HER2 Positive vs. HER2 Negative Breast Cancer

Aggressiveness, Treatment, and Survival

Human epidermal growth factor receptor 2 (HER2) status, along with the cancer’s hormone status, helps determine the pathology of a specific breast cancer. HER2 status also helps your doctor determine how aggressive the cancer is and treatment options. There are many differences between HER2 positive and HER2 negative breast cancers, from the biology of the tumors, to risk factors, aggressiveness, and much more. Understanding these differences is critical for anyone who has learned they have a positive HER2 status. 

HER2 proteins are found on the surface of breast cells. They are either involved in normal cell growth or their levels are higher than normal. The presence of too much HER2 protein could cause cancer to grow and spread too quickly.   Her2 positive breast cancers have abnormally high levels of HER2 proteins whereas HER2 negative breast cancers don’t have abnormal levels of HER2 proteins. But the differences don't end there.

Breast Cancer Receptor Status

Breast cancer is not a single disease and researchers now have the ability to breakdown breast cancer into different subtypes based on the receptor status of the tumors. Breast cancers differ in the proteins found on cell surfaces, which are responsible for the growth of the tumors. These proteins are related to different abnormalities in the genetic material of cancer cells.

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

What occurs with HER2 positive breast cancers is similar, but it is a different type of receptor on the surface of the cancer cell, a driving force in 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.

Biology of HER2 Positive Tumors

The HER2 gene is a gene present in everyone that codes for proteins involved in the growth of breast cells. 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 of HER2.

It's important to note all breast cells—both cancerous and noncancerous—have HER2 receptors other their surfaces. The difference is that HER2 positive breast cancer cells have 40 to 100 times more than. When growth factors in the body bind to these receptors, there is overgrowth of the breast cells.

HER2 Positive Status: Good or Bad?

HER2 positive breast cancers account for 30 percent of all breast cancers. Ultimately, many people want to know what effect having HER2 positive breast cancer has on survival. Unfortunately, these 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, but this can be somewhat misleading. In younger people, the disease is often diagnosed in more advanced stages. Therefore, 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.

In order to determine whether HER2 positive status is good or bad, one must look at the ways in which HER2 status may affect a cancer. This includes:

  • The stage at which HER2 cancers are diagnosed
  • Whether the tumor is also estrogen receptor positive
  • The treatments available
  • The risk of recurrence
  • Overall survival rates

It's also important to note HER2 status is sometimes inaccurate and can change after a recurrence.

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. What they found was that: 

  • Women who have tumors with over-expression 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.
  • HER2 positive tumors 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.
  • 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

    There are different forms of testing for HER2 status 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 over-expression of HER2 rather than being HER2 positive.

    It's now recommended 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

    HER2 status can change. 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.

    HER2 Positive Cancers: Behavior

    Once a breast cancer is diagnosed (regardless of risk factors), HER2 positive tumors can behave differently in a number of ways.

    Aggressiveness/Tumor Grade

    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.

    Risk of Recurrence

    HER2 positive breast cancer is more likely to recur (come back) then HER2 negative breast cancer. Research has shown 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.

    Despite the fact that HER2 positive and estrogen receptor negative tumors are more likely to recur early on than estrogen receptor positive and HER2 negative cancers, late recurrences (for example, 10 years later or even further down the road), are less common. In other words, HER2 cancers may be less treatable in some ways, but are potentially more curable.

    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.

    HER2 Positive Cancers: Treatment

    Treatment choices are significantly different for HER2 positive and HER2 negative breast cancers, both for early-stage disease, and with metastatic (stage IV) cancers.

    Treatment Response in Early Stage Tumors

    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). 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. 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.

    Metastatic HER2 Positive Cancers

    There are also differences in the best treatments for HER2 negative cancers, and the treatments for metastatic HER2 positive tumors. As with early-stage tumors, HER2 targeted therapies often improve survival, whereas anti-estrogen therapies are often ineffective. These tumors may also respond differently to treatments ranging from chemotherapy to immunotherapy drugs.

    Misdiagnosis

    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.

    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 although some HER2 negative tumors have responded to Herceptin.

    Prognosis

    The differences between HER2 positive and HER2 negative breast cancers 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

    There are certainly exceptions to these findings and it's important 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 with the reduced risk for recurrence. And with newer multiple newer treatments that have been approved in recent years, more and more people are surviving HER2 breast cancers than ever before.

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