The signalling cascade from initial stimulus to downstream effector — and where therapeutic intervention is possible at each node.
Human epidermal growth factor receptor 2 (HER2/ErbB2) is a receptor tyrosine kinase that lacks an identified endogenous ligand and instead functions as the preferred dimerisation partner for all other ErbB family members (EGFR/HER1, HER3, HER4). HER2 gene amplification or protein overexpression, occurring in approximately 15-20% of breast cancers and 10-15% of gastric/gastro-oesophageal junction (GOJ) cancers, drives constitutive receptor dimerisation, kinase activation, and downstream signalling through both the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK cascades, resulting in uncontrolled proliferation, suppressed apoptosis, and enhanced invasiveness and metastatic potential.
The HER2-positive breast cancer subtype, defined by immunohistochemistry (IHC 3+ or IHC 2+/FISH amplified) per ASCO/CAP guidelines, was historically associated with aggressive biology and poor prognosis. Anti-HER2 therapy has transformed this outlook: trastuzumab (anti-HER2 monoclonal, blocks domain IV) combined with pertuzumab (blocks domain II, preventing HER2/HER3 heterodimerisation) provides complementary receptor blockade. The development of HER2-targeted antibody-drug conjugates (ADCs) — trastuzumab emtansine (T-DM1, linking trastuzumab to the microtubule inhibitor DM1) and trastuzumab deruxtecan (T-DXd, with a topoisomerase I inhibitor payload and high drug-to-antibody ratio) — has extended benefit into trastuzumab-resistant disease and, critically, into HER2-low tumours (IHC 1+ or IHC 2+/FISH non-amplified) previously considered HER2-negative.
The concept of HER2-low breast cancer, affecting approximately 50-60% of all breast cancer patients, has been established as a clinically actionable entity following the DESTINY-Breast04 trial of T-DXd, which demonstrated significant PFS and OS benefit versus chemotherapy. This paradigm shift has broadened the HER2-targeted treatment population substantially. Small-molecule HER2 TKIs (lapatinib, neratinib, tucatinib) offer oral administration and CNS penetration — tucatinib in combination with trastuzumab and capecitabine demonstrating intracranial response rates in HER2-positive brain metastases, an area of significant unmet need.
Upstream blockade vs downstream blockade — understanding the distinction is critical for treatment selection and sequencing.
Clinically actionable insights for treatment selection and sequencing
Human epidermal growth factor receptor 2 (HER2/ErbB2) is a receptor tyrosine kinase that lacks an identified endogenous ligand and instead functions as the preferred dimerisation partner for all other ErbB family members (EGFR/HER1, HER3, HER4).
HER2 gene amplification or protein overexpression, occurring in approximately 15-20% of breast cancers and 10-15% of gastric/gastro-oesophageal junction (GOJ) cancers, drives constitutive receptor dimerisation, kinase activation, and downstream signalling through both the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK cascades, resulting in uncontrolled proliferation, suppressed apoptosis, and enhanced invasiveness and metastatic potential.
The HER2-positive breast cancer subtype, defined by immunohistochemistry (IHC 3+ or IHC 2+/FISH amplified) per ASCO/CAP guidelines, was historically associated with aggressive biology and poor prognosis.
Anti-HER2 therapy has transformed this outlook: trastuzumab (anti-HER2 monoclonal, blocks domain IV) combined with pertuzumab (blocks domain II, preventing HER2/HER3 heterodimerisation) provides complementary receptor blockade.
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