Guiding targeted therapies for breast cancer

Human epidermal growth factor receptor 2 (HER2) is one of the most important markers for stratifying breast cancer patients and determining the optimal therapeutic pathway.¹ HER2 is a transmembrane receptor tyrosine kinase that plays a key role in cell growth and survival, and was first identified as a breast cancer marker in 2005.^2,3 Tumours have typically been classified as either HER2-positive or -negative, with HER2 positivity being defined as protein overexpression or equivocal expression with evidence of HER2 gene amplification.⁴ HER2-positive breast cancer constitutes 13 to 15 per cent of all cases, and shows variable response to anti-HER2 therapies such as trastuzumab, pertuzumab and trastuzumab emtansine (T-DM1).^5-7

In recent years, the DESTINY-Breast04 trial revealed the clinical relevance of a third subgroup, HER2-low, defined by immunohistochemistry (IHC) scores of 1+ or 2+ without HER2 gene amplification.8 More recently still, researchers have begun to recognise a potential fourth category — HER2-ultralow — comprising tumours with minimal focal staining that fall just above the IHC 0 threshold, often involving incomplete membrane staining in fewer than 10 per cent of cells.⁹

These two newer subgroups previously fell within the HER2-negative group, and therefore were ineligible for targeted anti-HER2 therapy.8 However, trastuzumab deruxtecan (T-DXd), an antibody drug conjugate (ADC), has shown clinical benefit in HER2-low tumours. HER2-ultralow tumours are not yet formally defined in clinical guidelines, but may also respond to emerging ADCs.¹⁰