Joint Analysis of NSABP B-31 and NCCTG

Study Design1,3

  • Two cooperative group trials (NSABP B-31 and NCCTG N9831) with similar protocols evaluated the efficacy of adding 12 months of Herceptin to standard therapy in the adjuvant treatment of HER2+ breast cancer.
    • Results were combined in a Joint Analysis
  • All patients received doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T), and received hormonal therapy and/or radiotherapy as appropriate (n=3752).
    • For patients in the Herceptin arm, Herceptin was given weekly following completion of AC, in combination with paclitaxel for 12 weeks and then as a monotherapy
Diagram: Joint Analysis Study Design

*In NCCTG N9831, there was a sequential third arm that was not analyzed by investigators.

Joint Analysis showed 12 months of Herceptin significantly improved DFS

Herceptin reduced the risk of recurrence by 52%1,3

Chart: Important Data From BCIRG 006

Absolute risk was reduced by 15.3% in the Herceptin-containing arm at year 3.5 (95% confidence interval: 11.9%-18.6%)2

Consistent benefit seen across diverse patient subgroups

Joint Analysis showed consistent improvements in DFS regardless of age, hormone-receptor status, or tumor size1,2

DFS by subgroup - Joint Analysis

Boxed WARNINGS and Additional Important Safety Information

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 syndrome. Exacerbation of chemotherapy-induced neutropenia has also occurred.

Cardiac findings and risk factors from Joint Analysis

Patients developing CHF

Incidence of CHF

Median durations of follow-up were 23 months in the AC→T arm and 24 months in the AC→T+H arm1

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.
  • 6% of patients did not receive any Herceptin due to cardiac decline during treatment with AC.

Cardiac risk factors4

  • 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

†Defined as NYHA Class III or IV CHF or possible/probable cardiac death.

Cardiac follow-up in the Joint Analysis

Follow-up of LVEF4

  • In NSABP B-31, patients who discontinued Herceptin due to asymptomatic LVEF decline continued to be followed for changes in LVEF.
    • A significant number of patients experienced LVEF increases
LVEF follow-up in a cohort of patients who discontinued Herceptin due to asymptomatic LVEF decline

‡Analysis limited to patients followed for > 6 months after discontinuation of Herceptin.

Cardiomyopathy follow-up1

  • Among the 32 patients who developed CHF 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.

§Defined as LVEF > 50%.

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
  • 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. Data on file. Genentech, Inc.
  • 3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2+ breast cancer. N Engl J Med. 2005; 353:1673-1684 and supplementary appendix.
  • 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2+ breast cancer. N Engl J Med. 2005; 353: 1659-1672.


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