Trastuzumab Mechanism of Action
Trastuzumab works primarily by binding with high affinity to the extracellular domain of the HER2 receptor, inhibiting proliferation of tumor cells that overexpress HER2, and mediating antibody-dependent cellular cytotoxicity (ADCC) against cancer cells. 1, 2
Primary Mechanisms of Action
Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2) 2
Trastuzumab inhibits ligand-dependent dimerization of the HER2 receptor and its downstream signaling pathways, blocking important cellular protection and growth promotion pathways 1
Trastuzumab acts as a mediator of antibody-dependent cellular cytotoxicity (ADCC), preferentially targeting cancer cells that overexpress HER2 compared to cancer cells that do not overexpress HER2 1, 2
In vitro and animal studies have demonstrated that trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2 2
Clinical Relevance of HER2 in Breast Cancer
HER2 is a proto-oncogene that is amplified and overexpressed in approximately 15-30% of newly diagnosed breast cancers and is associated with more aggressive tumor behavior 1, 3
Patients with HER2-positive tumors (defined as IHC 3+ or FISH ratio >2.0) benefit from trastuzumab therapy, while those with HER2-negative status (IHC 0-2+ and FISH negative) should not receive trastuzumab 3
Patients with a HER2 overexpression level of 3+ using immunohistochemistry (IHC) or a positive HER2 result using fluorescence in situ hybridization (FISH) benefit more from trastuzumab therapy than those with tumors overexpressing at a level of 2+ 4
Evidence from Clinical Studies
Clinical studies have demonstrated that trastuzumab improves response rates, time to progression, and overall survival when combined with chemotherapy compared with chemotherapy alone in the metastatic setting 3, 5
As a single agent, trastuzumab induces responses in approximately 15-25% of selected patients with metastatic breast cancer 3, 4
In HER2-low breast cancer, classic anti-HER2 drugs like trastuzumab have failed to provide benefit, as demonstrated in the large randomized phase III NSABP-B47 trial 3
Mechanism in HER2-Low Breast Cancer
Unlike in HER2-positive breast cancer, trastuzumab alone does not show clinically meaningful activity in HER2-low breast cancer 3
The only class of HER2-targeted drugs showing activity in HER2-low breast cancer is represented by second-generation antibody-drug conjugates (ADCs), where the mechanism is primarily related to the delivery of cytotoxic molecules rather than the blockade of the HER2 pathway 3
Cardiotoxicity Mechanism
Trastuzumab-induced cardiotoxicity differs fundamentally from that of anthracyclines; trastuzumab does not cause myocyte loss 1
The primary mechanism for trastuzumab-induced cardiac toxicity appears to be the inhibition of HER2 in cardiomyocytes, which is an important protective, growth-promoting, and anti-apoptotic pathway in the myocyte 1
Trastuzumab reduces AMP kinase activity and decreases the amount of ATP available to the myocyte, which may explain the differences in cardiovascular risk between trastuzumab and other HER2-targeted agents 1
Cardiotoxicity induced by trastuzumab appears to be reversible after discontinuing treatment, resulting in a good cardiovascular prognosis 1
Resistance Mechanisms
Several mechanisms may contribute to trastuzumab resistance, including obstacles preventing trastuzumab binding to HER2, upregulation of HER2 downstream signaling pathways, signaling through alternate pathways, and failure to trigger immune-mediated mechanisms to destroy tumor cells 6
Understanding these resistance mechanisms is critical for developing strategies to overcome resistance and for developing tools for efficient patient selection 6