FDA Approval: Trastuzumab (Herceptin) for Breast Cancer

The letter, and what it authorized

On 25 September 1998 the FDA approved the biologics license application for trastuzumab. Genentech was authorized to market it under U.S. License No. 1048, with the tradename Herceptin.

The letter sets out two indications.

The first covers metastatic breast cancer whose tumors overexpress the HER2 protein, in people who had already received one or more chemotherapy regimens for metastatic disease.

The second covers trastuzumab combined with paclitaxel, for metastatic breast cancer that overexpresses HER2 in people who had not yet received chemotherapy for metastatic disease.

Both indications turn on one word: overexpress. Without that, neither applies.

What HER2 is

HER2 is a receptor that sits on the surface of cells and signals them to grow. Every cell has some.

In roughly a quarter to a third of breast cancers, the HER2 gene is amplified — there are extra copies — and the cell studs its surface with far more receptors than normal. The growth signal never switches off. Before 1998, tumors with this feature were among the most aggressive.

Trastuzumab is a monoclonal antibody. It is a laboratory-made protein designed to bind one target, and its target is HER2.

This made trastuzumab an early example of a drug that only works if a test says it should. Our page on biomarker testing and precision medicine covers how that testing is done and reported.

What the pivotal trial found

The evidence came from a randomized trial of 469 women with metastatic breast cancer that overexpressed HER2. It was published in the New England Journal of Medicine in 2001 by Slamon and colleagues.

Women received standard chemotherapy alone or the same chemotherapy plus trastuzumab. The chemotherapy backbone depended on prior treatment: doxorubicin and cyclophosphamide for those who had not previously had an anthracycline, and paclitaxel for those who had.

Adding trastuzumab improved every measure the trial recorded.

Time to disease progression rose from a median of 4.6 months to 7.4 months. The response rate rose from 32% to 50%. Median duration of response rose from 6.1 months to 9.1 months.

Deaths at one year fell from 33% to 22%. Median overall survival rose from 20.3 months to 25.1 months, a 20% reduction in the risk of death.

The report noted that the HER2 gene is amplified and the protein overexpressed in 25 to 30 percent of breast cancers, and that this increases the aggressiveness of the tumor.

The heart problem

The trial's most important safety finding was cardiac.

Heart dysfunction of New York Heart Association class III or IV occurred in 27% of women given an anthracycline, cyclophosphamide, and trastuzumab. It occurred in 8% of those given the anthracycline combination without trastuzumab.

With paclitaxel the figures were 13% with trastuzumab and 1% without.

The authors described the cardiotoxicity as potentially severe and in some cases life-threatening, while noting that symptoms generally improved with standard medical management.

That finding shaped practice permanently. It is why anthracyclines and trastuzumab are not given together in routine care, and why heart function is measured before and during treatment.

When to get checked

Anyone on trastuzumab should have heart function monitored on the schedule their team sets. Between checks, new breathlessness on mild exertion, waking at night short of breath, swelling in the ankles, or a persistent cough should be reported rather than waited out.

For breast cancer itself, NCI is direct that early disease often causes no symptoms, which is why screening matters. When changes do appear, NCI says to check with a doctor about:

• A lump in or near the breast, or a lump under the arm.
• A thick or firm area or mass in or near the breast or under the arm.
• A change in the size or shape of the breast.
• Nipple changes or discharge.

NCI's advice is to check with a doctor when any of those changes appear, rather than waiting to see whether they settle. Most turn out to be benign. Our overview of breast cancer covers what happens after a change is found.

The population behind the numbers

SEER, the federal cancer surveillance program, publishes American Cancer Society projections of about 321,910 new female breast cancer diagnoses and 42,140 deaths in the United States in 2026. The median age at diagnosis is 64.

Sixty-four percent is found while still confined to the breast, 27% after spread to nearby lymph nodes, and 6% after spread to distant sites.

Five-year relative survival is essentially 100% for localized disease, 87.5% for regional, and 33.8% for distant. Across all stages it is 91.9% for women diagnosed from 2016 through 2022.

Those figures cover every subtype together, including HER2-positive, hormone-receptor-positive, and triple-negative disease, which behave differently. They are registry averages and describe no individual.

What this approval cannot tell you

The 1998 approval covered metastatic disease only. Use of trastuzumab after surgery for early breast cancer came later, from different trials, and cannot be read back into this letter.

The trial also compared chemotherapy plus trastuzumab against chemotherapy alone. It says nothing about how trastuzumab compares with the HER2-targeted drugs developed since, and nothing about how they should be sequenced.

And an approval is not a prediction. Half the women in the trial's trastuzumab arm did not have their tumors respond. What the evidence establishes is a shift in the odds for a defined group, tested by a specific assay — not an outcome for any one person.

Sources

• FDA approval letter, trastuzumab (Herceptin), 1998
• Slamon DJ et al., N Engl J Med 2001 (NCBI E-utilities)
• NCI: Breast Cancer Signs and Symptoms
• NCI PDQ: Breast Cancer Treatment (Health Professional Version)
• NCI SEER Stat Facts: Female Breast Cancer

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

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