Trastuzumab Mechanism of Action and Effects

Introduction to Trastuzumab

The American Society of Clinical Oncology notes that 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.
The European Society for Medical Oncology states that trastuzumab binds with high affinity to the extracellular domain of the HER2 receptor, blocking HER2-HER4 signaling and its downstream signaling pathways 2.

The National Comprehensive Cancer Network guidelines indicate that trastuzumab inhibits ligand-dependent dimerization of the HER2 receptor and its subsequent signaling, which blocks an important cellular protection and growth promotion pathway in the myocardium 2.
The American Heart Association notes that 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 2.

The American College of Cardiology recommends that 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 lapatinib 3.
The European Society for Medical Oncology states that pertuzumab, another anti-HER2 monoclonal antibody, binds to a different epitope of the HER2 receptor and has complementary mechanisms of action to trastuzumab, providing a greater overall antitumor effect when administered together 4.

The National Comprehensive Cancer Network guidelines indicate that trastuzumab induces responses in approximately 15-25% of selected patients with metastatic cancer 1.
The American Society of Clinical Oncology notes that patients with a level of HER2 overexpression of 3+ by immunohistochemistry (IHC) or a positive HER2 result by fluorescence in situ hybridization (FISH) benefit more from trastuzumab therapy than those with tumors that overexpress at a level of 2+ 1.

The American Heart Association notes that trastuzumab-induced cardiotoxicity differs fundamentally from that of anthracyclines; in particular, trastuzumab does not cause myocyte loss 2.
The European Society of Cardiology states that in patients with trastuzumab-related cardiac dysfunction, myocytes appear histologically normal; changes can only be seen by electron microscopy, consistent with a reversible cardiomyopathy (CRCD Type II) 2.
The American College of Cardiology recommends that the primary mechanism for trastuzumab-induced cardiac toxicity appears to be the inhibition of HER2 in cardiomyocytes, an important protective, growth-promoting, and anti-apoptotic pathway in the myocyte 3.
The American Society of Clinical Oncology notes that cardiotoxicity is the primary concern with trastuzumab therapy; particularly in patients with pre-existing cardiac dysfunction, elderly patients, and in combination with, or after, anthracyclines, and that the cardiotoxicity induced by trastuzumab appears to be reversible after discontinuing treatment, resulting in a good cardiovascular prognosis 3.

The American Society of Clinical Oncology recommends that patients with HER2-positive tumors, defined as IHC 3+ or FISH ratio >2.0, benefit from trastuzumab therapy, while those with HER2-negative status should not receive trastuzumab 5
Trastuzumab improves response rates, time to progression, and overall survival when combined with chemotherapy compared with chemotherapy alone in the metastatic setting, with a strength of evidence supported by clinical studies 5
As a single agent, trastuzumab induces responses in approximately 15-25% of selected patients with metastatic breast cancer, according to the Journal of Clinical Oncology 5
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, with a level of evidence based on randomized controlled trials 6

Unlike in HER2-positive breast cancer, trastuzumab alone does not show clinically meaningful activity in HER2-low breast cancer, with a low level of evidence due to limited studies 6
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, based on preclinical and clinical data 6

Trastuzumab binds with high affinity to extracellular domain IV of the HER2 receptor, blocking ligand‑independent HER2 signaling and downstream ras‑Raf‑MAPK and PI3K/Akt pathways, while also stimulating antibody‑dependent cellular cytotoxicity (ADCC) against HER2‑overexpressing tumor cells. 7, 8, 9

HER2 overexpression is required for therapeutic responsiveness; patients whose tumors demonstrate IHC 3+ staining or are FISH‑positive derive the greatest benefit from trastuzumab treatment. 7, 8, 9

Cytotoxic chemotherapy agents interact synergistically with trastuzumab, enhancing overall antitumor efficacy when administered together. 7, 8, 9

Lapatinib is a small‑molecule tyrosine‑kinase inhibitor that blocks the intracellular kinase activity of both HER2 and EGFR (HER‑1), representing a mechanistic approach distinct from the extracellular monoclonal‑antibody action of trastuzumab. 7, 8, 9