From the Guidelines
Herceptin (trastuzumab) is a monoclonal antibody that targets the HER2 receptor protein on cancer cells, working by binding to the extracellular domain of the HER2 receptor and blocking growth signals that stimulate cancer cell proliferation. The mechanism of action of Herceptin involves binding to the HER2 receptor, which is overexpressed in approximately 20-25% of breast cancers and some other malignancies like gastric cancer 1. When Herceptin attaches to these receptors, it not only blocks growth signals but also activates antibody-dependent cellular cytotoxicity (ADCC), recruiting immune cells to attack the cancer cells it has bound to. Additionally, Herceptin prevents HER2 receptor dimerization, necessary for downstream signaling pathways that promote cell growth and survival. It can also induce downregulation of HER2 receptors from the cell surface and inhibit angiogenesis (formation of new blood vessels) that tumors need to grow.
Key Points About Herceptin's Mechanism of Action:
- Binds to the extracellular domain of the HER2 receptor
- Blocks growth signals that stimulate cancer cell proliferation
- Activates antibody-dependent cellular cytotoxicity (ADCC)
- Prevents HER2 receptor dimerization
- Induces downregulation of HER2 receptors from the cell surface
- Inhibits angiogenesis
The most recent and highest quality study, from 2025, discusses the importance of HER2-targeted therapies in the treatment of HER2-positive metastatic breast cancer, highlighting the role of trastuzumab in improving outcomes 1. Typical dosing for breast cancer is an initial loading dose of 4 mg/kg intravenously, followed by a maintenance dose of 2 mg/kg weekly or 6 mg/kg every three weeks. Cardiac monitoring is essential during treatment as Herceptin can cause cardiotoxicity, particularly when combined with anthracycline chemotherapy. The evidence from various studies, including those from 2017 and 2015, supports the efficacy of trastuzumab in treating HER2-positive breast cancer but also underscores the need for careful patient selection and monitoring due to its potential cardiotoxic effects 1.
From the FDA Drug Label
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2 Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
The mechanism of action of Herceptin (trastuzumab) is:
- Inhibition of proliferation of human tumor cells that overexpress HER2
- Antibody-dependent cellular cytotoxicity (ADCC), which is preferentially exerted on HER2 overexpressing cancer cells 2
From the Research
Mechanism of Action of Herceptin (Trastuzumab)
Herceptin, also known as trastuzumab, is a therapeutic monoclonal antibody that targets the human epidermal growth factor receptor type 2 (HER2), a cell-surface tyrosine kinase receptor overexpressed by 25% to 30% of breast cancers 3. The mechanism of action of trastuzumab involves binding with high affinity to the extracellular domain of HER2, inhibiting the proliferation of tumor cells that overexpress HER2 4.
Key Aspects of Trastuzumab's Mechanism
- Trastuzumab is a humanized monoclonal antibody specific for the HER2 receptor 3.
- It inhibits the growth of human breast cancer cells overexpressing HER2 in vitro and in vivo 5.
- Trastuzumab shows additive antitumor activity in vitro and in vivo when administered with paclitaxel, doxorubicin, various cytokines, or tamoxifen 5.
- The drug is associated with a moderate response rate as a single agent and can produce greater response rates and prolong the survival of women with advanced breast cancer when combined with standard chemotherapy 3.
Resistance to Trastuzumab
- Development of resistance to trastuzumab is common, and insulin-like growth factor-I (IGF-I) receptor signaling can interfere with the growth-inhibitory action of trastuzumab 6.
- Strategies that target IGF-I receptor signaling may prevent or delay the development of resistance to trastuzumab 6.
Clinical Use of Trastuzumab
- Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2 4.
- It is an effective first-line single-agent therapy for a predictable cohort of metastatic breast cancers and can be used as a platform for therapeutic discovery against tumors that overexpress HER2 7.