HER2 Testing in Breast Cancer

Among the many things that will be done when you are being diagnosed with breast cancer is HER2 testing of your tumor. Human epidermal growth factor (HER2) is a protein that, if present in high amounts, prompts a cancer to grow and metastasize more rapidly. It's especially important to be aware if you are HER2-positive or HER-2 negative, as your status will dictate which treatments may be most effective for you.

Understanding HER2

HER2 proteins occur on the surface of breast cells, whether cancerous or normal. A gene we all have (HER2 or ERBB2) carries the instructions or blueprint for manufacturing these proteins.

Each cell contains two copies of the gene. When there are extra copies of this gene (HER2 amplification) the result is an increased number of HER2 receptors on the surface of breast cells (HER2 overexpression). While normal breast cells have these receptors, HER2-positive breast cancer cells have up to 100 times as many.

Simplistically, when growth factors in the body attach to these extra receptors, it signals the cell (in this case, breast cancer cells) to divide and results in out-of-control growth.

Importance of Testing

It is important to have an accurate HER2 status result in order to treat HER2-positive breast cancer as effectively as possible. This includes the option of targeted therapies such as Herceptin (trastuzumab), Perjeta (pertuzumab), Tykerb (lapatinib), and Nerlynx (neratinib)—drugs that specifically address this protein.

The particular types of chemotherapy for breast cancer that work best can also vary with HER2 status.

An accurate HER2 status is also important in the treatment for metastatic HER2-positive breast cancer. The pattern of metastases, as well as treatment of specific sites of metastases, can vary based on HER2 status.

When to Test

Everyone with any type of invasive (infiltrating) breast cancer should have their tumor tested for HER2 status. "Invasive" breast cancer is defined as any cancer that is beyond stage 0 or carcinoma in situ.

All other stages of breast cancer, from stage I to stage IV, should be tested for HER2 status at the time of diagnosis and before treatment begins.

If you are unsure of your HER2 status, be sure to ask your oncologist.

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Repeat Testing

There are also circumstances in which testing should be repeated. These include:

• At the time of recurrence, whether it is a local, regional, or metastatic recurrence
• If a breast cancer spreads and with any new metastases
• If you and your oncologist feel that the HER2 test you had done is not as accurate as newer tests

Types of Tests

There are two tests that can be done on a tumor to determine whether or not it is HER2-positive. These are done in a lab using a sample of the tumor:

• HER2 immunohistochemistry (IHC): IHC is a measurement of the number of HER2 protein receptors on the surface of breast cancer cells, or HER2 overexpression.
• In situ hybridization (ISH): ISH is a measure of the number of copies of HER2 in each breast cancer cell, or HER2 amplification. There are two different ISH assays: Fluorescence in situ hybridization (FISH) and bright field ISH.

IHC tends to be cheaper to perform and results are usually back quickly, which is why it is usually used first. FISH, however, is believed to be more accurate. It is often used when IHC results aren't definitive.

Since this area is changing very rapidly, it's important to talk to your oncologist about the test you have done and why that particular method may be preferred.

Test Results

Though they are intended to do the same thing, these tests have different possible results.

Possible IHC results are more nuanced:

The results of the FISH test are more clear-cut, although equivocal (non-definitive) results are possible.

According to 2013 ASCO/CAP guidelines, if an HER2 test comes back as borderline/equivocal, reflex testing (proceeding immediately to another test) should be done with an alternative assay.

IHC 3+ and FISH positive results means you will be treated with medications that target HER2-positive breast cancers. 

Limitations

While important tests, there are important limitations of HER2 testing that must be kept in mind:

• Inaccuracy (errors): Sometimes, test results are inconclusive. In these instances, testing another sample might be needed, which means patients must comply with repeat testing in order to get an accurate result.
• Heterogenicity: There may be parts of a tumor that test HER2-positive and others that test HER2-negative.
• Change: Tumors can change HER2 status, so the results you may receive after one test may not hold true for the duration of your disease course.

Understanding more about changes in HER2 status can help you better understand these test limitations.

Changes in HER2 Status

People often think of cancer cells as clones of one errant cell, but this is simply not the case. Cancer cells continue to develop new mutations and change. Different parts of a single tumor mass can have cancer cells with different characteristics (tumor heterogeneity), and these changes can become even more apparent when a tumor progresses, such as with a recurrence or metastatic disease.

It is not only HER2 status that can change. Estrogen receptor (ER) and progesterone receptor (PR) status may also change when a tumor recurs or metastasizes, and this change in receptor status is referred to as discordance. A tumor may change from being positive to negative for one of these receptors, or conversely, from being negative to positive.

The chance of discordance between the original tumor and a first or second metastasis (either from negative to positive or from positive to negative) is as follows:

As long as the change is detected (by doing repeat testing) so that the best treatments can be recommended, it does not seem that a change in receptor status plays a large role in prognosis. In this study tumors which were discordant for HER2 (changed to become either positive or negative) had a similar prognosis to those tumors which did not change HER2 receptor status.

This study found discordance between the original metastases and a first or second metastasis, but discordance may occur between a first and second metastasis as well.

Misdiagnosis

If your tumor is truly HER2 positive but you get a HER2 negative result, you may not receive potentially survival improving therapies. On the other hand, if your HER2 status is truly negative but you get a positive HER2 status result, you risk exposure to the side effects of HER2-targeted therapies with little benefit (although some people who are HER2 negative have tumors which have responded to these targeted therapies).

A Word From Verywell

HER2 testing, along with estrogen and progesterone receptor testing, should be done on all invasive (stage I to stage IV) breast cancers at the time of diagnosis and before any treatment is done (with the occasional exception of a surgical excision).

Testing should also be repeated if you had a test that came back as indeterminate, if your oncologist feels a different type of test is more accurate, or if your cancer recurs or spreads. The HER2 status of a tumor can change over time, even in different areas of a single tumor.

An accurate HER2 status is important in choosing the best treatment options for your cancer while minimizing the side effects of treatments less likely to be effective. There is some controversy over the best tests for HER2, and newer and modified tests are being evaluated today. What this means is that it's important to ask questions and be your own advocate in your cancer care.