A 52-year-old Indian woman with newly diagnosed HER2-positive metastatic breast cancer presents to the oncology clinic. She has bony metastases and hepatic involvement. Her baseline LVEF is 55% (normal). She is started on trastuzumab (Herceptin) as part of her chemotherapy regimen. After 3 months of therapy, she develops progressive dyspnea and orthopnea. Echocardiography reveals LVEF of 42% with global hypokinesis. Which of the following best explains the mechanism of this adverse effect?

Explanation

## Mechanism of Trastuzumab-Induced Cardiotoxicity **Key Point:** Trastuzumab cardiotoxicity is a class effect of HER2-targeted monoclonal antibodies and occurs through loss of HER2-mediated cardioprotection, NOT through direct myocardial damage like anthracyclines. ### Pathophysiology HER2 signaling in cardiomyocytes activates the PI3K/Akt pathway, which provides: - Anti-apoptotic effects - Metabolic homeostasis - Mitochondrial protection When trastuzumab blocks HER2, this protective signaling is interrupted, rendering cardiomyocytes vulnerable to stress and leading to: - Reversible systolic dysfunction (unlike anthracycline cardiotoxicity) - Reduced ejection fraction - Heart failure symptoms **High-Yield:** Trastuzumab cardiotoxicity is typically **reversible** with cessation of the drug and heart failure management, whereas anthracycline cardiotoxicity is dose-dependent and often irreversible. ### Clinical Features - Onset: typically within 3–6 months of initiation - Presentation: dyspnea, orthopnea, edema - LVEF decline: ≥10% drop or to <50% is considered significant - Troponin and BNP may be elevated **Clinical Pearl:** Baseline LVEF assessment and serial echocardiography every 3 months are mandatory during trastuzumab therapy. Risk factors for cardiotoxicity include age >50, prior anthracycline exposure, and baseline LVEF borderline-low. ### Management - Discontinue trastuzumab if LVEF drops significantly - Initiate ACE inhibitor and beta-blocker - Consider cardiology referral - LVEF may recover over weeks to months after drug cessation [cite:Harrison 21e Ch 397]