In certain cancers, the human epidermal growth factor receptor 2 (HER2) gene is amplified and overexpressed. Trastuzumab (Herceptin) is a humanized monoclonal antibody, HER2 protein receptor antagonist, which may be used for the treatment of certain cancers which overexpress HER2.
The human epidermal growth factor receptor 2 (HER2) gene located on chromosome 17q, encodes a transmembrane ligand orphan receptor tyrosine kinase that amplifies the signal provided by other members of the HER family (HER1/epidermal growth factor receptor [EGFR], HER3, and HER4) by forming heterodimers with them. HER2 activation and dimerization causes alterations in several complex downstream-signaling cascades that are involved in regulation of cell growth, proliferation, migration, adhesion, and survival and thus have been implicated in oncogenesis.
The HER2 gene is amplified and overexpressed in 20–30% of breast cancers, a finding which has been associated with more aggressive disease and higher relapse and mortality rates. HER2 may also be overexpressed in other epithelial cancers, including ovarian, thyroid, lung, salivary gland, stomach, colon, and prostate, making it a logical target for antibody-mediated therapy.
Trastuzumab has only received U.S. Food and Drug Administration (FDA) marketing approval for specific patients with breast cancer and gastric or gastroesophageal junction adenocarcinoma. However, its activity has been investigated in the preoperative (neoadjuvant) setting for breast cancer, in combination with regimens besides those specified in the FDA-approved product label, and in a wide range of other types of cancer that overexpress HER2.
Trastuzumab (Herceptin®) is a humanized monoclonal antibody against the extracellular domain of HER2. Trastuzumab has received FDA marketing approval for treatment of HER2-positive breast cancer, in both the adjuvant and metastatic settings, and metastatic gastric or gastroesophageal junction adenocarcinoma. It first received FDA approval in September 1998 for use in metastatic breast cancer, as a first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy.
The current FDA-approved labeling, as of October 2010, indicates Trastuzumab is indicated as follows:
- For adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer:
- as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel;
- as part of a treatment regimen of docetaxel and carboplatin; or
- as a single agent following multi-modality anthracycline-based therapy.
Trastuzumab is administered by IV infusion weekly or every three weeks for a total of 52 weeks depending on the dosing schedule and chemotherapy used for adjuvant treatment.
- For treatment of HER2 overexpressing metastatic breast cancer in combination with paclitaxel for first-line treatment or as a single agent in patients who have received one or more chemotherapy regimens for metastatic disease. Trastuzumab is administered by IV infusion weekly until disease progression.
- For treatment of HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment for metastatic disease. Trastuzumab is administered by IV infusion every three weeks until disease progression.
Appropriate patient selection for trastuzumab therapy is predicated on detection of HER2 overexpression. HER2 overexpression should be assessed only by facilities with demonstrated proficiency in the specific assay being used. Unreliable results may result from improper assay performance. Several assays are commercially available to aid selection of patients for trastuzumab therapy. These include the HercepTest™ and Pathway® HER2/neu, which are immunohistochemical assays (IHC), and PathVysion® and HER2 FISH pharmDx™, which are fluorescence in situ hybridization assays (FISH).