ~35% of TNBC). HER2-ultralow: IHC 0 with membrane staining in ≤10% of cells. DESTINY-Breast04 and -06 showed T-DXd benefit in both, redefining 'HER2-negative' and putting pressure on pathology to score the low end reliably.
Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.
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.