HER2 Ultra-Low: A New Target in Breast Cancer?

In this CHM Conversations episode, Drs. Paolo Tarantino and Jason Mouabbi dismantle the notion that HER2-low breast cancer constitutes a true biological subtype. Instead, starting from NSABP B-47 to Destiny-Breast 04 & 06, they argue that HER2 expression at low levels functions purely as a pharmacologic target—irrelevant to tumor biology but critical for ADC delivery.

They spotlight how T-DXd exploits even minimal HER2 presence via a Trojan horse mechanism, reshaping post-endocrine therapy options in HR+ disease, as seen in DESTINY-Breast04. With pathologists now parsing the subtle continuum from HER2-zero to ultra-low (1–10% staining), the therapeutic imperative, not intrinsic oncogenicity, drives new classification schemes—formalized by ESMO’s endorsement of “positive,” “low,” “ultralow,” and “zero” categories.