HER2+ Disease

HER2+ status associated with more aggressive disease and poorer outcomes

HER2+ breast cancer is an especially aggressive form of the disease 1-3

  • HER2 overexpression has been associated with increased metastasis and angiogenesis 4
  • Patients with HER2+ disease experience increased risk of disease recurrence and inferior survival 1, 5

Increases risk in node-negative tumors

In a retrospective study of node-negative invasive breast cancer, HER2 gene amplification strongly impacted the risk for both early recurrence and disease-related death 6

Relative risk of early recurrence (n=242)
Relative risk of disease-related death (n=232)

*Based on a sample of 324 node-negative archival breast cancer specimens. Patients were treated by surgery only. Early recurrent disease (n=242 cases) was defined as occurring within 24 months of diagnosis. Evaluation of disease-related death was restricted to 232 patients known to have died of disease, or who had at least 36 months of follow-up.

†Small tumors defined as ≤ 1.0 cm in diameter; large tumors defined as >1.0 cm in diameter.

  • HER2 gene amplification is the underlying biologic change that results in continuous HER2 overexpression 7
  • HER2 overexpression continues throughout the course of the disease and drives tumor growth 7-9

Increases risk in hormone-receptor-positive (HR+) tumors 10

  • HER2 overexpression predicts poor results even in patients whose breast cancers overexpress hormone-receptors (HR+ tumors)
    • Based on a 2005 clinical study by Gago et al, HER2+ tumors are associated with significantly worse disease-free survival (DFS) (P<0.001) and overall survival (OS) (P=0.001) than HER2-negative tumors
DFS in patients with HR+ tumors
OS in patients with HR+ tumors

Study design: This prospective clinical trial included 516 consecutive patients with previously untreated stage I or stage II primary breast cancer, 180 of whom had HR+ tumors. All patients received tamoxifen alone or chemotherapy plus tamoxifen. Patients were followed for 5 to 10 years (mean of 7.3). Immunohistochemistry of tumor biopsies was used to determine protein expression.

  • 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. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neuoncogene. Science. 1987; 235:177-182.
  • 2. Paik S, Hazan R, Fisher ER, et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. JClin Oncol.1990;8:103-112.
  • 3. Ross JS, Fletcher JA.HER-2/neu (c-erb-B2) gene and protein in breast cancer. AmJClin Pathol.1999;112(suppl 1):S53-S67.
  • 4. Niu G, Carter WB. Human epidermal growth factor receptor 2 regulates angiopoietin-2 expression in breast cancer via AKT and mitogen-activated protein kinase pathways. Cancer Res. 2007; 67:1487-1493.
  • 5. Witton CJ, Reeves JR, Going JJ, et al. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. JPathol. 2003; 200: 290-297.
  • 6. Press MF, Bernstein L, Thomas PA, et al.HER-2/neu gene amplification characterized by fluorescence in situhybridization: poor prognosis in node-negative breast carcinomas. JClin Oncol.1997;15: 2894-2904.
  • 7. Pegram M, Slamon D. Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. Semin Oncol.2000;27(suppl 9):13-19.
  • 8. Simon R, Nocito A, Hubscher T, et al. Patterns of Her-2/neu amplification and overexpression in primary and metastatic breast cancer. JNatl Cancer Inst. 2001;93:1141-1146.
  • 9. 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.
  • 10. Gago EE, Fanelli MA, Ciocca DR. Co-expression of steroid hormone-receptors (estrogen receptor alpha and/or progesterone receptors) and Her2/neu (c-erbB-2) in breast cancer: clinical outcome following tamoxifen-based adjuvant therapy. JSteroid Biochem Mol Biol.2006; 98:36-40.


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