Trastuzumab


Article Author:
Karl Greenblatt


Article Editor:
Karam Khaddour


Editors In Chief:
Jesse Cole


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/11/2019 1:01:38 PM

Indications

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.

Mechanism of Action

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.

Administration

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]

Adverse Effects

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

Contraindications

  • 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.

Monitoring

Routine echocardiographic assessment is universally recommended before initiating trastuzumab treatment. Cardiac risk factors such as hypertension and smoking should also be optimized. The role of screening echocardiography for asymptomatic patients during treatment is uncertain. A reasonable, guideline-based alternative is to obtain echocardiography at baseline, at the conclusion of treatment, and 6 to 12 months following treatment.[16] In clinical practice, asymptomatic patients receiving anthracyclines or with baseline cardiac risk factors often undergo echocardiography frequently as every 2 to 3 months. Patients with metastatic disease receiving indefinite therapy may also undergo routine echocardiography.[17] Symptomatic patients should receive immediate echocardiography, cardiac biomarker testing, and referral to a cardiologist. Trastuzumab should be discontinued if LVEF is less than 50% and is decreased by more than 10% from baseline, or if LVEF is decreased by more than 16% from baseline. In select cases, trastuzumab may be restarted if there is documented recovery of LVEF.

When trastuzumab is combined with paclitaxel, increased serum concentration of trastuzumab has been observed. Serum paclitaxel concentrations may also be decreased in the presence of trastuzumab.[18] The mechanism and clinical significance of these interactions are unknown.

When added to cytotoxic chemotherapy, trastuzumab may further increase the risk of neutropenia, infections, and anemia. Trastuzumab should not be used in combination with belimumab due to an increased risk of neutropenia and infection.

Enhancing Healthcare Team Outcomes

Trastuzumab is a biologic agent primarily used in the treatment of HER2-positive breast cancer. It may be used as adjuvant therapy for localized disease or as first-line therapy for metastatic disease. The development of trastuzumab has significantly increased survival associated with HER2-positive breast cancer; notably, trastuzumab also carries considerable historical importance as one of the first “targeted” chemotherapeutic agents developed. It is typically given in combination with one or more cytotoxic agents, most commonly anthracyclines (e.g., doxorubicin) and taxanes (e.g., paclitaxel). Trastuzumab has also demonstrated efficacy in the treatment of HER2-positive metastatic gastric cancer. The most significant adverse event associated with trastuzumab is cardiotoxicity; this is usually mild and reversible with discontinuation, but it may progress to irreversible, clinically significant cardiac failure. The risk of cardiotoxicity is highest in patients receiving concomitant anthracycline therapy. All patients should receive a baseline echocardiogram before initiating therapy and must be monitored closely for the development of palpitations, dyspnea, chest pain, and/or peripheral edema. Certain patients may benefit from more frequent echocardiographic assessment. Immediate discontinuation of trastuzumab is warranted if a decreased LVEF is discovered. Clinicians and clinical staff must also be aware of the potential for serious infusion reactions, especially following the initial dose. Trastuzumab is likely a human teratogen; it should be avoided in patients who are pregnant, and patients of childbearing potential must use contraception during treatment.


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Trastuzumab - Questions

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A 62-year-old female is evaluated for a breast lump and is ultimately determined to have breast cancer. She undergoes surgery and radiation, followed by treatment with trastuzumab, epirubicin, cyclophosphamide, and 5-fluorouracil. Which of the following is most likely true of her breast cancer?



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A female has been found to have a 3 cm cancerous breast lesion. At surgery, no lymph nodes are identified. The mass is found to be positive for HER2/Neu and negative for both estrogen and progesterone receptors. What is the best treatment?



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A female with breast cancer has been found to be positive for the HER2 protein. Her oncologist will likely suggest treatment with which one of the following?



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A 47-year-old female presents to a health care provider after discovering a lump in her right breast. She has not had any other symptoms. Physical examination reveals a 2.5 cm, firm, fixed, nontender mass in the upper, outer quadrant of the right breast. Diagnostic mammography shows the presence of suspicious calcifications and biopsy demonstrates invasive ductal carcinoma. Molecular testing reveals that the tumor is positive for HER2 and negative for estrogen receptor and progesterone receptor. The patient undergoes partial mastectomy and sentinel lymph node biopsy, which indicates the presence of regional nodal metastasis. A post-operative positron emission tomography (PET) scan shows no evidence of distant metastases. In addition to radiation therapy, treatment with which of the following is most appropriate?



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A 53-year-old female is diagnosed with stage 2 breast cancer that is positive for HER2 and negative for estrogen receptor (ER) and progesterone receptor (PR). She undergoes successful surgical excision of the primary tumor, and she begins neoadjuvant therapy with cyclophosphamide, 5-fluorouracil, paclitaxel, and trastuzumab. Three months after beginning this regimen, she presents to her oncologist with a complaint of progressive shortness of breath. It is worse with exertion and lying flat; on two occasions, she has awakened in the middle of the night gasping for breath. She has also noticed swelling of her ankles. Which of the following is the most likely cause of her new symptoms?



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A 62-year-old female is discovered to have metastatic breast cancer that is positive for HER2 and negative for estrogen receptor (ER) and progesterone receptor (PR). Treatment with trastuzumab and paclitaxel is planned. Which of the following studies should be obtained prior to the initiation of therapy?



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In addition to breast cancer, trastuzumab is licensed for the treatment of which of the following malignancies?



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Trastuzumab - References

References

Bang YJ,Van Cutsem E,Feyereislova A,Chung HC,Shen L,Sawaki A,Lordick F,Ohtsu A,Omuro Y,Satoh T,Aprile G,Kulikov E,Hill J,Lehle M,Rüschoff J,Kang YK, Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (London, England). 2010 Aug 28     [PubMed]
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Farolfi A,Melegari E,Aquilina M,Scarpi E,Ibrahim T,Maltoni R,Sarti S,Cecconetto L,Pietri E,Ferrario C,Fedeli A,Faedi M,Nanni O,Frassineti GL,Amadori D,Rocca A, Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart (British Cardiac Society). 2013 May     [PubMed]
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Furtlehner A,Schueller J,Jarisch I,Ostermann E,Czejka M, Disposition of paclitaxel (Taxol) and its metabolites in patients with advanced breast cancer (ABC) when combined with trastuzumab (Hercpetin). European journal of drug metabolism and pharmacokinetics. 2005 Jul-Sep     [PubMed]

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