How Trastuzumab Works: Targeting the HER2 Receptor

What HER2 Does When Amplified

HER2 (ERBB2) is a receptor tyrosine kinase with no known ligand of its own; it works by pairing with other ErbB receptors. When the HER2 gene is amplified, the protein is so abundant that receptors pair and signal without needing a growth factor, driving continuous PI3K-AKT and RAS-MAPK activity.

Trastuzumab binds an outer region (domain IV) of the HER2 protein on the cell surface.

Several Overlapping Effects

Binding of trastuzumab reduces HER2 signalling, promotes internalisation and degradation of the receptor, and interferes with the shedding of HER2's extracellular domain. It also blocks ligand-independent HER2-HER3 pairing to some extent.

Critically, the antibody's Fc region engages immune cells, triggering antibody-dependent cellular cytotoxicity in which natural killer cells destroy the coated tumour cell. This immune contribution is part of why trastuzumab works.

Why HER2 Testing Is Essential

Trastuzumab only helps tumours that overexpress HER2, defined by validated immunohistochemistry and in-situ hybridisation. Giving it to HER2-negative disease exposes patients to cardiac risk (it can cause a usually reversible drop in heart function) without benefit.

The definition of 'HER2-positive' has itself evolved, and a separate 'HER2-low' category now matters for antibody-drug conjugates but not for trastuzumab monotherapy.

Resistance and the Next Generation

Resistance arises through PI3K pathway activation (PIK3CA mutation, PTEN loss), signalling from other receptors, incomplete HER2 blockade, and loss of the immune effector response. This drove development of pertuzumab (blocks HER2-HER3 pairing), the tyrosine kinase inhibitors lapatinib, neratinib and tucatinib, and antibody-drug conjugates that use trastuzumab as a delivery vehicle for a cytotoxic payload.

Trastuzumab is now most often used in combination rather than alone.

HER2 Testing in Practice

HER2 status is determined by immunohistochemistry scored 0 to 3+, with equivocal 2+ cases reflexed to in-situ hybridisation, which counts HER2 gene copies against the centromere of chromosome 17. A 3+ result, or amplification by hybridisation, defines the HER2-positive disease eligible for trastuzumab.

Interpretation has pitfalls: patchy staining within a tumour, fixation effects, extra copies of chromosome 17, and the distinction between amplification and an activating HER2 point mutation, which is a different situation that trastuzumab does not address. HER2 status can also change between the primary tumour and a metastasis, so re-biopsy is sometimes warranted.

Dosing, Cardiac Safety and Biosimilars

Trastuzumab is given intravenously or, for some indications, as a fixed-dose subcutaneous injection, on a weekly or three-weekly schedule — for a defined period in early breast cancer and until progression in advanced disease. Left ventricular ejection fraction is measured at baseline and roughly every three months, and the drug is held for a significant asymptomatic fall or any symptomatic decline; function usually recovers after a pause.

The cardiac risk is higher when trastuzumab overlaps with an anthracycline, which is why regimens sequence rather than combine them where possible. Several trastuzumab biosimilars are approved and are regarded as equivalent in efficacy and safety.

Key Takeaways

• ·Trastuzumab binds cell-surface HER2, cutting signalling and recruiting natural killer cells to kill the cell.
• ·It only benefits validated HER2-positive tumours and carries a reversible cardiac risk.
• ·PI3K-pathway activation is a common resistance route; newer HER2 agents build on trastuzumab.