Diagnosis and Testing for HER2 Positive Breast Cancer

Types of Testing, Accuracy, and Changes in HER2 Testing

lab tech working on cancer
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If you’ve had a biopsy or surgery for breast cancer you’ve likely heard that your tumor is HER2 positive or negative. If you haven’t heard, you should ask your oncologist about the results of this test. It's important to understand HER2 testing and results, even if your tumor is HER2 negative.

Basics of HER2+ Cancer

HER2 proteins occur on the surface of breast cells, whether cancerous or normal. A gene (the HER2 or ERBB2 gene) we all have 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 the breast cell (HER2 overexpression). While normal breast cells have roughly two million of these receptors, HER2 positive breast cancer cells have up to 100 times this many.

Simplistically, when growth factors in the body attach to these extra receptors, it signals the cell to divide and results in the out-of-control growth of the breast cells that we call cancer.

Roughly 25 percent of people with breast cancer will be HER2 positive. In the past, being HER2 positive was associated with a poor prognosis. Now that we have targeted therapies (such as Herceptin (trastuzumab)) available, which can interfere with these receptors, the prognosis of HER2 breast cancer is much better.

Importance of Testing

It is important to have an accurate HER2 status result in order to receive the best treatment options for HER2 positive breast cancer.

This includes the option of targeted therapies such as Herceptin (trastuzumab), Perjeta (pertuzumab), Tykerb (lapatinib), and Nerlynx (neratinib). The particular types of chemotherapy for breast cancer which 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 which 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.

Types of Tests

There are different types of tests that can be done on a tumor to determine whether or not it is HER2 positive. These include:

  • 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 (FISH) and bright field ISH.

There is controversy over which testing measures are more accurate. Some researchers believe that FISH ISH is more accurate, but IHC is more commonly performed in the United States. 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

According to 2013 ASCO/CAP guidelines, if an HER2 test comes back as borderline or equivocal, "reflex testing" (proceeding immediately to another test) should be done with an alternative assay. For example, if an IHC gave borderline results, an ISH should be done on the same sample, and if an ISH is borderline, an IHC should be performed before the results are reported.

Sometimes the result of different HER2 tests, for example, both an IHC and a FISH ISH will be borderline, indeterminate, or equivocal. We do not currently have standard guidelines on how to proceed if this is the case, and you and your oncologist will need to discuss how to proceed.

Testing Limitations

In addition to having test results which are not positive or negative but rather borderline or equivocal, there are other possible limitations in HER testing. These include:

  • Inaccuracy (errors): With any type of laboratory test there is always the risk of errors.
  • Failure to repeat testing if a result is borderline, indeterminate, or equivocal: If a test comes back as borderline, it should be repeated.
  • Heterogenicity: The concept of tumor heterogeneity is fairly new and can be confusing. Since cancer cells are continually changing, there may be parts of a tumor which test HER2 positive and other parts which test HER2 negative. This is easier to understand when we realize that different types of a tumor may have very different cell types under the microscope as well.
  • Change: Tumors can change a different HER2 status.

Changes in HER2 Status

We tend to think of cancers as being a clone of one errant cell in which all of the cells are the same, but this is simply not the case. We know that 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 which 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.

How often do tumors change? 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:

  • ER: 20.7 percent
  • PR: 40.7 percent
  • HER2: 19.6 percent

In this study, almost 20 percent of tumors changed status from HER2 positive to negative or negative to positive. Knowing whether a tumor has changed is very important in selecting the best treatment options,

Is it good or bad if HER2 receptor status changes? 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.

Repeat Testing

In addition to the HER2 testing which should be done for everyone at the time of diagnosis, there are 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.

Misdiagnosis

What happens if your HER2 status is misdiagnosed? 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.

Sources:

American Society of Clinical Oncology. Practice and Guidelines. Breast Cancer. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer Update. http://www.asco.org/practice-guidelines/quality-guidelines/guidelines/breast-cancer#/9751

Lim, T., Lim, A., Thike, A., Tien, S., and P. Tan. Implications of the Updated 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations on Human Epidermal Growth Factor Receptor 2 Gene Testing Using Immunohistochemistry and Fluorescence In Situ Hybridization for Breast Cancer. Archives of Pathology and Lab Medicine. 2016. 140(2):140-7.

Lower, E., Khan, S., Kennedy, D., and R. Baughman. Discordance of the Estrogen Receptor and HER-2/neu in Breast Cancer From Primary Lesion to First and Second Metastatic Site. Breast Cancer (Dove Medical Press). 2017. 5:515-520.

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