Targeted therapy for breast cancer

As researchers have learned more about the gene changes in cells that cause cancer, they have been able to develop newer drugs that specifically target these changes. These targeted drugs work differently from standard chemotherapy (chemo) drugs. They often have different (and less severe) side effects. They are most often used along with chemo at this time.

Drugs that target the HER2/neu protein

Trastuzumab (Herceptin): Trastuzumab is a type of drug known as a monoclonal antibody—a man-made version of a very specific immune system protein. It attaches to a growth-promoting protein known as HER2/neu (or just HER2), which is present in larger than normal amounts on the surface of the breast cancer cells in about 1 of 5 patients. Breast cancers with too much of this protein tend to grow and spread more aggressively. Trastuzumab can help slow this growth and may also stimulate the immune system to more effectively attack the cancer.

Trastuzumab is given as an injection into a vein (IV), usually once a week or as a larger dose every 3 weeks. The optimal length of time to give it is not yet known.

Trastuzumab is often used (along with chemo) as adjuvant therapy for HER2-positive cancers to reduce the risk of recurrence. It is given with chemo at first, and then given on its own, usually for a total of a year of treatment. This may also be started before surgery as neoadjuvant therapy. Although this drug is usually given for a year, studies are looking at how long this drug needs to be given to be most effective.

Trastuzumab is also used to treat HER2-positive advanced breast cancers that return after chemo or continue to grow during chemo. Treatment that combines trastuzumab with chemo generally works better than chemo alone. If a cancer gets worse while a patient is getting trastuzumab and chemo, often the trastuzumab is continued and the chemo is changed.

Compared with chemo drugs, the side effects of trastuzumab are relatively mild. These side effects are rare and may include fever and chills, weakness, nausea, vomiting, cough, diarrhea, and headache. These side effects are generally mild and occur less often after the first dose.

A more serious potential side effect is heart damage leading to a problem called congestive heart failure. For most (but not all) women, this effect has been temporary and has improved when the drug is stopped. The risk of heart problems is higher when trastuzumab is given with certain chemo drugs such as doxorubicin (Adriamycin) and epirubicin (Ellence). For this reason heart function is checked regularly during treatment with trastuzumab. Major symptoms of congestive heart failure are shortness of breath, leg swelling, and severe fatigue. Women having these symptoms should call their doctor right away.

Trastuzumab should not be given to women who are pregnant because it may harm and even cause death to the fetus. Women who could become pregnant need to use effective birth control during treatment.

Pertuzumab (Perjeta™): Like trastuzumab, pertuzumab is a monoclonal antibody that attaches to the HER2 protein. It seems to target a different part of the protein than trastuzumab does. This drug is used to treat advanced breast cancer. When given along with docetaxel (Taxotere) and trastuzumab to patients who have not yet received chemotherapy for their advanced breast cancer, it has been shown to cause tumors to shrink or stop growing for about 6 months longer than giving docetaxel and trastuzumab alone.

This drug is given as an infusion into a vein every 3 weeks. When given with trastuzumab and docetaxel, common side effects included diarrhea, hair loss, nausea, fatigue, rash, and low white blood cell counts (sometimes with fever). Many side effects, such as hair loss, nausea, and fatigue occur at about the same rate as in those who get just docetaxel and trastuzumab.

This drug caused fetal harm and even death of the fetus in animal studies, so it should not be given to women who are pregnant. Women who could become pregnant need to use effective birth control during treatment. Although so far it has not been shown to affect heart function, there is concern that it can, so it cannot be given to patients with poor heart function. As with trastuzumab, your doctor will check tests of heart function every few months while you are treated with this drug.

Lapatinib (Tykerb): Lapatinib is another drug that targets the HER2 protein. This drug is given as a pill to women with advanced HER2-positive breast cancer that is no longer helped by chemo and trastuzumab. It is also being studied as an adjuvant therapy in patients with HER2-positive cancer. The chemo drug capecitabine (Xeloda) is often given in combination with lapatinib to treat metastatic breast cancer. It may also be given with letrozole (Femara) in patients with HER2-positive advanced breast cancer that is also ER-positive.

In one study, giving lapatinib along with trastuzumab helped patients with advanced breast cancer live longer than giving it alone.

The most common side effects of this drug include diarrhea, nausea, vomiting, rash, and hand-foot syndrome (this was discussed in the section about chemotherapy). Diarrhea is a common side effect and can be severe, so it is very important to let your health care team know about any changes in bowel habits as soon as they happen.

In rare cases lapatinib may cause liver problems or a decrease in heart function (that can lead to shortness of breath), although this seems to go away once treatment is finished.

Everolimus (Affinitor^®)

Everolimus is a type of targeted therapy that blocks mTOR, a protein in cells that normally promotes their growth and division. By blocking this protein, everolimus can help stop cancer cells from growing. Everolimus may also stop tumors from developing new blood vessels, which can help limit their growth. In treating breast cancer, this drug seems to help hormone therapy drugs work better.

Everolimus is a pill taken once a day.

This drug was recently approved to treat advanced hormone receptor−positive, HER2−negative, breast cancer in women who have gone through menopause. It is meant to be used with exemestane (Aromasin) in these women if their cancers have grown while they were being treated with either letrozole or anastrazole. This approval was based on a study that showed that giving everolimus with exemestane was better than exemestane alone in shrinking tumors and stopping their growth in post-menopausal women with hormone receptor−positive, HER2−negative breast cancer that had stopped responding to letrozole or anastrazole.

Common side effects of this drug include mouth sores, diarrhea, nausea, fatigue, feeling weak or tired, low blood counts, shortness of breath, and cough. Everolimus can also increase blood lipids (cholesterol and triglycerides) and blood sugars, so your doctor will check your blood work periodically while you are on this drug. It can also increase your risk of serious infections, so your doctor will watch you closely for infection while you are on treatment.

Everolimus is also being studied for use with other hormone therapy drugs and for earlier stage breast cancer. This is discussed further in the section, “What’s new in breast cancer research and treatment?”

Bevacizumab (Avastin^®)

Tumors need to develop and maintain new blood vessels to grow. Drugs that target these blood vessels are helpful against a variety of cancers, and have been studied for use in breast cancer.

Bevacizumab is a monoclonal antibody that has been used in patients with metastatic breast cancer. This antibody is directed against vascular endothelial growth factor, a protein that helps tumors form new blood vessels.

Bevacizumab is given by intravenous (IV) infusion. It is most often used in combination with chemo.

Rare, but possibly serious side effects include bleeding, holes forming in the colon (requiring surgery to correct), and slow wound healing.

More common side effects include high blood pressure, tiredness, blood clots, low white blood cell counts, headaches, mouth sores, loss of appetite, and diarrhea. High blood pressure is very common, so it very important that your doctor watches your blood pressure carefully during treatment.

Bevacizumab was first approved by the US Food and Drug Administration (FDA) as part of the treatment for metastatic breast cancer in 2008. The approval was based on a study in which the women who received bevacizumab with the chemo drug paclitaxel (Taxol) had a longer time without their cancers growing than the women who received paclitaxel alone.

New study results that were presented at a July 2010 FDA meeting did not show a real benefit for the women receiving bevacizumab as a part of their treatment. Although bevacizumab seemed to slow cancer growth for a short-time in some of the women, it didn't help them live longer. Those given bevacizumab also had much more severe side effects. The FDA concluded that in the treatment of metastatic breast cancer, the risks of this drug outweigh the benefits. On November 18, 2011, the FDA withdrew the breast cancer "indication" for bevacizumab. This does not mean that the drug will become unavailable, since it is still FDA-approved to treat some other cancers. It does mean that the company making bevacizumab can’t market the drug for breast cancer—the company can’t tell doctors or patients that the drug is useful in treating breast cancer. At this time, women who are taking bevacizumab can continue to do so, but they should discuss this treatment with their doctors.