Treating Metastatic HER2-Positive Breast Cancer

Your options depend on several factors

Metastatic (stage 4) HER2-positive breast cancer is not curable—but it is treatable, and options continue to expand and improve. Given the generally aggressive and rapid growth of HER2-positive tumors and the need to uniquely target the human epidermal growth factor receptor 2 (HER2) protein to be most effective, this is promising. In addition, targeted therapies tend to have far fewer side effects than chemotherapy drugs.

The HER2-positive breast cancer treatment that is right for you will depend on several factors, including whether your tumor is also estrogen-receptor positive, where the cancer has metastasized to, and what treatment you received in the past if you were previously HER2-positive.

Approach to Treatment

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 to many.

With HER2-positive cases specifically, HER2 genes overproduce HER2 proteins. Growth factors bind to these receptor proteins on breast cancer cells, causing the growth characteristic of these tumors.

As metastatic HER2-positive breast cancer is both advanced and aggressive, it's important that treatment addresses the activity of these HER2 proteins so that therapeutic efforts zero in on this important factor in progression both specifically and quickly.

But unlike with early-stage breast cancer—in which several options (surgery, chemotherapy, radiation, etc.) may be used in combination to prevent recurrence, if possible—such treatment of stage 4 breast cancer doesn't improve survival. It does, however, increase side effects. As such, the least amount of treatment needed to control the disease is what doctors aim for in metastatic cases.

Receptor Status Change

Many people are surprised to learn that the receptor status of their cancer changed after it recurred (for example, an HER2-negative status can turn to HER2-positive, 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.

Primary Treatment Options

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 that target HER2 have been developed, leaving options even when one drug (or even two) fails.

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.

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 depend, in part, on the medications with which you were treated (if you're experiencing a recurrence). 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 can improve survival in HER2-positive metastatic breast cancer.

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.

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

Even in people who had progressed on two previous HER2-targeted drugs, treatment with TDM1 improved overall survival more than an oncologist's choice of other available regimens (including several chemotherapy drugs) in a 2017 study published in Lancet Oncology.

Third line options will vary depending on prior treatments. For those who haven't yet been treated with T-DM1, this drug 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 from the phase III trial (SOPHIA) found that people who had received several treatments for metastatic HER2-positive cancer had better progression-free survival when treated with the investigational monoclonal antibody margetuximab than with the combination of Herceptin and chemotherapy.'

Evolving Thoughts on Surgery

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 that primary surgery in people with stage 4 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

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. This means that the disease is different than if the cancer originated in these areas.

Treatment is decided on accordingly, and an approach for metastases of breast cancer to any site usually involves hormonal drugs, HER2-positive-targeted therapies, or chemotherapy.

That said, treatments that are "metastasis-specific" may be used as well. These are treatments that specifically address the area to which the cancer has spread.

Bone Metastases

Bone metastases with breast cancer are very common, found in around 70 percent of people with metastatic disease. In addition to systemic treatment options addressing breast cancer itself, metastasis-specific treatment for bones can reduce pain and also improve survival (overall, 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 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, those 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 throughout 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 considered as well. 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 to manage this symptom 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 over.

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 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, and bone marrow. 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.

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