Trastuzumab is a biologic antineoplastic agent that, at the time of its FDA approval in 1998, was among the first available “targeted” chemotherapies. In the United States, it is licensed for the treatment of the following:

• HER2-positive breast cancer: adjuvant therapy - Approved for combination use with anthracycline- or taxane-based chemotherapy. The maximum recommended duration of adjuvant treatment is 1 year.
• Metastatic HER2-positive breast cancer - Approved as monotherapy or for combination use with paclitaxel.
• HER2-positive gastric cancer - Used in combination with cisplatin-based chemotherapy. Compared with chemotherapy alone, trastuzumab plus chemotherapy modestly improved survival (median 13.8 months vs. 11.1 months).[1]

Trastuzumab has reported efficacy for the off-label neoadjuvant treatment of HER2-positive breast cancer.[2] For the treatment of metastatic breast cancer, trastuzumab has also been used in combination with lapatinib,[3] anastrozole,[4] cyclophosphamide,[2] pertuzumab,[2] [5] and several other agents.

Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). Trastuzumab binds to an extracellular domain of this receptor and inhibits HER2 homodimerization, thereby preventing HER2-mediated signaling. It is also thought to facilitate antibody-dependent cellular cytotoxicity, leading to the death of cells that express HER2.[6] Its mechanism differs slightly from that of the newer agent pertuzumab; the latter inhibits hetero-dimerization of HER2 with HER3, a related growth factor receptor. 

In the U.S., a biosimilar molecule is commercially available (trastuzumab-dkst). The product ado-trastuzumab emtansine is an antibody-drug conjugate consisting of trastuzumab and emtansine, an anti-microtubule cytotoxic agent.

Trastuzumab is administered as an intravenous infusion over 30 to 90 minutes. It should not be administered as a bolus and should not be administered together with D5W. Per the National Institute for Occupational Safety and Health (NIOSH) guidelines, due to trastuzumab’s status as a potentially hazardous drug, double-gloves, a gown, and closed-system transfer devices are required during administration. The recommended maintenance dose is 2 mg/kg infused weekly or 6 mg/kg infused once every 3 weeks. Initial loading doses up to 8 mg/kg may be administered. No dose adjustment is recommended for patients with mild to moderate renal insufficiency; trastuzumab has not been studied in patients with hepatic impairment or end-stage renal disease. The estimated elimination half-life of trastuzumab is 28 days;[7] a higher tumor burden may increase the elimination half-life.[8] Interpatient variability in drug clearance rates is considerable; increased body weight and decreased serum albumin have been associated with increased clearance.[9]

Trastuzumab is known to cause cardiotoxicity, usually manifested as a decrease in left-ventricular ejection fraction (LVEF). The exact pathogenesis of this event is unknown but may involve decreased clearance of reactive oxygen species in cardiac myocytes.[10] In the U.S., trastuzumab carries a black box warning regarding subclinical and clinical cardiac failure. According to the product label, a decrease in LVEF of at least 10% has been observed in up to 22% of patients, although some studies have reported an incidence as high as 44%.[11] Symptomatic congestive heart failure during treatment is less common, with an estimated incidence of 2% to 7%. The major risk factor for the development of cardiotoxicity is concurrent treatment with anthracyclines; the risk of severe cardiotoxicity is three to four times higher in patients receiving both trastuzumab and anthracyclines.[12] Increased age, hypertension, coronary artery disease, and hyperlipidemia may also contribute to increased risk. In clinical practice, most cases of trastuzumab-induced cardiotoxicity appear to be reversible upon discontinuation of treatment.[13][14] In some patients, however, long-term echocardiographic evidence of myocardial dysfunction persists.[15]

Severe infusion reactions have been observed upon administration of trastuzumab. These may include angioedema, anaphylaxis, interstitial pneumonitis, and acute respiratory distress syndrome. Trastuzumab also carries a black box warning to this effect. Most severe events have occurred within 24 hours of the initial infusion. All patients should be monitored for significant dyspnea, hypotension, or signs of angioedema; trastuzumab should be discontinued if these are observed. Some, but not all, patients have tolerated re-treatment after pre-medication (e.g., with acetaminophen and/or diphenhydramine).

Rare cases of nephrotic syndrome have been associated with trastuzumab, with the greatest incidence in patients with metastatic gastric cancer.

Other adverse effects commonly reported with trastuzumab monotherapy include:

• Headache
• Chills
• Gastrointestinal symptoms (nausea and vomiting; abdominal pain, diarrhea)
• Cough 
• Back pain      
• Upper respiratory symptoms (rhinitis, pharyngitis)
• Weakness and fatigue

• Pregnancy: Trastuzumab is believed to be a human teratogen. Fetal exposure has been associated with the development of oligohydramnios, leading to pulmonary hypoplasia and death. Patients of childbearing potential should use at least one form of contraception while receiving trastuzumab. It is unknown if trastuzumab is secreted in human breast milk.
• Cardiac Dysfunction: Due to the risk of cardiotoxicity, trastuzumab should be used with extreme caution in patients with pre-existing structural heart disease.