Randomized trial data from the advanced disease setting has demonstrated that in women with HER2 overexpressing breast cancers, the combination of trastuzumab plus chemotherapy — using either doxorubicin-cyclophosphamide or paclitaxel — results in improved progression-free and overall survival compared to the same chemotherapy given without trastuzumab. A recent report by Vogel of trastuzumab monotherapy demonstrated comparable antitumor activity to what has been reported with trastuzumab plus chemotherapy. Trastuzumab alone is frequently utilized as first-line therapy, particularly in women with non-life threatening metastases or with comorbid conditions. The optimal duration of therapy is being studied in clinical trials. The efficacy of trastuzumab in the advanced disease setting has led to a new generation of phase 3 randomized trials evaluating this agent in the adjuvant setting.

SURVIVAL ADVANTAGE IN METASTATIC DISEASE

We found that trastuzumab-based combination therapy was effective in that it reduced the relative risk of death by 20% at a median follow-up of 30 months. Few studies of metastatic breast cancer have demonstrated a survival advantage of this magnitude in association with the addition of a single agent. ...Given the extremely poor prognosis of patients with HER2- positive metastatic breast cancer, the cardiotoxicity of trastuzumab must be weighed against its potential clinical benefit. We recommend a cautious approach to the use of trastuzumab in patients who have previously received anthracyclines and in those who are currently receiving anthracyclines. The adjuvant use of trastuzumab will be an important research topic, but since many patients with early-stage breast cancer can be cured by surgery and radiotherapy, the cardiotoxicity of trastuzumab will be a critical consideration.

— Dennis J Slamon, MD, PhD et al.
N Engl J Med 2001;344(11):783-792.

CONTINUATION OF TRASTUZUMAB AFTER DISEASE PROGRESSION IN THE METASTATIC SETTING

My standard practice is to use trastuzumab until progression or toxicity. Whether it should be continued after disease progression is an issue we’re wrestling with on a day-to-day basis, and nobody knows the answer. We will join Dr. Pusztai from MD Anderson in his trial to help us answer this question in patients who have progressed on a taxane-trastuzumab combination.

The randomization will be to continue on trastuzumab and add vinorelbine or stop the trastuzumab and use vinorelbine alone. Everybody should embrace this study, because it will help us answer this very, very important question.

—Edith A Perez, MD

ADJUVANT CLINICAL TRIALS OF TRASTUZUMAB

Intergroup trial 9831 is an adjuvant study that was activated in May 2000. NSABP B-31 has very similar eligibility criteria. If someone uses adjuvant trastuzumab outside of a clinical trial setting, they’re essentially shooting in the dark. We do not yet understand how long this therapy should be given, what schedule should be used in combination with chemotherapy, and the potential risks or benefits the patients may derive from such treatment.

—Edith A Perez, MD

NCCTG-N9831: PHASE III RANDOMIZED STUDY OF DOXORUBICIN PLUS CYC LOPHOSPHAMIDE FOLLOWED BY PACLITAXEL WITH OR WITHOUT TRASTUZUMAB (HERCEPTIN) IN PATIENTS WITH HER2 OVEREXPRESSING BREAST CANCER OPEN PROTOCOL   NSABP B-31 TRIAL: PHASE III RANDOMIZED STUDY OF DOXORUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL WITH OR WITHOUT TRASTUZUMAB IN WOMEN WITH NODE-POSITIVE BREAST CANCER THAT OVEREXPRESSES HER2 OPEN PROTOCOL   BCIRG-006: PHASE III RANDOMIZED STUDY OF ADJUVANT DOXORUBICIN, CYCLOPHOSPHAMIDE, AND DOCETAXEL WITH OR WITHOUT TRASTUZUMAB VERSUS TRASTUZUMAB, DOCETAXEL, AND EITHER CARBOPL ATIN OR CISPLATIN IN WOMEN WITH HER2-NEU-EXPRESSING NODE-POSITIVE OR HIGH-RISK NODE-NEGATIVE OPERABLE BREAST CANCER OPEN PROTOCOL   ROCHE-BO16216; GENENTECH-H2223G: PHASE II/III RANDOMIZED STUDY OF ANASTROZOLE WITH OR WITHOUT TRASTUZUMAB (HERCEPTIN) IN POSTMENOPAUSAL WOMEN WITH HORMONE RECEPTOR-POSITIVE HER2-OVEREXPRESSING METASTATIC BREAST CANCER OPEN PROTOCOL   Would you recommend first-line trastuzumab therapy for the following women with ER-negative, HER2+(IHC 3+) metastatic breast cancer? O N C O L O G I S T S Asymptomatic 43-year-old woman with bone metastases who received adjuvant AC-T 65% Asymptomatic 63-year-old woman with bone metastases who received adjuvant AC-T 65% Very ill 43-year-old woman with liver and lung metastases who received adjuvant AC-T 85% Very ill 63-year-old woman with liver and lung metastases who received adjuvant AC-T 80% A 57-year-old woman has HER2-positive breast cancer and on first relapse is treated with paclitaxel/trastuzumab. After 4 months, she has had a good response and is doing well. Generally, how long would you would you continue trastuzumab? Continue after progression and add another chemo agent 65% Continue until progression, then stop 25% Stop before progression 10%

Cobleigh MA 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. Abstract

Hortobagyi GN. Optimal duration of therapy with trastuzumab. Semin Oncol 2001;28:33-40. Abstract

Hortobagyi GN, Perez EA. Integration of trastuzumab into adjuvant systemic therapy of breast cancer: Ongoing and planned clinical trials. Semin Oncol. 2001;28:41-6. Abstract

Seidman AD et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001;19:2587- 95. Abstract

Slamon DJ 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. Abstract

Vogel CL et al. First-line Herceptin monotherapy in metastatic breast cancer. Oncology 2001;61 Suppl 2:37-42. Abstract

Winer EP, Burstein HJ. New combinations with Herceptin in metastatic breast cancer. Oncology. 2001;61 Suppl 2:50-7. Abstract

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