Proposed Mechanisms of Action

Based on preclinical studies, Herceptin suppresses HER2 activity via two domains

Herceptin works on both the extracellular and the intracellular domains of the HER2 receptor 2-5

  • Continuously suppresses HER2 activity that may lead to tumor proliferation 3
  • Leads to cell stasis and death
Herceptin proposed mechanisms of action
  • In preclinical studies, synergy with Herceptin (trastuzumab) enhanced the effects of chemotherapy 4,6,7
  • Herceptin provides continuous inhibition of the HER2 receptor
    • Extended half-life enables Herceptin to maintain constant exposure1
  • Because Herceptin works on both the intracellular and extracellular domains of the HER2 receptor:
    • Mechanisms promoting resistance within the cell may not render Herceptin inactive
    • Herceptin that is bound to a HER2 receptor may still work extracellularly to signal the immune system to destroy the cell
  • Adjuvant indications
  • Herceptin is indicated 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 containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • With docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline-based therapy

† High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

  • Metastatic indications
  • Herceptin is indicated:
  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Boxed WARNINGS and Additional Important Safety Information

  • Cardiotoxicity
  • Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF).
    • The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens.
    • Discontinue Herceptin treatment in patients receiving adjuvant therapy for breast cancer and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.
  • Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death.
    • In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens.
    • Herceptin can also cause asymptomatic decline in LVEF.
  • Cardiac Monitoring
  • Candidates for treatment with Herceptin should undergo a thorough baseline cardiac assessment, including history, physical examination, and an assessment of LVEF by echocardiogram or MUGA scan.
    • Patients should undergo frequent monitoring for decreased left ventricular function during and after Herceptin treatment.
    • More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction.
  • Infusion reactions and Pulmonary Toxicity
  • Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported.
    • In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension.
    • Patients should be monitored until signs and symptoms completely resolve.
    • Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress
  • Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia.
    • In postmarketing reports, serious and fatal infusion reactions have been reported. Discontinue Herceptin in all patients with severe or life-threatening infusion reactions.
  • Herceptin use can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis.
    • Such events can occur as sequelae of infusion reactions.
    • Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
  • Neutropenia
  • Exacerbation of chemotherapy-induced neutropenia has also occurred
    • In controlled clinical trials, severe neutropenia and febrile neutropenia occurred more frequently in metastatic breast cancer patients receiving Herceptin with myelosuppressive chemotherapy compared to chemotherapy alone.
    • The incidence of septic death was not significantly increased.
  • Pregnancy Category D
  • Herceptin can cause fetal harm when administered to a pregnant woman.
  • Post-marketing reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimester.
  • Most Common Adverse Events
  • The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Please see the Herceptin full Prescribing Information including Boxed WARNINGS and additional important safety information.

  • References:
  • 1. Herceptin Prescribing Information. Genentech, Inc. March 2009.
  • 2. Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999;26(suppl 12):60-70.
  • 3. Yakes FM, Chinratanalab W, Ritter CA, et al. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and AktIs required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res.2002; 62(14):4132-4141.
  • 4. Arnould L, Gelly M, Penault-Llorca F, et al. Trastuzumab-based treatment of HER2+ breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer.2006;94(2):259-267.
  • 5. Bianco AR. Targeting c-erbB2 and other receptors of the c-erb B family: rationale and clinical applications. JChemother. 2004; 16 Suppl 4:52-54.
  • 6. Pegram MD, Konecny GE, O'Callaghan C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. JNatl Cancer Inst. 2004; 96: 739-749.
  • 7. Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin™) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res.1998;58:2825-2831.
  • 8. Lewis GD, FigariI, Fendly B,et al. Differential responses of human tumor cell lines to anti p185HER2 monoclonal antibodies. Cancer Immunol Immunother.1993;37(4):255-263.
  • 9. Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61(suppl2):1 13.
  • 10. Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene. 2000;19(53):6102-6114.


Herceptin® (trastuzumab)Herceptin® (trastuzumab)