Herceptin's companion diagnostic ushers in precision oncology

Historical milestone — this page describes an event dated 1998. It is not current breaking news.

Two approvals on the same day

On September 25, 1998, the FDA approved trastuzumab, sold as Herceptin, under biologics licence 103792 held by Genentech. It was a priority review.

On that same date the FDA also approved a laboratory test, HercepTest, under premarket approval P980018. The test measures how much HER2 protein a breast tumor makes.

That pairing is the point. HER2 is a protein on the surface of cells that tells them to grow. Some breast cancers make far too much of it. Trastuzumab is an antibody that binds HER2, and it only helps tumors that overexpress it. So the test decides who gets the drug. This is what the field now calls a companion diagnostic, and 1998 is where it starts.

The label spelled out the rule

The 1998 prescribing information is unusually blunt about this. Herceptin, it says, "should only be used in patients whose tumors have HER2 protein overexpression."

The evidence came from two trials. One randomized 469 women with metastatic breast cancer to chemotherapy alone or chemotherapy plus Herceptin. The other gave the drug alone to 222 women. In both, eligibility depended on a lab score.

Tumor tissue was stained and scored 0, 1+, 2+ or 3+, with 3+ the strongest. Only 2+ and 3+ tumors could enroll, and the label records that this was about 33% of those screened. Two thirds of women who volunteered were sent away by a lab result.

The label goes further. Data from both trials, it says, suggest the benefit was largely limited to the women with the highest level of overexpression, the 3+ group. The test was not a formality. It graded the size of the effect.

Why this changed how trials get built

Run the counterfactual. Enroll everyone with metastatic breast cancer, and roughly three quarters of the participants cannot benefit from the drug because their tumors do not carry the target. Any real effect in the quarter who can benefit is diluted until the trial cannot detect it.

Selecting patients by a molecular feature turned an undetectable signal into a clear one, in a trial of a few hundred people rather than several thousand. That logic, more than the drug itself, is what spread. Today biomarker tests decide access to targeted therapy across many cancers. Our page on biomarker testing and precision medicine covers how those tests work now.

The other thing on that label

Herceptin's 1998 label carried a boxed warning for cardiomyopathy, meaning damage to the heart muscle. It stated that the drug can cause ventricular dysfunction and congestive heart failure, that left ventricular function should be checked before and during treatment, and that stopping should be strongly considered if heart function drops meaningfully.

The warning noted the risk was particularly high when Herceptin was combined with anthracycline chemotherapy plus cyclophosphamide. That combination is why cardiac monitoring, usually an echocardiogram or a MUGA scan, became routine for people on HER2 treatment.

Precision does not mean gentle. A drug aimed at one protein can still harm tissue that uses the same protein, and heart muscle does.

What HER2 testing looks like today

The picture has become more detailed. Tumors are still stained and scored 0 to 3+ by immunohistochemistry. A 2+ result is ambiguous, so it is usually resolved by a second test, FISH, which counts copies of the HER2 gene inside the cell.

Cut-offs and scoring rules have been revised several times since 1998, and results depend on how the tissue was fixed, handled and read. A category called HER2-low has since emerged for tumors that were once simply called negative, because newer drugs work in them. Our guide to HER2-positive and HER2-low breast cancer explains what the categories mean.

When to get checked

This page is about a test, not a symptom. Two practical points follow from it.

If you have been diagnosed with breast cancer, HER2 status is one of the results that shapes treatment, alongside estrogen and progesterone receptor status. It belongs on the pathology report.

For finding breast cancer in the first place, see a doctor about:

• A new lump or thickened area in a breast or armpit
• Skin that has become dimpled, puckered, red or scaly
• A nipple that has turned inward, or discharge that is new, especially if bloody
• A change in the size or shape of one breast
• Breast pain in one spot that does not come and go with your cycle

Any of these lasting more than two weeks deserves an appointment, whatever a recent mammogram showed.

What this does not mean

• HER2 testing is not perfect. Results depend on tissue handling and on who scores the slide, and thresholds have changed repeatedly since 1998.
• A HER2-negative result does not mean fewer treatment options. It means different ones.
• The 1998 approval covered metastatic breast cancer. Use in earlier-stage disease came later, from separate trials.
• This describes one marker in one cancer. Extending the same model to other cancers took many more years, and it has not worked everywhere.
• The 1998 label quoted here is not the current one. Nothing here is advice about anyone's treatment.

Sources

• FDA, HERCEPTIN (trastuzumab) prescribing information, BLA 103792, approved 25 September 1998 — https://www.accessdata.fda.gov/drugsatfda_docs/label/1998/trasgen092598lb.pdf
• FDA, Herceptin approval letter, 25 September 1998 — https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/trasgen092598L.pdf
• FDA openFDA Drugs@FDA API record for BLA 103792 — https://api.fda.gov/drug/drugsfda.json?search=openfda.brand_name:%22HERCEPTIN%22&limit=3
• FDA openFDA device PMA API record for P980018 (DAKO HercepTest) — https://api.fda.gov/device/pma.json?search=trade_name:%22HERCEPTEST%22&limit=5
• SEER Cancer Stat Facts, Female Breast Cancer — https://seer.cancer.gov/statfacts/html/breast.html

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.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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