Metastatic HER2 Positive Breast Cancer: Treatments and Coping

What Are the Best Treatments for Stage 4 HER2-Positve Breast Cancer?

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If you have been diagnosed with metastatic HER2-positive breast cancer, it's likely that much of the information you find pertains to early stage cancers or stage 4 breast cancer in general. Treatment will depend on whether your tumor is also estrogen-receptor positive, the treatment you received in the past if you were previously HER2 positive, and more. For those treated with Herceptin in the past, Perjeta or TDM1 may be used. It's important to note that receptor status can change when a breast cancer metastasizes, and may become HER2 negative if previously positive, and vice versa. Let's look at the treatment approaches for stage 4 HER2 positive cancers, including treatments that may be used for metastases to bones, the brain, or lungs.

Metastatic HER2 Positive Breast Cancer

You may have learned that you have stage 4 (metastatic) breast cancer when you were first diagnosed with the disease, but more commonly, distant metastases occur as a recurrence of a tumor that was initially an early stage tumor years earlier. As such, the diagnosis often comes as a shock and can feel overwhelming.

Not only is the prognosis not as good when breast cancer has spread, but the thought of going through treatment again may leave you feeling discouraged. While stage 4 HER2 positive breast cancer is not curable, it is treatable, and treatments designed to target HER2 continue to expand and improve. These treatments also usually have far fewer side effects than chemotherapy drugs.

Roughly one in five breast cancers are HER2-positive breast cancer. What this means is that some breast cancers have HER2 genes which overproduce HER2 proteins. Growth factors bind to these receptor proteins on breast cancer cells, causing the growth characteristic of these tumors. In general, HER2 breast tumors are aggressive and rapidly growing tumors.

Until 1998, when Herceptin was approved, HER2 positive tumors had a poorer prognosis, especially for those who also had estrogen and progesterone receptor negative tumors. Since that time other targeted drugs have been developed which also target HER2, leaving options even when one drug, or even two, fails.

Receptor Status Can Change

Many people are surprised to learn that the receptor status of their cancer changed after it recurred. If you had an estrogen receptor positive tumor when you were diagnosed with early stage breast cancer the recurrence may be estrogen receptor negative (or vice versa). Likewise, if you had a HER2/neu positive tumor earlier, it may be negative now and vice versa.

This is why a biopsy and re-checking receptor status is so important if you have a distant recurrence of your disease.

General Management

The general management of metastatic breast cancer often comes as a surprise for those who have had a distant recurrence after having early stage breast cancer in the past. With early stage breast cancer, treatment is usually aggressive, with surgery, chemotherapy, targeted therapies, and/or radiation, and the goal is to prevent recurrence if at all possible.

With stage 4 breast cancer the treatment approach is usually different, and many people wonder why the approach is not more aggressive (and feel anxious because of this). The goal with metastatic breast cancer is usually to use the least amount of treatment needed to control the disease. For the most part, very aggressive treatment of stage 4 breast cancer doesn't improve survival—but does increase the side effects. What this means is that frequently only one type of treatment at a time is used (if it slows the growth of the cancer) rather than the several modalities combined as with early stage disease.


First line treatment for metastatic breast cancer depends largely on receptor status, and if it is a recurrence, both your estrogen and progesterone receptor status and HER2/neu status should be tested (since as noted above, this can change).

If your tumor is both estrogen receptor positive and HER2 positive, initial treatment may include hormonal therapy, a HER2 targeted therapy, or both. This decision will also depend on the medications with which you were treated prior to your recurrence (if your cancer is a distant recurrence rather than a tumor which is stage 4 at the time of diagnosis). Chemotherapy may also be used for four to six months (usually a Taxane such as Taxol). It's thought that giving the most active treatments as soon as possible with HER2 positive metastatic breast cancer can improve survival.

If you have not previously been treated with a HER2 targeted drug, treatment is usually started with Herceptin (trastuzumab) or Perjeta (pertuzumab). For those who have previously been treated with Herceptin, another HER2 targeted drug may be used, such as Perjeta (pertuzumab). Even in people who had progressed on two previous HER2 targeted drugs, treatment with trastuzumab emtansine (TDM1) improved overall survival more than an oncologist's choice of other available regimens (including several chemotherapy drugs) in 2017 study published in Lancet Oncology.

If a cancer has progressed on Herceptin or within 12 months of stopping the drug, T-DM1 (trastuzumab emtansine) is the preferred option second-line.

Third line options will vary depending on prior treatments. For those who haven't yet been treated with T-DM1, this is an option. Perjeta may also be used for those who have not yet received it in combination with Herceptin. For those who have been treated with Perjeta and T-DM1 and still progressed, options include the combination of Xeloda (capecitabine) and the targeted therapy Tykerb (lapatinib), hormonal therapy for those who have estrogen receptor positive tumors, and other chemotherapy regimens in combination with HER2 targeted drugs.

Preliminary findings (2019) in a phase III trial (SOPHIA) found that people who had received several treatments for metastatic HER2 positive cancer (called "heavily pretreated" in studies) had better progression free survival (fewer progressions or deaths) when treated with the investigational monoclonal antibody margetuximab than with the combination of Herceptin and chemotherapy.

Tumors That Are Metastatic at the Time of Diagnosis

The majority of people who have metastatic HER2 positive breast cancer develop metastases as a recurrence (most had previously had early stage breast cancer). When breast cancer is metastatic at the time of diagnosis, surgery has not usually been done, as it was believed that it didn't improve survival rates. This thought appears to be changing, with evidence in 2019 that primary surgery in people with stage IV HER2 positive breast cancer improves overall survival. In addition, when a breast tumor is causing symptoms (if it is painful, bleeding, draining, or becomes infected), palliative mastectomy may significantly reduce symptoms. In a 2018 study, palliative mastectomy was found to improve quality of life for some people.

Metastasis-Specific Treatment

General treatment for metastases (spread) of breast cancer to any site is usually treated with hormonal drugs, HER2 positive targeted therapies, or chemotherapy. This can be confusing for some people. Why would cancer cells in the lungs, for example, be treated with hormonal therapies?

It's important to note that when breast cancer spreads to other organs, such as the bones, brain, liver, and lungs, it is cancerous breast cancer cells that spread in those organs.

Treatments that are "metastasis-specific" may be used as well. These are treatments that specifically address the area of metastases, such as bone metastases. Liver and brain metastases are more common in women with HER2/neu positive breast cancer than in those who are HER2 negative.

Bone Metastases

Bone metastases with breast cancer are very common, being found in around 70 percent of people with metastatic disease. In addition to systemic treatment options addressing breast cancer itself, metastasis-specific treatment for bone metastases can reduce pain and also improve survival, and bone metastases have a better prognosis than other sites of metastatic disease. Of note is that the complications of bone metastases, such as fractures, become extra important as many of the treatments for breast cancer can lead to bone loss.

Options include:

  • Bone modifying agents including bisphosphonates, such as Zometa (zoledronic acid) can decrease complications such as fractures and also have strong anti-tumor effects. Xgeva (denosumab) is another option that also appears to have anti-cancer properties.
  • Radiation therapy can reduce pain and may reduce the risk of pathologic fractures(fractures that occur in a region of bone that's been weakened by tumor).
  • Radiopharmaceuticals can be helpful for those who have extensive bone metastases. With this treatment, particles of radiation attached to another chemical are injected into the bloodstream, and carried to bones all over the body.

Liver Metastases

Liver metastases from breast cancer are the second most common site of metastases and occur more often among people with HER2 positive tumors. Radiation therapy is commonly used in addition to other treatments for the cancer. Other treatments such as embolization may be used. In this treatment, an injection causes blockage in an artery to the liver that supplies the area that contains tumor, resulting in death of the tissue.

If there are only a few sites of metastasis (oligometastases), surgical removal or stereotactic body radiotherapy (SBRT) can improve survival. SBRT differs from conventional radiation therapy in that a very high dose of radiation is delivered to a precise area of tumor, with the intent of eradicating the metastasis.

Liver metastases often cause ascites (abdominal swelling) and paracentesis (removing the fluid in the abdomen through a long thin needle) is often needed to reduce discomfort. Itching is also very common with liver metastases and treatment for the itching can improve quality of life.

Brain Metastases

While metastases from breast cancer are often treated as part of general metastatic breast cancer treatment, brain metastases can pose a unique challenge. The blood-brain barrier is a collection of tightly knit capillaries that prevents many toxins and medications, including many chemotherapy drugs, from accessing the brain. Thankfully, some drugs are able to cross the barrier.

A 2017 review of the literature found that Herceptin (trastuzumab) clearly improves survival for those with HER2 positive breast cancer with brain metastases. Trastuzumab emtansine (T-DM1) and Perjeta (pertuzumab) are also promising. In contrast, Tykerb (lapatinib) appears to have little effect on brain metastases (as of 2017 studies) and has a high toxicity profile. When lapatinib is combined with chemotherapy, however, the response rates are better.

Lung Metastases

Lung metastases from breast cancer are primarily treated with general measures to treat the breast cancer, such as hormonal therapies, HER2 targeted drugs, and chemotherapy, rather than any specific treatments. When only a few metastases are present, treating these with surgery or SBRT may be considered, but studies have not yet shown an increased survival rate from this practice.

Other Distant Metastases

Breast cancer can spread to many other distant regions of the body as well, including the skin, muscle, fatty tissue, bone marrow, and other areas. Most of the time these distant metastases are treated with general treatment for metastatic HER2 positive cancer, but when isolated metastases occur, options such as surgery or radiation therapy may be considered.


Coping with metastatic breast cancer is a challenge no matter the type or molecular profile. If you have had prior treatment for early stage disease and your cancer recurred, the general approach to metastatic cancer may be disconcerting at first, as the goal is usually to use as little treatment as possible to control the disease, rather than the aggressive treatment you likely had with early stage breast cancer.

The saying that "it takes a village" was never more appropriate than in the setting of advanced cancer. There are many support groups and online breast cancer communities available, but most people with metastatic breast cancer prefer groups which include primarily those who have stage 4 breast cancer rather than those which include people with early stage breast cancer.

For Loved Ones

If it is your loved one who is living with stage 4 breast cancer, take a moment to familiarize yourself with things not to say to someone with metastatic breast cancer. For example, many people ask people with metastatic breast cancer when they will be done with treatment. Since treatment usually continues for the rest of their lives, this question can be painful to hear.

A Word From Verywell

Metastatic HER2 positive breast cancer may be treated with hormonal therapies (for those who are also estrogen receptor positive) and chemotherapy, but the option to use HER2 targeted therapies adds yet another modality in this setting.

HER2 positive tumors are more likely to spread to the brain and liver than HER2 negative tumors. When these metastases occur, both general treatment and metastasis specific treatment may be considered. Fortunately, and unlike many medications, Herceptin and probably pertuzumab appear to cross the blood brain barrier to effectively treat these metastases.

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