Inhibition of HER2
In This Section:
Inhibition of HER2
The epidermal growth factor receptor family consists of four cell surface receptors: EGF receptor, also called HER1; HER2/neu; HER3; and HER4. Binding of specific growth factors, or ligands, to three of these receptors causes them to interact, or dimerize, either with a receptor of the same type or with another family member. HER2 is called an "orphan receptor" because it does not interact directly with any ligand. Instead, it dimerizes with ligand-bound EGF receptor, HER3, or HER4.
Receptor dimerization activates signaling pathways inside the cell. These pathways lead to cell growth, proliferation, and survival.
HER2 in Cancer Cells
The HER2 gene is amplified in 20% of breast cancers. This means that the cells of these cancers have extra copies of the HER2 gene. Breast cancers with amplified HER2 genes, referred to as HER2-positive cancers, make more HER2 protein than HER2-negative cancers.
The extra HER2 protein causes increased signal pathway activation, which contributes to the uncontrolled growth and survival of these cancers.
Breast tumors that overexpress HER2 protein are more aggressive than other breast tumors. Patients with these tumors have a poorer prognosis and decreased chance of survival compared with patients whose tumors do not overexpress HER2.
Herceptin® (trastuzumab) may also interfere with cancer cell growth by activating an immune response.
Herceptin® (trastuzumab) is used to treat breast cancer only if the tumor overexpresses HER2. It has been approved by the FDA for the treatment of metastatic breast cancer in combination with or following administration of standard chemotherapy. Herceptin® (trastuzumab) has also been approved by the FDA as an adjuvant treatment for some earlier-stage breast cancers. Adjuvant therapy is treatment given after primary therapy--for example, surgery--to increase the chances of long-term survival.
Herceptin® (trastuzumab) is approved by the FDA for the adjuvant treatment of HER2-overexpressing breast cancer that is either (1) axillary lymph node-positive or (2) axillary lymph node-negative with at least one high-risk feature (e.g., estrogen receptor/progesterone receptor-negative, pathologic tumor size greater than 2 cm, Grade 2-3, age less than 35 years):
- As part of a treatment regimen consisting of doxorubicin (an anthracycline drug), cyclophosphamide, and either paclitaxel or docetaxel
- With docetaxel and carboplatin
- As a single agent following multimodality anthracycline-based therapy.
Herceptin® (trastuzumab) is also approved by the FDA for use:
- In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer.
- As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
Drugs that target EGFR family members (HER1 and HER2)
|Generic Name||Trade Name||Drug Type|
|EGFR (HER1) inhibitors||Cetuximab||Erbitux®||Monoclonal antibody|
|HER2 inhibitors||Trastuzumab||Herceptin®*||Monoclonal antibody|
* Agents that have been approved by the FDA for treatment of breast cancer and/or reduction of risk of breast cancer
The small molecule inhibitors--Tykerb® (lapatinib), Iressa® (gefitinib), and Tarceva® (erlotinib)--interfere with the kinase activity of their target proteins. The monoclonal antibodies--Erbitux® (cetuximab), Herceptin® (trastuzumab), and Omnitarg™(pertuzumab)--interact with the extracellular portion of their target receptor proteins and prevent receptor interaction with growth factor and/or dimerization with other receptors.
For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.
- Possible mechanisms of action of Herceptin® (trastuzumab) include:
- Activation of an immune response.
- Reduction of circulating levels of growth factor.
- Both A and B.
- Correct Answer: a
Herceptin® (trastuzumab) is thought to activate an immune response called antibody-dependent cell-mediated cytotoxicity. Other possible mechanisms of action include preventing the dimerization of EGFR family receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.
Herceptin® (trastuzumab) interacts with HER2, which is a cell surface receptor, and does not influence levels of circulating growth factor. Potential mechanisms of action of trastuzumab include activating an immune response, preventing the dimerization of EGFR family receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.
Trastuzumab interacts with HER2, which is a cell surface receptor, and does not influence levels of circulating growth factor. Potential mechanisms of action of Herceptin® (trastuzumab) include activation of an immune response, preventing the dimerization of EGFR receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.