HER2 Positive vs. HER2 Negative Breast Cancer: Important Differences

Is It Good or Bad to Have HER2 Positive Breast Cancer?

protein receptors on the surface of a cell
Protein receptors on the surface of a cell. Istockphoto.com/Stock photo©Ugreen

If you’ve been told that your breast cancer is HER2 positive, you probably have many questions about what this means. But if you are like many others, your first question might be, “Is it good or bad to be HER2 positive?” In other words, is it "better" if your tumor is HER2 positive or HER2 negative?

As we learn that breast cancer is not one disease but rather many diseases which differ at a molecular level, these are important questions.

The quick answer is that HER2 positivity can be both good and bad. Let's explore how HER2 status affects everything from the aggressiveness of a tumor, to treatment options, to the risk of recurrence and prognosis.

A Brief Review

Breast cancer is not a single disease—actually, no two cancers are alike—but we now have the ability to break these cancers down into different subtypes based on the "receptor status" of the tumors. Breast cancers differ in the proteins found the cell surface, proteins which are responsible for the growth of the tumors. These proteins are in turn related to different abnormalities in the genetic material of the cancer cells.

Many people are familiar with estrogen receptor-positive breast cancer, in which estrogen binds to the increased numbers of these receptors on breast cancer cells to stimulate the growth of the tumor.

What occurs with HER2 positive breast cancers in similar, but it is a different type of receptor on the surface of the cancer cell which drives the growth and spread of the tumor.

In addition to estrogen receptors on the surface of the cells (which are stimulated by estrogen), there are HER2 receptors on the surface of the cells (which are co-stimulated by growth factors to drive growth).

The HER2 gene (epidermal growth factor receptor 2 or HER2/neu) is a gene (one that we all have) that codes for proteins involved in the growth of breast cells.

It is also called the ERBB2 gene and is a gene (protooncogene) found on chromosome 17.

HER2 genes carry the instructions for making HER2 proteins. These proteins function as receptors on breast cells. When too many copies of the HER2 gene are present (due to damage to the genetic material in the cell or mutations) it results in the overproduction (or "overexpression") of HER2.

It's important to note that all breast cells—both cancerous and noncancerous—have HER2 receptors on the surface of the cell. The difference is that HER2 positive breast cancer cells have 40 to 100 times this number. When growth factors in the body bind to these receptors, it results in the overgrowth of the breast cells.

Just as we have medications that interfere with the estrogen receptor (or reduce estrogen in the body) to treat estrogen receptor-positive breast cancer, we now have medications which interfere with the HER2 receptors on HER2 positive breast cancers.

Roughly 25 percent (15 to 30 percent) of breast cancers are positive for HER2 (HER2 overexpression).

HER2 Positive Status: Good or Bad?

In order to properly answer the question as to whether it’s a good thing or a bad thing to be HER2 positive, it’s important to talk about the differences between tumors that are HER2 positive and those which are HER2 negative.

The quick answer is that it can be good or bad. Ultimately, many people want to know what effect having HER2 positive breast cancer has on survival, yet even those statistics can be misleading without an understanding of how being HER2 positive affects the growth of these cancers.

An example to illustrate this point is that of breast cancer in young women. Overall, survival rates are lower for very young women with the disease but this can be somewhat misleading. In younger people, the disease is often diagnosed in more advanced stages. So even though a younger woman may tolerate treatments better and have a better survival rate at a particular stage, the overall survival rate is lower due to higher stages at diagnosis.

The quick answer to whether having a HER2 positive breast cancer is good or bad is that "it depends." Therefore we need to look at the ways in which HER2 status may affect a cancer. These include:

  • The type of people who develop this type of tumor (for example, the average age)
  • The stage at which HER2 cancers are diagnosed, versus HER2 negative tumors
  • Whether the tumor is also estrogen receptor positive
  • Treatment options available
  • The risk of recurrence
  • Overall survival rates

It's also important to note that HER2 status is sometimes inaccurate and can change after a recurrence (see below).

Differences in Risk

While there is certainly much overlap, some people are more likely than others to have HER2 positive breast cancer. Two studies, the LACE study and the PATHWAYS study, have looked into the characteristics of people who are more likely to be HER2 positive or negative. 

  • Women who have tumors with overexpression of HER2 and estrogen receptor negative are more likely to be younger, are less likely to have used hormone replacement therapy, and are more likely to be Asian or Hispanic.
  • Tumors that are HER2 positive don't appear to be associated with alcohol intake or smoking, and unlike estrogen receptor positive tumors physical activity does not seem to have a protective effect against the disease.
  • Men with breast cancer are less likely than women to have HER2 positive tumors.
  • Interestingly, it's been found that ductal carcinoma in situ (DCIS) or stage 0 tumors are more likely to be HER2 positive than invasive breast cancers, which some researchers believe is related to the process of tumor development.
  • Some types of breast cancers may be less likely to be HER2 positive. For example, it is uncommon for mucinous (colloidal) breast cancermedullary carcinoma, or tubular carcinoma of the breast to be HER2 positive.
  • HER2 status can vary with genetic risk factors for breast cancer. For example, BRCA1 associated breast cancers are less likely to be HER2 positive.

Test Accuracy and Change in Status

We often talk about HER2 status as if it is black and white, but that's not always the case. There are different forms of testing which can vary in accuracy. There are also different "levels" of positivity. For example, a tumor may be 1+, 2+, or 3+. Tumors that are "less positive" may be referred to as having an overexpression of HER2 rather than being HER2 positive.

It's now recommended that women who have had one type of testing be retested, as some testing methods are less accurate than others. Retesting is also recommended if a test is returned as being "borderline." It's also important to mention the heterogeneity of tumors; one part of a breast tumor may be HER2 positive while another section is HER2 negative.

HER2 status can change, and this has been confusing to many people. A tumor that is initially HER2 positive may be HER2 negative if it recurs or spreads. Likewise, a tumor which is initially HER2 negative may become HER2 positive if it recurs. HER2 status should always be retested following a recurrence.

Aggressiveness

HER2 positive breast cancers tend to be more aggressive than HER2 negative tumors.

Breast tumors are given a tumor grade at the time of diagnosis based on the appearance of the cells under the microscope. Tumor grade is a number which is given to describe the aggressiveness of a tumor, with a number of one being least aggressive, and a number of three being the most aggressive. HER2 positive tumors are more likely to have a tumor grade of three. These tumors tend to grow faster than tumors of lower grade and are more likely to spread to lymph nodes.

Spread to Lymph Nodes

HER2 breast cancers are more likely to spread to lymph nodes. As such, the stage at diagnosis may also be higher than for HER2 negative tumors.

Treatment Response

Prior to the development of targeted therapies for HER2 positive breast cancer, such as Herceptin (trastuzumab), the treatment response for people with HER positive breast cancer was not as good for those with HER2 negative disease.

Targeted therapy for HER2 positive breast cancer has changed the prognosis, and now treatment outcomes are essentially the same as for HER2 negative tumors (though HER2 tumors tend to be larger). According to the National Cancer Institute, these medications have changed the prognosis for stage I to stage III HER2 positive breast cancer from poor to good.

Herceptin reduces the risk of recurrence and improves 10-year survival rates for those with stage I to stage III disease by around 30 percent. 

There is, however, a greater risk of relapse and metastasis with a positive HER2 status, and survival rates are somewhat lower than for HER2 negative but estrogen receptor-positive tumors. 

People with HER2 positive tumors are less likely to respond to breast cancer chemotherapy than those who are negative.

Risk of Recurrence

HER2 positive breast cancer is more likely to recur (come back) then HER2 negative breast cancer. Studies have found that early breast cancers (stage I and stage II) are two to five times more likely to recur than HER2 negative tumors. Even very small HER2 positive tumors (less than 1 cm or half an inch in diameter) with negative lymph nodes have a much higher risk of recurrence relative to tumors which are HER2 negative. Treatment with Herceptin can cut this risk by half.

The pattern of breast cancer recurrence may also differ. Small tumors are also more likely to have a metastatic recurrence (in contrast to local or regional recurrence) if they are HER2 positive.

Metastasis

Whether HER2 positive tumors are more likely to metastasize than negative tumors depends on the sites of breast cancer metastases we are considering. The risk of metastases overall, especially brain metastases, is thought to be increased, but many of the studies were done prior to the widespread use of Herceptin.

Studies done after the introduction of Herceptin (and other HER2 targeted therapies) have found that HER2 positive breast cancers continue to have a relatively high incidence of brain metastases. HER2 positive tumors tend to spread early in the course of the disease to axillary lymph nodes, the lungs, the bone marrow, the ovaries, and the adrenal glands.

The likelihood of metastases with HER2 positive tumors may be different depending on whether or not the tumor is also estrogen receptor positive. The risk of brain, liver, bone, and lung metastases in HER2 positive tumors is also affected by whether the tumor is estrogen receptor positive or negative as well.

The risk of metastases may also depend on associated factors. For example, the risk of liver metastases from breast cancer is higher with HER2 positive tumors if people also smoke.

Triple Positive Breast Cancer

Roughly 50 percent of HER2 positive tumors will also be estrogen receptor positive. Studies have found that this combination may result in a different pattern of relapse, but only a few studies have looked at the characteristics and impact of triple positive tumors.

Breast cancers that are estrogen receptor positive and HER2 negative (luminal A) have the best prognosis overall. Those that are estrogen receptor positive and HER positive (luminal B) have a somewhat poorer prognosis, but prognosis remains better than for people with triple-negative or estrogen receptor negative and HER2 over-expressing breast cancer.

Errors in Diagnosis

This discussion wouldn’t be complete without mentioning that sometimes a breast cancer is mistakenly diagnosed as HER2 positive or HER2 negative. The tests available for determining HER2 status are not foolproof. It's important to ask your oncologist which test was done and whether or not you should be retested.

An error in diagnosis (a misdiagnosis) in which a HER2 positive tumor is accidentally diagnosed as negative could result in a person not being offered targeted therapy; treatments which can improve survival. Of course, being diagnosed with HER2 positive disease which is actually HER2 negative could result in using medications which are ineffective (though some HER2 negative tumors have responded to Herceptin).

Summary of Differences

This article reviewed many differences between HER2 positive and HER2 negative breast cancers, and how those differences may affect prognosis. 

HER2 positive breast cancers in comparison with estrogen receptor-positive tumors tend to be:

  • More aggressive (have a higher tumor grade)
  • Found in younger women (and breast cancer in young women tends to be diagnosed in more advanced stages)
  • Roughly equally likely to respond to treatment now that HER2 targeted therapies available
  • More likely to relapse/recur
  • More likely to metastasize, at least to sites such as the brain

These tumors also have a somewhat poorer prognosis (though newer agents have been approved, one in 2017, and we don't know how this will affect prognosis.)

There are certainly exceptions to these findings and we need to keep in mind that every person, and every breast cancer, is unique.

A Word From Verywell

While overall the prognosis of HER2 positive tumors tends to be somewhat poorer than for those which are estrogen receptor positive but HER2 negative, the widespread adoption of HER2 therapies is making a difference in survival rates as well as the risk of recurrence.

Since HER2 therapies are relatively new on the scene, and multiple newer treatments have been approved in 2017 alone, statistics are not necessarily very meaningful. If you are living with HER2 positive breast cancer, the fact that the response to treatment now in HER2 positive tumors equals that of estrogen receptor positive tumors is encouraging.

With all of the changes going on in treatment, and with further medications being studied in clinical trials, it's more important than ever to take an active role in your treatment. Take a moment to review some tips on how to be your own advocate in your cancer care.

Sources:

Ellingiord-Dale, M., Vos, L., Hjerkind, K., Hjartaker, A. et al. Alcohol, Physical Activity, Smoking and Breast Cancer Subtypes in a Large Nested Case-Control Study From the Norwegian Breast Cancer Screening Program. Cancer Epidemiology Biomarkers and Prevention. 2017 Sep 6. (Epub ahead of print).

National Cancer Institute. A Story of Discovery: HER2’s Genetic Link to Breast Cancer Spurs Development of New Treatments. https://www.cancer.gov/research/progress/discovery/HER2

Parise, C., and V. Caggiano. Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification According to Tumor Grade and Immunohistochemical Biomarkers. Journal of Cancer Epidemiology. 2014. 469251:1-11.

Schettini, F., Buono, G., Cardalesi, C. et al. Hormone Receptor/Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Where We Are Now and Where We Are Going. Cancer Treatment Reviews. 2016. 46:20-6.

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