Trastuzumab (Herceptin)

Mechanism of action:
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein related to the epidermal growth factor receptor. HER2 protein is overexpressed in 25%–30% of primary breast cancers.

 
Trastuzumab (Herceptin) is a recombinant DNA- derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Consequently, it prevents the epidermal growth factor from binding to the HER2 receptor thus blocking its growth and cell division stimulatory effect.

Uses:
Trastuzumab is used in the treatment of breast cancers with histological proved HER2 overexpression.
Metastatic and advanced breast cancer:
Trastuzumab (Herceptin), is given in combination with paclitaxel as first line treatment for patients with metastatic breast cancer overexpressing HER2. It also can be given as a single agent second or third line treatment in the same type of patients.
Adjuvant therapy:
Trastuzumab (Herceptin), is added to regimens containing doxorubicin, cyclophosphamide, and paclitaxel as part of an adjuvant treatment of patients with HER2-overexpressing, node positive breast cancer postoperative.

Three main large studies showed consistent results supporting the clinical benefit from Herceptin in the adjuvant setting in terms of DFS and OS these trails are: The NSABP B31, the NCCTG N9831and the European trial, the HERA trial.

They all showed almost 50% reduction of systemic recurrence and improved DFS compared to standard therapy alone.

The first two trials used Trastuzumab for a total of 52 weeks and showed statistically significant improvement in DFS (50% increase) and OS (from 92 to 94%) in the Trastuzumab arm.

In HERA trial Trastuzumab was continued for 2 years and there was not statistically significant improvement in OS in the Trastuzumab arm although a magnitude difference was seen and the FU period was only 25 month.

Another important trial is the FinHer study, in which Trastuzumab was given for only 9 weeks in combination with Docetaxel or Vinorelbine.

So basically the randomization was in 4 arms in the group of patients who are Her2 positive as follows.

Docetaxel vs vinorelbine for 3 cycles then FEC 3 cycles.

Trastuzumab added to either vinorelbine or Docetaxel in another two arms for 9 weeks only (during the 3 cycles).

Results:

Docetaxel was superior to vinorelbine.

Trastuzumab improved significantly DFS and considerably OS with marginal P value of 0.07.

And this is the only regimen in which Trastuzumab can be given for only 9 weeks.

Obviously the cardiac toxicity from Trastuzumab in this study was insignificant.

Dose and administration:
Herceptin is given by intravenous drip (infusion). It is usually given at a dose of:
4 mg/kg IV loading dose, then 2 mg/kg weekly or
8 mg/kg IV loading dose, then 6 mg/kg every 3 weeks

The first dose is given slowly, usually over about an hour and a half and over 30 minutes thereafter with special precautions to possible infusion reactions.

Duration of therapy:
In metastatic breast cancer:
Trastuzumab is administered until tumor progression.
In the adjuvant setting:
AC-T.
It is very important not to remember that Herceptin is not given concurrently but following completion of doxorubicin and cyclophosphamide regimen. Herceptin is administered weekly for 52 weeks concurrently with paclitaxel during the first 12 weeks.
 

Toxicity:
The most serious toxicities of Herceptin are:
• Cardiomyopathy
• Pulmonary toxicity (respiratory failure, pneumonitis, pulmonary infiltrates)
• Infusion reactions
• Febrile neutropenia/exacerbation of chemotherapy-induced neutropenia

Cardiac:
Herceptin may induce heart problems like congestive heart failure due to left ventricular dysfunction. The incidence of cardiac problems increases in patients receiving concurrent anthracyclin and taxol. Patients should be monitored with Echocardiograph estimating the LVEF left ventricular ejection fraction as indicator for cardiac function. A decline of 15 point from the base line value or LVEF below 50% are characteristics for myocardial dysfunction and are limitations to give herceptin.Cardiac toxicity tends to occur in patients older than 50 years and with initial EF of about 50%.
 

Pulmonary Toxicity:
Herceptin use can cause serious pulmonary toxicity in the form of dyspnea, pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. These events may occur as sequelae of infusion reactions. Rarely, a fatal level of toxicity occurs. It should be noted that in most cases, symptoms occurred during or within 24 hours of drug administration.
Infusion reactions (Flu-like symptoms). Herceptin infusion may cause high temperature (fever) and chills which are more common during the first infusion. They are rarely severe to cause change in the infusion rate or stop the infusion.
 

Allergic reactions:

This is a rare side effect of Herceptin. Signs of this include skin rashes and itching, wheezing, difficulty breathing, and breathlessness.
 

Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. It should be discontinued if fatal reactions occur.
 

Refrences:

The information contained in this page is based on Trastuzumab (Herceptin®) factsheet which is prodived by relaible sources which you can visit for more information like:

- FDA website.
- National Comprehensive Cancer Network NCCN.