Cardiac Safety Profile

Cardiac dysfunction, cardiac monitoring, and treatment modifications

Incidence of time to first LVEF decline of >-10% from baseline in adjuvant Herceptin trials1

Chart: Incidence of CHF
Chart: Incidence of CHF
Chart: Incidence of CHF

Cardiac dysfunction, cardiac monitoring, and treatment modifications

Reduced risk of congestive heart failure in non-anthracycline regimen1

  • In BCIRG 006, a lower rate of congestive heart failure (CHF) was seen with the TCH regimen vs the AC→TH regimen
Chart: Incidence of CHF
  • Patients were ineligible if they had a history of CHF, myocardial infarction, grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic >100 mm Hg), any T4 or N2 or known N3 or M1 breast cancer
  • The incidence of NCI-CTC grade 3/4 cardiac ischemia/infarction was higher in the Herceptin-containing regimens as compared with AC→T
  • 0.3% (3/1068) with AC→TH; 0.2% (2/1056) with TCH; and 0% with AC→T

Reduced risk of asymptomatic LVEF drops in non-anthracycline regimen1

Table: Per-patient incidence of new-onset cardiac dysfunction (by LVEF)

Cardiac Monitoring1

  • Patients receiving Herceptin should undergo monitoring for deteriorating left ventricular function prior to Herceptin treatment, and frequently during and after Herceptin treatment
Recommended cardiac monitoring schedule

Treatment modifications for cardiac issues1

  • Discontinue Herceptin for clinically significant decreases in left ventricular function (CHF)
  • In patients with asymptomatic declines in LVEF, Herceptin may be held and resumed up to three times, using the following management protocol
Herceptin administration for asymptomatic decreases in LVEF

Treatment modifications for infusion reactions1

  • Treatment should be modified as follows for infusion reactions:
  • Decrease the rate of infusion for mild or moderate infusion reactions
  • Interrupt the infusion in patients with dyspnea or clinically significant hypotension
  • Discontinue Herceptin for severe and life-threatening infusion reactions

BOXED Warnings and Additional Important Safety Information

Herceptin (trastuzumab) 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/CHF 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

  • Herceptin can also cause asymptomatic decline in LVEF

Consistent safety profile when used sequentially with different anthracycline-based chemotherapy regimens and dosing schedules1

Rate of congestive heart failure in HERA study Rate of congestive heart failure in Joint Analysis study

* As determined by an external review committee.

† As reported by investigators.

Median durations of follow-up were:

  • Joint Analysis studies: 23 months in the AC→T arm and 24 months in the AC→T+H arm
  • HERA: 12.4 months in the observation arm and 12.6 months in the 1-year Herceptin arm

Cardiac risk factors2

In NSABP B-31, a safety analysis was conducted for patients with symptoms suggestive of CHF.

    Source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE)‡

    An analysis of potential risk factors for Herceptin/chemotherapy-induced CHF was conducted

Contributing and non-contributing factors in risk of congestive heart failure

‡ Defined as NYHA class III or IV CHF or possible/probable cardiac death.

Discontinuation for cardiac cause1

Among women receiving adjuvant therapy for breast cancer in NSABP B-31, 16% discontinued Herceptin therapy due to clinical evidence of myocardial dysfunction or significant decline in LVEF.

In HERA, 2.6% of patients (44/1678) discontinued Herceptin due to cardiac toxicity.

Cardiomyopathy follow-up in the Joint Analysis1

Among the 32 patients with clinical cardiac events, as determined by the Adjuvant Cardiac Review and Evaluation Committee (ACREC), in the Joint Analysis:

  • One patient died of cardiomyopathy
  • All other patients were receiving cardiac medication at last follow-up
  • Approximately half of the surviving patients had recovery to a normal LVEF§ on continuing medical management

The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

Mechanisms of cardiotoxicity

Mechanisms of cardiotoxicity for Herceptin and anthracyclines

  • Anthracyclines and Herceptin are both considered to be valuable treatment options for HER2+ breast cancer patients in the adjuvant setting
  • However, both therapies have also been associated with an increased risk of cardiotoxicity1-2,4-6,8-9
  • Understanding the mechanisms of cardiotoxicity for these 2 therapies can clarify the potential risks that each poses for a patient3-9
Herceptin-associated cardiotoxicity
  • Anthracycline acts as a primary cardiotoxin that promotes production of free radicals, resulting in mitochondrial damage to the myocyte and myocardial cell death4,9
  • Anthracycline-associated cardiotoxicity is largely dose-dependent, generally not recoverable, and may result in ultrastructural damage6,9
  • 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:
  • § Defined as > 50%.
  • 1. Herceptin Prescribing Information. Genentech, Inc. March 2009.
  • 2. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophospahmide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005; 23:7811-7819.
  • 3. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001; 344: 783-792.
  • 4. Love N, Steingart RM. Cardiologic issues in breast cancer management: proceedings and interviews from a closed roundtable meeting of clinical investigators and practicing oncologists. BCU Cardiac. 2007;1(1):3-10.
  • 5. Chien KR. Herceptin and the heart-a molecular modifier of cardiac failure. N Engl J Med. 2006;354(8):789-790.
  • 6. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumabrelated cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005; 23(31):7820-7826.
  • 7. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999; 17:2639-2648.
  • 8. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002; 20:1215-1221.
  • 9. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996; 125(1):47-58.


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