Trastuzumab; Uses, Dosage, Side Effects, Drug Interactions

Mechanism of Action of Trastuzumab

The HER2 gene (also known as HER2/neu and ErbB2 gene) is amplified in 20–30% of early-stage breast cancers. Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and downregulation of HER2. It may also upregulate cell cycle inhibitors such as p21^Waf1 and p27^Kip1.In some types of cancer, HER2 may send signals despite the absence of growth factors arriving and binding to the receptor, making its effect in the cell constitutive; however, trastuzumab is not effective in this case.

The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation. The EGF pathway includes the receptors HER1 (EGFR), HER2, HER3, and HER4; the binding of EGF to HER is required to activate the pathway. The pathway initiates the MAP kinase pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway. In cancer cells, the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). This overexpression leads to strong and constant proliferative signaling and hence tumor formation. Overexpression of HER2 also causes deactivation of checkpoints, allowing for even greater increases in proliferation.

The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell (molecules called EGFs) to inside the cell and turn genes on and off. The HER (human epidermal growth factor receptor) protein, binds to human epidermal growth factor and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over-expressed and causes cancer cells to reproduce uncontrollably.

HER2 extends across the cell membrane and carries signals from outside the cell to the inside. Signaling compounds called mitogens (specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link (dimerize), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the PI3K/Akt pathway and the MAPK pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor (angiogenesis).

Normal cell division — mitosis — has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called cdk2 (CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion. This is caused by phosphorylation by Akt.

Trastuzumab binds to domain IV of the extracellular segment of the HER2/neu receptor. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER-2 expression, but downregulates activation of AKT.In addition, trastuzumab suppresses angiogenesis both by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. One of the most relevant proteins that trastuzumab activates is the tumor suppressor p27 (kip1), also known as CDKN1B. Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells. Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such antibody-dependent cell-mediated cytotoxicity is another important mechanism of action.

Indications of Trastuzumab

• Cancer, breast
• Metastatic breast cancer
• Metastatic gastroesophageal junction adenocarcinoma
• Breast cancer, adjuvant
• Esophageal carcinoma
• Breast cancer
• Breast cancer, metastatic
• Gastric cancer
• Salivary gland cancer
• Trastuzumab is used to treat metastatic (spread) breast cancer.  It is effective against tumors that overexpress the HER2/neu protein.
• As part of chemotherapy regimen for adjuvant treatment of lymph-node positive, HER2/neu protein positive breast cancer.
• Treatment of gastric (stomach) cancer.
• It is not known whether or not trastuzumab may be effective in other cancers that may also have this HER-2/neu protein, including ovarian, colon, endometrial, lung, bladder, prostate, and salivary gland tumors.

Contra-Indications of Trastuzumab

• Anemia
• Decreased Neutrophils a Type of White Blood Cell
• High blood pressure
• Disease of the Muscle of the Heart with Enlargement
• Heart Failure
• Obstruction of a Blood Vessel by a Blood Clot
• Abnormally low blood pressure
• Interstitial Pneumonitis
• Acute? Respiratory Distress Syndrome
• Lung Disease
• Pregnancy

Dosage? of Trastuzumab

Strengths: 150 mg; 440 mg

Breast Cancer

Metastatic Breast Cancer

• Initial dose: 4 mg/kg IV over 90 minutes, alone or with paclitaxel
• Maintenance dose: 2 mg/kg IV over 30 minutes once weekly

Breast Cancer – Adjuvant

Adjuvant Treatment of Breast Cancer

If given with, or following, paclitaxel, docetaxel, or docetaxel/carboplatin

• Initial dose: 4 mg/kg IV over 90 minutes, then 2 mg/kg IV over 30 minutes weekly for 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin)
• Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks, starting one week after completion of weekly dosing

If used as a single agent within 3 weeks after multi-modality anthracycline-based regimens

• Initial dose: 8 mg/kg IV over 90 minutes
• Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks
• Duration of therapy: 52 weeks

Esophageal Carcinoma

Metastatic Gastric Cancer

• Initial dose: 8 mg/kg IV over 90 minutes
• Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks
• Duration of therapy: Until disease progression

Gastric Cancer

Metastatic Gastric Cancer

• Initial dose: 8 mg/kg IV over 90 minutes
• Maintenance dose: 6 mg/kg IV over 30 to 90 minutes every 3 weeks
• Duration of therapy: Until disease progression

Side Effects of Trastuzumab

The most common

• chest pain
• a headache
• joint painPain
• dizziness
• nausea and vomiting
• Severe stomach ache
• epigastric pain,
• diarrhea,
• anorexia,
• flatulence,
• a headache,
• dizziness,
• fainting, fast or pounding heartbeats.

More common

• Fast or irregular heartbeat
• appetite loss
• changes in nails
• constipation
• fatigue
• fever
• Back pain
• dizziness
• headache
• increased cough
• Acid or sour stomach
• decreased appetite
• Agitation
• chest congestion
• chest pain
• cold sweats
• confusion
• decreased sexual ability or desire
• stomach or abdominal cramps, gas, or pain
• trouble sleeping

Less common

• bleeding gums
• blood in the urine or stools
• chest pain
• diarrhea
• Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
• difficulty in moving
• feeling of warmth
• muscle stiffness
• redness of the face, neck, arms and occasionally, upper chest
• sudden sweating
• lack or loss of strength
• muscle spasm
• difficult or labored breathing
• difficulty in swallowing
• dry mouth
• fever?
• headache
• hoarseness
• increased blood pressure

Drug Interactions of Trastuzumab

Trastuzumab may interact with following drugs ,suppliments & may decrease the efficacy of drug

• azathioprine
• belimumab
• corticosteroids (e.g., budesonide, dexamethasone, hydrocortisone, fluticasone, prednisone)
• cyclosporine
• infliximab
• mycophenolate
• other medications to treat cancer (e.g., carboplatin, cyclophosphamide, doxorubicin, ifosfamide, vincristine)
• sirolimus
• tacrolimus
• beclomethasone, inhaled
• cholera vaccine?
• daclizumab
• denosumab
• dichlorphenamide
• fingolimod
• paclitaxel
• paclitaxel protein bound

Pregnancy & Lactation of Trastuzumab

Pregnancy

This medication can cause harm to the fetus if used during pregnancy. Women who could become pregnant should use effective contraception while receiving this medication and for 7 months after stopping it. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if trastuzumab passes into breast milk. If you are a breast-feeding mother and are receiving this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

References