HER2 Positive vs. HER2 Negative Breast Cancer

Aggressiveness, Treatment, and Survival

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Human epidermal growth factor receptor 2 (HER2) proteins are found on the surface of breast cells and are involved in normal cell growth. Too much HER2 protein, however, can cause some types of breast cancer to grow and spread. HER-2 positive breast cancers have abnormally high levels of HER2 receptors, whereas HER2-negative breast cancers don’t. 

There are a few differences between HER2-positive and HER2-negative breast cancers, including the tumor's risk factors, its biology, and its anticipated aggressiveness. HER2 status, along with a tumor's hormone status and other factors, helps determine the prognosis and treatment options for breast cancer.

HER2-positive breast cancers account for 30% of all breast cancers.

Why Receptor Status Matters

Breast cancer is not a single disease, and researchers now have the ability to break down breast cancer into different subtypes based on the receptor status of the tumors. Among the variations between different types of breast cancers are the proteins found on cell surfaces, which are involved tumor growth. These proteins are related to the genetic material of cancer cells.

For example, with estrogen receptor-positive breast cancer, estrogen binds to specific receptors on breast cancer cells, stimulating proliferation. Similarly, HER2 receptors on the surface of breast cancer cells are stimulated by HER2 protein, promoting the growth and spread of breast cancer.

It's important to note, however, that 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 receptors than HER2-negative breast cancer cells or normal breast cells. In positive cases, the abundance of receptors fuels the cancer.

By knowing your HER-2 receptor status, your doctor can carefully select the best treatment to stop your breast cancer in its tracks. Options that target HER2 receptors are fruitless if your status is negative—but they are precisely what you need if you are positive.

How HER2-Positive Cancers Behave

HER2-positive tumors can behave differently in a number of ways.

Aggressiveness/Tumor Grade

Breast tumors are given a tumor grade at the time of diagnosis based on the appearance of the cells under the microscope. This number describes the aggressiveness of a tumor, with 1 being least aggressive and 3 being 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-positive 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, which can impact survival.

Risk of Recurrence

Research has shown the HER2-positive 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 centimeter, or half an inch in diameter) with negative lymph nodes have a much higher risk of recurrence relative to tumors that are HER2-negative. Treatment with Herceptin (trastuzumab) 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.

Metastasis

Whether HER2-positive tumors are more likely to metastasize than negative tumors depends on the sites of breast cancer metastases. The risk of metastases overall, especially brain metastases, is thought to be increased, but many of the studies on this 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.

There are certainly exceptions to these findings and it's important to keep in mind that every person, and every breast cancer, is unique.

Who's at Risk?

All women have HER2 genes that code for HER2 proteins, which are involved in the growth of breast cells. When too many copies of the HER2 gene are present—due to damage to the genetic material in the cell or mutations—overproduction of HER2 results.

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 HER2-negative. What they found was that: 

  • Women who have tumors with over-expression of HER2 and who are 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.

    Determining Your HER2 Status

    A breast biopsy is used to determine HER2 status. The biopsy can be sent for laboratory testing with an immunohistochemistry test. The fluorescence in situ hybridization test looks for the HER2 gene in breast cancer cells.

    The results of an immunohistochemistry test show different levels of HER2 positivity. For example, a tumor may be reported as 0, 1+, 2+, or 3+. Tumors with a higher number may be referred to as having an overexpression of HER2.

    According to the American Cancer Society , immunohistochemistry test results should be considered as follows:

    Designation Meaning
    0 HER2-negative
    1+ HER2-negative
    2+ Equivocal (Follow-up with fluorescence in situ hybridization is usually recommended.)
    3+ HER2-positive

    The impact of being HER2-positive on breast cancer survival is, of course, a top concern. Unfortunately, statistics can be misleading without considering other aspects of your diagnosis, including cancer stage at diagnosis and whether the tumor is also estrogen and/or progesterone receptor-positive.

    With this in mind, you may also be tested for progesterone and estrogen receptors. Triple-negative breast cancers are negative for HER2, estrogen, and progesterone, while triple-positive breast cancers are positive for all three.

    Misdiagnosis

    It's also important to mention the heterogeneity of tumors; i.e., one part of a breast tumor may be HER2-positive while another section is HER2 negative. The results you receive will depend on which section of the tumor was sampled in a biopsy.

    A misdiagnosis in which a HER2-positive tumor is diagnosed as negative could result in not being offered optimal (targeted HER2) therapy. Of course, being mistakenly diagnosed as HER2-positive if your tumor is HER2-negative could result in using HER2-directed medications, which may be ineffective for you as well. (Note, however, that some HER2-negative tumors have responded to Herceptin, which is the treatment used for HER2-positive tumors.)

    Status Changes

    It's also important to know that HER2 status can change. A tumor that is initially HER2-positive may become 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.

    Treatment Options

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

    Early-Stage Tumors

    Prior to the development of targeted therapies for HER2-positive breast cancer, such as Herceptin, the treatment response for people with HER2-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-positive 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.

    A Word From Verywell

    While overall the prognosis of HER2-positive tumors tends to be somewhat poorer than for those that 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-positive breast cancers than ever before.

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    Article Sources

    1. American Cancer Society, Understanding a Breast Cancer Diagnosis, Breast Cancer HER2 Status, What is HER2/neu and what does it mean?

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