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Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2

Why this mattered

This paper helped turn HER2 from a marker of poor prognosis into an actionable therapeutic target. Before trastuzumab, HER2 amplification identified a biologically aggressive subtype of breast cancer, but this trial showed that selecting patients by tumor HER2 overexpression and adding a monoclonal antibody to chemotherapy could improve response, delay progression, and extend overall survival in metastatic disease. That was a major conceptual shift: a molecular abnormality in the tumor could define both the patient population and the treatment strategy, making breast cancer therapy less purely organ- and histology-based and more biomarker-driven.

The result also established a template for modern targeted oncology trials. The benefit was clinically meaningful, but it came with a clear toxicity signal, especially cardiac dysfunction when trastuzumab was combined with anthracycline-based chemotherapy. That dual finding shaped later practice: HER2 testing became central to treatment selection, trastuzumab moved into earlier-stage disease, and cardiac monitoring and non-anthracycline regimens became important parts of HER2-directed care.

Subsequent HER2 breakthroughs built directly on this foundation. Later agents, including pertuzumab, lapatinib, T-DM1, trastuzumab deruxtecan, and other HER2-directed strategies, extended the same principle: HER2-positive breast cancer is a distinct therapeutic category in which outcomes can be repeatedly improved by rationally targeting the driver pathway. The paper therefore mattered not only because it changed metastatic breast cancer treatment, but because it helped validate the broader paradigm of matching targeted biologic therapies to molecularly defined cancers.

Abstract

BACKGROUND: The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. METHODS: We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). RESULTS: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. CONCLUSIONS: Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.

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