A 52-year-old woman with metastatic HER2-positive breast cancer presents to the oncology clinic. She has completed 6 cycles of chemotherapy (doxorubicin + cyclophosphamide) followed by paclitaxel, and imaging shows partial response. Her LVEF is 50% (baseline 55%). The oncologist plans to add trastuzumab to her regimen. Which of the following best explains the mechanism of action of trastuzumab and the rationale for cardiac monitoring?

Explanation

## Mechanism of Trastuzumab **Key Point:** Trastuzumab is a recombinant humanized monoclonal antibody (IgG1) that binds to the extracellular domain of HER2 (human epidermal growth factor receptor 2) and inhibits HER2-mediated proliferation and survival signalling in cancer cells. ### Dual Anti-Tumour Effects 1. **Direct signalling blockade** — Prevents HER2 homodimerization and heterodimerization with other ErbB family members, suppressing downstream PI3K/Akt and MAPK/ERK pathways. 2. **Antibody-dependent cellular cytotoxicity (ADCC)** — The Fc region recruits natural killer cells and macrophages to destroy HER2-expressing tumour cells. ### Cardiotoxicity Mechanism **Clinical Pearl:** HER2 is expressed on cardiomyocytes and plays a role in maintaining myocardial contractility and cardioprotection. Trastuzumab-induced cardiotoxicity is thought to occur via: - Loss of HER2-mediated survival signalling in myocytes - Impaired myocardial energetics and mitochondrial function - Reduced LVEF (typically reversible but requires monitoring) **High-Yield:** Unlike chemotherapy-induced cardiomyopathy (which is dose-dependent and often irreversible), trastuzumab cardiotoxicity is: - Often reversible upon drug discontinuation - Not dose-dependent - Exacerbated by prior anthracycline exposure (as in this patient) ### Monitoring Strategy | Parameter | Baseline | During Trastuzumab | Action Threshold | |-----------|----------|-------------------|------------------| | LVEF (echocardiography) | ≥50% | Every 3 months | Drop >10% or <40% → hold/discontinue | | Troponin | Optional | Consider if symptomatic | Elevation suggests myocardial injury | | BNP/NT-proBNP | Optional | Consider baseline | Rising levels suggest HF risk | **Tip:** In this patient, baseline LVEF is already borderline (50%); close cardiac surveillance is essential before and during trastuzumab therapy. [cite:Harrison 21e Ch 397]