Treatment of Stage III Breast Cancer

If you have stage III breast cancer, your cancer has one of the following characteristics:

• Stage IIIA - The cancer (1) measures less than 5 centimeters (2 inches) and has spread to four to nine lymph nodes in your armpit (axilla); or (2) to lymph nodes in your rib cage (near the breast bone); or (3) it is larger than 5 centimeters and has spread to one to nine underarm or rib cage lymph nodes.
• Stage IIIB - The tumor has grown into your chest wall or skin, and may have spread to as many as nine underarm lymph nodes.
• Stage IIIC - The cancer has spread to (1) 10 or more lymph nodes under your arm and one or more under or above the clavicle; or (2) to the nodes in your rib cage.

Breast cancer that has spread to your lymph nodes is called node-positive breast cancer. Effective treatment of stage III breast cancer requires both local treatment and systemic treatment. Local treatment consists of surgery and/or radiation therapy. It can get rid of cancer cells in or near your breast, but not cancer cells that have spread to other parts of your body. Systemic treatment can reach cancer cells throughout your body. It may include chemotherapy, antihormonal therapy, or targeted therapy. Sometimes these are given before surgery. In that case, they are called neoadjuvant or primary systemic therapy.

Local Treatment: Surgery and Radiation Therapy

Surgery and radiation therapy are considered local treatments. They can treat the cancer in your breast and prevent cancer recurrence in that breast and the surrounding area. They cannot, however, treat cancer that has already spread to other parts of the body.

Surgery - Doctors currently recommend that all women with stage III breast cancer have surgery to remove the cancer. Surgery for stage III breast cancers may consist of a mastectomy or lumpectomy. A mastectomy involves removal of your entire breast.

A lumpectomy involves removal of the cancer and some surrounding tissue. A lumpectomy alone is associated with a higher rate of local cancer recurrence than a mastectomy. So if you have a lumpectomy, you will also be given radiation therapy. This combination of a lumpectomy and radiation therapy is called breast-conserving therapy.

Clinical studies have shown that breast-conserving therapy is associated with a lower risk of local cancer recurrence compared with a lumpectomy alone. Importantly, women who have breast-conserving therapy and women who have a mastectomy live equally long.

Some women who initially cannot have breast-conserving therapy due to tumor size and issues of postoperative esthetics may be able to have the therapy after chemotherapy. Chemotherapy given before surgery is called neoadjuvant or primary chemotherapy. It is a recommended treatment for some women with stage III breast cancer.

Surgery for early-stage breast cancer may also involve checking the lymph nodes in your armpit (axilla) to see if the cancer has spread outside your breast. This helps doctors tell the stage of your cancer. It is important for determining if you need additional systemic treatments beyond local therapies, such as chemotherapy. There are two ways to check these lymph nodes:

• Axillary lymph node dissection - For more than 30 years, the standard of practice for determining the stage of breast cancer has included the removal of anywhere from 10 to 25 axillary lymph nodes to help tell if the cancer has spread. This procedure is called an axillary lymph node dissection. But a problem with this procedure is that in some patients it can have long-lasting side effects. They include pain, limited motion of your shoulder, numbness, and swelling of your arm.
• Sentinel lymph node biopsy - A new way of telling if cancer has spread to your lymph nodes is a sentinel lymph node biopsy. This procedure involves removing only a single lymph node—called the sentinel lymph node. This is the first lymph node to collect lymph drainage from surrounding the cancer.

Before surgery, blue dye or a radioactive tracer is injected near the cancer. The dye drains from the area containing the cancer into the nearby lymph nodes through the sentinel node. The node containing the dye is removed during surgery and checked under a microscope to see if it has cancer in it.

Research indicates that sentinel node biopsy appears to be just as effective as an axillary lymph node dissection in determining cancer spread to lymph nodes and results in fewer side effects in women with early-stage breast cancer. When performed by an experienced surgeon, the number of patients with incorrect results (false-positive or false-negative) is quite small.

Radiation therapy - It is recommended that women with stage III breast cancer who have a lumpectomy have additional treatment with radiation therapy. The addition of radiation therapy decreases the risk of a local recurrence of the cancer and improves survival.

Systemic Treatment: Chemotherapy, Targeted Therapy, and Antihormonal Therapy

Systemic treatment is directed at destroying cancer cells throughout your body. Despite surgery and radiation, some women with stage III breast cancer already have cancer cells that have spread outside their breast. These are called micrometastases. They cannot be detected with any of the currently available tests. These micrometastases cause breast cancer to recur after surgery and/or radiation therapy. An effective treatment is needed to get rid of micrometastases, so that women can live longer and have a better chance of a cure.

The three main kinds of systemic treatment used for stage III breast cancer are discussed below. Also, some women who initially cannot receive breast-conserving therapy may be able to if they have systemic therapy first. Chemotherapy, endocrine therapy, and/or trastuzumab can be given before surgery. This is called neoadjuvant or primary systemic therapy. It is the recommended approach for many women with stage III breast cancer.

Chemotherapy

Chemotherapy involves the use of drugs to kill cancer cells. It is a standard adjuvant therapy for early-stage breast cancer. Chemotherapy may consist of single drugs or combinations of drugs—called regimens. It can be given through your vein or taken by mouth in the form of a pill.

Chemotherapy options - There are many different chemotherapy drugs and regimens. The CMF regimen (cyclophosphamide, methotrexate, and fluorouracil) has been used for many years. CMF chemotherapy is typically given for six cycles over a period of about 4 to 6 months.

Research shows that the inclusion of the chemotherapy drug Adriamycin^® (doxorubicin) in adjuvant chemotherapy increases the number of women who survive without evidence of cancer compared with combination chemotherapy without doxorubicin. Combination approaches, such as CAF (cyclophosphamide, doxorubicin, and fluorouracil) and AC (doxorubicin and cyclophosphamide), are also considered standard chemotherapy regimens for the treatment of early-stage breast cancer. But they typically have more side effects than CMF.  More recently there has been much interest in identifying who benefits from anthracycline-based therapy. Some data suggest that only a small group of women garner benefit. There are data to suggest the benefit of non-anthracycline based therapy such as TC (docetaxel and cyclophosphamide) in some women with early stage breast cancer.

Taxanes - The taxanes are a group of chemotherapy drugs that include Taxotere (docetaxel) and Taxol (paclitaxel). These drugs improve cancer-free survival in women with stage II or stage III breast cancer. Docetaxel appears to be more effective than paclitaxel in the treatment of advanced breast cancer. The taxanes are typically combined with AC chemotherapy. More recently the docetaxel/cyclophosphamide regimen (TC) has been to be at least as effective as AC without the risk of cardiac toxicity.

Dose-dense chemotherapy - AC, TAC, CMF, and other chemotherapy regimens are typically given every 3 weeks. Dose-dense chemotherapy refers to chemotherapy treatment that is given more frequently--every 2 weeks. This is done to increase the total amount of chemotherapy used to treat the cancer.

Neoadjuvant chemotherapy - Neoadjuvant chemotherapy is chemotherapy given before surgery. This therapy aims to treat the cancer immediately and shrink the tumor, so that there is a better chance that the cancer can be completely removed with surgery. A committee of doctors has published treatment guidelines stating that neoadjuvant chemotherapy is "the treatment of choice" for some women with stage III breast cancer.

The long-term benefits of neoadjuvant chemotherapy are currently unknown. But the results of clinical trials clearly show that this therapy increases the likelihood that women can have breast-conserving surgery instead of a mastectomy.

Targeted Therapy

Targeted therapy is designed to treat only cancer cells and minimize the damage to healthy cells. Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. So healthy cells are commonly damaged during treatment. This causes side effects. These side effects may be severe. They can reduce your quality of life, compromise your ability to have full treatment, and sometimes limit your chance for the best outcome from treatment.

Treatments that target cancer cells may offer the advantages of reduced side effects and improved outcomes. Advances in science and technology have led to the development of several different types of targeted therapies.

Monoclonal antibodies - These are a type of targeted therapy. They are now being used in the treatment of breast cancer. Monoclonal antibodies can be made in the laboratory. They are designed to recognize and bind to specific proteins that occur in large quantities on the surface of some cancer cells. This binding promotes anticancer benefits by:

• Getting rid of the stimulus that makes the cancer cells grow
• Activating your immune system to attack and kill the cancer cells

Some breast cancers have too much of a protein called HER2 on their surface. These are called HER2-positive breast cancers. The HER2 protein binds only with other proteins in your blood—called growth factors. This binding leads to the uncontrolled growth of the cancer cells. About one in four women with breast cancer have HER2-positive breast cancer.

Herceptin^® (trastuzumab) - This is a monoclonal antibody that binds to the HER2 protein. Results from an important clinical trial indicate that adding trastuzumab to chemotherapy improves survival for women with advanced HER2-positive breast cancer. Trastuzumab is the first monoclonal antibody to be approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer. The addition of  trastuzumab to specific adjuvant chemotherapy programs has been shown to significantly reduce the risk of  recurrence in patients who have HER2-positive breast cancer. Research is continuing to determine which patients with HER2-positive disease gain the most benefit.

Antihormonal Therapy

The growth of some breast cancer cells can be prevented or slowed by reducing their exposure to estrogen. This is the goal of antihormonal therapy in the treatment of breast cancer.

Estrogen is a hormone made by your ovaries and other tissue in your body. It serves many critical functions. These include developing your female sex organs in puberty, preparing your breasts and uterus for pregnancy in adulthood, and maintaining your cardiovascular and bone health. Without estrogen, your body cannot sustain pregnancy and is susceptible to heart disease and osteoporosis (thinning of your bones).

Estrogen can also make some cancers grow. Your breasts, uterus, and other female organs are made of cells that are stimulated to grow when exposed to estrogen. These cells have areas on their surface called estrogen receptors. Estrogen in your blood binds to these receptors and stimulates the cells to grow. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer's growth. Cancers that have estrogen receptors are called estrogen receptor-positive (ER-positive) cancers.

The growth of ER-positive breast cancer cells can be prevented or slowed by reducing their exposure to estrogen. This is the goal of antihormonal therapy for breast cancer. But reducing estrogen levels can also have side effects. This happens because estrogen is necessary for important body functions, such as bone growth and cardiovascular health.

Lower estrogen levels lead to thinner bones and heart disease. Antihormonal therapy appears to benefit all women with early-stage breast cancer. Two types have been studied in the treatment of early-stage breast cancer:

• Tamoxifen
• Antiaromatase drugs (aromatase inhibitors)

Also, there is some evidence that some women who have been treated with tamoxifen for 2 to 5 years may attain benefit from switching to an antiaromatase drug.

Tamoxifen for Early-Stage Breast Cancer

The results of several clinical studies indicate that antihormonal therapy with tamoxifen, either alone or following treatment with adjuvant chemotherapy, can reduce the rate of cancer recurrence or improve the duration of survival in women with ER-positive breast cancer.  Experts currently recommend that tamoxifen be taken for 5 years if it is the only drug given.

Antiaromatase Drugs for Early-Stage Breast Cancer

Antiaromatase drugs, also called aromatase inhibitors, provide a greater reduction in the risk of cancer recurrence on postmenopausal women and have a different side effect profile than tamoxifen. The antiaromatase drugs that are approved for the treatment of early-stage breast cancer include Arimidex^® (anastrozole), Femara^® (letrozole), and Aromasin^® (exemestane). Unlike tamoxifen, which blocks estrogen receptors on cells, preventing estrogen from helping the cancer grow, aromatase inhibitors prevent the production of an enzyme—called aromatase—that leads to the production of estrogen.

Questions to Consider

Should I switch from tamoxifen to an antiaromatase drug? 
Three antiaromatase drugs have been evaluated in major studies in which women were initially treated with tamoxifen. The general outcome from these studies found that using the antiaromatase drugs in postmenopausal women provided a disease-free survival time advantage after 2 to 3 years of tamoxifen or after 5 years of antiaromatase therapy compared with 5 years of tamoxifen. However, there is still no clear agreement on which approach is "best." Research is ongoing to determine which option provides the best outcome.

Specifically:

• Anastrozole was shown to provide benefit after tamoxifen in the treatment of early-stage breast cancer.

Switching from tamoxifen to anastrozole also reduced the risk of a cancer recurrence. One study evaluated 400 postmenopausal women with ER-positive breast cancer who had already been treated with tamoxifen for at least 2 years. Women either kept taking tamoxifen for up to 5 years or switched to anastrozole for a comparable amount of time. There were 60 percent fewer cancer recurrences in the women who switched to anastrozole than in the women who took tamoxifen.

Letrozole was shown to reduce the risk of death and cancer recurrence when used after 5 years of tamoxifen. More than 5,000 postmenopausal women who had completed 5 years of treatment with tamoxifen participated in a clinical trial evaluating letrozole. About half received letrozole. The other half received a placebo (an inactive substitute).

Women treated with letrozole had an 18 percent reduced risk of death and a 40 percent reduced risk of cancer recurrence compared with those who received the placebo. Women with cancer that had spread to the lymph nodes (node-positive cancer) had an even greater benefit from letrozole, with a 39 percent reduced risk of death compared with a placebo.

About 5 percent of women treated with letrozole had a reduced quality of life compared with those treated with a placebo. This included decreased physical function (6 percent), increased pain (5 percent), and decreased vitality (5 percent). But a large proportion of women considered the side effects to be worth the reduced risk of a cancer recurrence. This trial was stopped early because the benefits of letrozole treatment were so significant. Even patients who started letrozole a few years after completing tamoxifen benefited from letrozole. Several clinical trials have also shown the benefit of switching to an aromatase inhibitor (exemestane, anastrozole) after 2 to 3 years of tamoxifen therapy compared to tamoxifen alone.

How long should I take antihormonal therapy? 
Tamoxifen has been the standard drug for antihormonal therapy. It is typically taken for 5 years. Research is ongoing to determine if very long durations of adjuvant endocrine therapy (10 to 15 years) offer additional benefit.

What is the best sequence of therapy? 
The sequence (order) of therapy may be important. A large clinical study looked at whether radiation therapy should be given before or after chemotherapy for women who had breast-conserving surgery. After this surgery, half of the women in this study had chemotherapy followed by radiation and half had radiation therapy followed by chemotherapy.

The women treated with chemotherapy followed by radiation were more likely to live 5 years or longer than the women treated with radiation followed by chemotherapy. Women treated with chemotherapy first lived longer because they were less likely to have a systemic recurrence of their cancer. Women treated with radiation first were less likely to have a local recurrence of their cancer.

It is much easier to treat a local recurrence of cancer than a systemic recurrence of cancer. This may explain why the women treated with chemotherapy followed by radiation lived longer than the women treated with radiation followed by chemotherapy.

The sequence of treatments is still being studied. But the current data suggest that standard treatment of early-stage breast cancer outside of a clinical study should include surgery followed by chemotherapy and lastly radiation therapy. Antihormonal therapy can begin during or after radiation therapy.