Biology and Treatment of HER2-Low Breast Cancer

BC express HER2 protein at different levels and until now only patients with HER2-positive disease were candidates for anti-HER2 therapies. For decades, HER2-low expression has been included in the HER2-negative subgroup, not influencing the clin-ical decision-making. Despite past failure with older drugs, a new generation of anti-HER2 agents has recently shown encouraging signs of clinical activity and safety in HER2-low BC, culminating in the positive phase III data observed with T-DXd in DESTINY-Breast04. In this setting, it is becoming clear that ADCs can exert their ac-tivity by targeting a biomarker that not necessarily has to be oncogenic, moving from the assumption of target oncogenicity to target detectability.49 Considering the poor prognosis of endocrine-resistant HR-positive BC and TNBC, expanding the treatment options for these patients with the use of T-DXd in the HER2-low disease will represent a major therapeutic step forward. Current thresholds of HER2 expression may not be adequate to identify the ideal population for these novel drugs, requiring a rethinking of HER2 assessment from predefined categories to continuum expression. Future research will be directed at improving our ability to properly identify patients with HER2-low BC who might benefit from novel anti-HER2 ADCs, as well as to uncover the clinical and biological characteristics of this subtype of BC.