Overview

Patients diagnosed with Stage IV or metastatic breast cancers have disease that has spread from the affected breast to one or more distant sites in the body. Historically, metastatic breast cancer has been considered incurable; the goal of treatment has been to provide relief from symptoms and prolong the duration and quality of life. However, there have been some important advances resulting in the addition of many more treatment options for managing this disease. These include the now widespread use of taxane chemotherapy, the development of targeted therapies, and the development of more active hormonal therapy drugs.

The following is a general overview of treatment for metastatic breast cancer. Treatment typically consists of chemotherapy and/or hormonal therapy. The presence of hormone receptors in the breast cancer cells determines whether hormonal therapy is a treatment option. If the cancer does not have estrogen or progesterone receptors, the mainstay of treatment is chemotherapy. Treatment may also include surgery, radiation, targeted therapy, or a combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment.

Circumstances unique to each patient’s situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

The topics covered in this section include:

• Hormonal Therapy
• Chemotherapy
• Targeted Therapy
• Treatment for Stage IV Disease with Specific Characteristics
  • Treatment for Bone Metastases
  • Treatment of Local-Regional Recurrence
  • Treatment of Stage IV No Evidence of Disease
• Strategies to Improve Treatment

Hormonal Therapy for Metastatic Breast Cancer

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

Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.

Estrogen can also cause some cancers to grow. The breasts, uterus, and other female organs are composed of cells that are stimulated to grow when exposed to estrogen. These cells contain estrogen receptors. Estrogen circulating in the blood binds to these receptors and stimulates growth-related activities in the cell. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER-positive) cancers.

Removal of the ovaries, the organ chiefly responsible for producing estrogen in premenopausal women, is one effective approach to eliminating estrogen production and is commonly used in many countries. Another approach is to utilize drugs that can accomplish a similar effect without removing the ovaries. Currently, many women with estrogen receptor-positive breast cancer are initially treated with a drug called tamoxifen (Nolvadex®), which blocks the growth stimulatory effects of estrogen. However, a new group of drugs, called aromatase inhibitors, have more recently been developed and approved by the FDA for the treatment of estrogen-positive breast cancer.

Aromatase inhibitors: Aromatase inhibitors work by inhibiting the formation of estrogen in the body. Aromatase is the enzyme (protein) that initiates the conversion of estrogen to its active form. Aromatase inhibitors work by inhibiting aromatase, thereby reducing the levels of active estrogen in the body. This is in contrast to tamoxifen, which works by blocking estrogen from entering a cell through direct binding to the cell’s estrogen receptors.

Currently, three aromatase inhibitors are approved for the treatment of postmenopausal women with breast cancer: Femara® (letrozole), Arimidex® (anastrozole), and Aromasin® (exemestane).[1][2][3] Research indicates that initial treatment of metastatic breast cancer with either Femara or Arimidex appears to produce better outcomes than treatment with tamoxifen.[4][5] The aromatase inhibitors delay the time before cancer recurs and may be associated with fewer side effects than tamoxifen.[6]

For more in depth information, go to Hormonal Therapy for Breast Cancer.

Chemotherapy Treatment of Metastatic Breast Cancer

Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Patients with breast cancer that does not have estrogen/progesterone receptors, those not responding to hormonal treatment, and individuals requiring symptomatic relief from progressive breast cancer may benefit from treatment with chemotherapy. There are currently several standard treatment regimens available, and approximately 25% of patients who undergo chemotherapy will experience a complete remission of their cancer.

The type of chemotherapy that is selected depends on the patient’s goal of treatment. If the goal of treatment is to reduce symptoms and improve quality of life, it may be more desirable to select a chemotherapy treatment with minimal side effects. On the other hand, if the goal of treatment is to attempt to cure the cancer, treatment with more aggressive chemotherapy regimens or participation in clinical studies evaluating new treatment strategies may be more appropriate.

It is important to carefully consider the goals of treatment. One reason for this is that initial treatment of Stage IV breast cancer is typically more effective than retreating cancer that has recurred. This is because cancer cells may become resistant to therapy. Patients who are interested in aggressive treatment and whose goal is cure may want to consider aggressive therapy or participation in a clinical study as their first or initial treatment.

Taxanes

In recent years, a class of chemotherapy drugs called the taxanes has been widely used in the treatment of breast cancer. Taxotere® (docetaxel) and Taxol® (paclitaxel) are both taxanes that, when used in combination or sequentially with other chemotherapy drugs, appear to have more anti-cancer activity than previous non-taxane chemotherapy for the treatment of metastatic breast cancer. The best schedule for administering taxanes is still being evaluated. Some research indicates that more frequent administration may be better than the standard schedule of every three weeks.[7]

Results from a large clinical trial indicate that Taxotere produces higher anti-cancer response rates, progression-free survival, and overall survival compared to Taxol (see table 1).[8]

Table 1: Taxotere versus Taxol in the treatment of breast cancer

Abraxane™ (nanoparticle albumin-bound paclitaxel): A new technique for delivering anti-cancer drugs has been recently developed, called nanoparticle albumin-bound (nab) technology. Abraxane™ is a treatment that delivers the anti-cancer drug paclitaxel using nab technology. This technique utilizes albumin, the most abundant protein in the body, to deliver the paclitaxel directly to cancer cells.

Abraxane offers several advantages over the conventional formulation of paclitaxel, which is known as the drug Taxol and is comprised of a toxic, chemical solvent in addition to the active drug. With Abraxane 50% more drug can be administered, more active drug is transported into the cancer cells, and patients experience fewer side effects.

In a clinical trial that directly compared of Abraxane to Taxol in the treatment of 454 patients with metastatic breast cancer, Abraxane doubled anti-cancer response rates and significantly prolonged time to disease progression with fewer side effects compared to Taxol.[9][10] (see table 2).

Table 2: Abraxane improves outcomes compared to Taxol

Combination Chemotherapy Regimens

Combinations of two or more chemotherapy drugs are referred to as regimens. Regimens have been shown to kill more cancer cells than single chemotherapy drugs. This is because each type of drug interrupts cells from replicating at different points in their lifecycle. Since all cancer cells are not at the same phase of development at the same time, chemotherapy regimens have the ability to interrupt and kill more cancer cells.

The optimal schedule for administering regimens is still being evaluated. Administering chemotherapy drugs in sequence (one following another), rather than together as a combination, has shown promise.

Regimens that Include a Taxane

Current research indicates that the following taxane-containing regimens improve outcomes over either a single drug or a conventional regimen:

Doxorubicin and paclitaxel (AT): Two clinical trials, published in 2001 and 2003, have shown that patients who receive AT live longer, are cancer-free longer, or experience a longer period of time before their cancer progresses than those who receive the common chemotherapy treatment consisting of fluorouracil, doxorubicin, and cyclophosphamide (FAC)[11][12] (see table 3).

Table 3: AT versus FAC in the treatment of metastatic breast cancer

TAC (Taxotere, doxorubicin, and cyclophosphamide): In an attempt to further improve treatment, a third drug has been added to the AT regimen and evaluated as initial treatment for patients with metastatic breast cancer. Partial or complete disappearance of cancer following treatment with TAC occurred in 77% of patients. Two years following treatment, nearly 60% of patients were still alive.[13]

Gemzar® (gemcitabine) and Taxol (GT): Results of a clinical trial reported in 2004 indicate that Gemzar and Taxol improves survival over Taxol alone in the treatment of patients with metastatic breast cancer who have stopped responding to anthracycline treatment (see table 4).[14]

Table 4: Survival benefit of Gemzar and Taxol over Taxol alone

In May of 2004, the FDA approved GT for initial treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy, unless anthracyclines were clinically contraindicated.

Targeted Therapy

Targeted therapies are treatments that can selectively target cancer cells and minimize damage to normal, healthy cells. This means that side effects of targeted therapy are generally less severe. Targeted therapies can be easily combined with chemotherapy. Advances in science and technology have led to the development of several different types of targeted therapies.

Human Epidermal Growth Factor Receptor-2 (HER2): Many targeted therapies work by targeting a protein, or receptor, that is abundantly present on the surface of cancer cells. HER2 is a protein that is overexpressed (present in greater quantities than normal) in approximately one out of three patients with breast cancer.[15] HER2 stimulates the uncontrolled growth and replication of the cancer cells by binding exclusively with other proteins called growth factors, which circulate in the blood.

Herceptin® (trastuzumab): Herceptin is a type of targeted therapy called a monoclonal antibody that binds to the HER2 protein. Results from an important clinical trial indicate that adding Herceptin to chemotherapy improves survival for patients with advanced HER2-positive breast cancer.[16]

Because HER2-positive breast cancer is known to respond to Herceptin, it is imperative that all breast cancer patients are tested for HER2 at the time of diagnosis to determine whether Herceptin should be part of their treatment plan.

Taxotere plus Herceptin: Research suggests that the addition of Herceptin to Taxotere significantly improves outcomes in the treatment HER2-positive metastatic breast cancer. Results of a 24-month study indicate that patients who received Taxotere plus Herceptin lived longer and experienced more anti-cancer responses than patients treated with Taxotere alone (see table 5).[17]

Table 5: Addition of Herceptin to Taxotere improves survival

Taxotere, paclitaxel, and Gemzar chemotherapy have all been effectively combined with Herceptin. Clinical trials are ongoing to determine which treatment regimen is the most active with the fewest side effects.

Avastin® (bevacizumab): Avastin is a targeted therapy that blocks a protein known as vascular endothelial growth factor (VEGF). VEGF stimulates the growth of new blood vessels. Drugs that interfere with VEGF can slow or stop the growth of cancer cells, and may also improve the delivery of chemotherapy to cancer cells by normalizing blood supply.

Among women with advanced, HER2-negative breast cancer who have not received prior treatment for metastatic disease, treatment with Avastin plus paclitaxel resulted in a longer time to cancer progression than treatment with paclitaxel alone.[18] The addition of Avastin did not, however, significantly improve overall survival.

Treatment of Stage IV Breast Cancers with Specific Characteristics

Some Stage IV breast cancers have specific characteristics; these include a recurrence at particular sites or spread to certain areas in the body. These cancers can typically be treated with surgery, radiation, or managed with specific medications. Types of Stage IV breast cancer include:

• Bone metastases: cancer that has spread to the bones
• Local-regional recurrence: cancer that has recurred within the previously affected breast, chest wall, or in the skin over the breast
• Stage IV No Evidence of Disease (NED): patients who have had a recurrence in a single area that was removed with surgery or radiation

Bone Metastases

Breast cancer cells that have spread to the bones are called bone metastases. Cancer can spread to the bones when individual cancer cells break off from the original tumor and travel in the circulatory or lymph system until they get lodged in a small vessel in a new area. The cell then grows into another tumor. Management of bone metastases may include a bisphosphonate drug.

Bisphosphonates: Bisphosphonates are a class of drugs that decrease the rate of bone destruction in patients with cancer. Clinical studies have demonstrated that bisphosphonates can significantly decrease the number of fractures occurring from cancer that has spread to the bone and reduce the pain associated with cancer involving the bone.

In November 2003, the American Society of Clinical Oncology recommended the use of the bisphosphonates Zometa® (zoledronic acid) or Aredia® (pamidronate) for treatment of patients with bone metastasis from breast cancer. The optimal duration of use or the optimal time to administer bisphosphonates is still being evaluated in clinical trials. Researchers are hopeful that bisphosphonates may help to prevent some patients from developing bone metastasis if they are administered prior to bone spread.

For more in depth information, go to the Bone Complications and Cancer.

Local-Regional Recurrence of Breast Cancer

After undergoing surgical treatment of breast cancer with mastectomy or breast-conserving surgery (lumpectomy plus radiation), some patients may experience a local recurrence, which is defined as cancer recurring within the previously affected breast, chest wall, or skin over the breast. The cancer may also recur regionally, involving the nearby lymph nodes. Patients who experience a regional recurrence are more likely to develop systemic disease.

Treatment for local recurrences depends on how the cancer was initially treated:

• For patients who underwent a mastectomy, additional radiation treatment can effectively control a local recurrence. In certain circumstances, surgery prior to the radiation therapy may be beneficial.
• For patients who underwent breast-conserving therapy, a mastectomy may be the best approach. Surgery with or without radiation may also be an option for some patients.

Despite effective local control with surgery and radiation, the large majority of patients who experience a local recurrence ultimately develop systemic cancer. Additional treatment with chemotherapy or hormonal therapy may help eradicate the remaining cancer cells that ultimately result in a systemic relapse. Unfortunately, this has not been well evaluated in controlled clinical trials.

Stage IV-No Evidence of Disease (NED)

Some patients experience a single location of cancer recurrence that can be effectively removed with surgery or radiation, eliminating all evidence of recurrent cancer. These patients are then considered to have Stage IV, but with no evidence of disease (NED). Even though cancer may be successfully eliminated with local therapy consisting of surgery and/or radiation, approximately 80% of these patients die from complications of metastatic disease within four years of treatment. This suggests that other locations of cancer that could not be detected with currently available tests existed at the time of surgical treatment. Additional treatment with systemic chemotherapy following surgery and/or radiation may improve outcomes.

Patients with Stage IV NED treated with local therapy, followed by doxorubicin-based chemotherapy, have been shown to live longer and be cancer-free longer than a similar group of patients who did not receive additional systemic therapy (see table 6).[19]

Table 6: Doxorubicin-based chemotherapy versus no additional systemic therapy

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of metastatic breast cancer will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of metastatic breast cancer include the following:

• Targeted Therapy
  • Epidermal Growth Factor Receptor (EGFR) Inhibitors
  • Tipifarnib (Zarnestra™)
  • Vaccines
• Advances in Hormonal Therapy
• Advances in Chemotherapy
• New Bisphosphonate Drugs

Targeted Therapy

Epidermal Growth Factor Receptor (EGFR) inhibitors: Epidermal growth factor receptors (EGFR) are small proteins that are found on the surface of all cells. EGFR binds exclusively to small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote controlled cellular growth. However, in many cancer cells, EGFR is either abundantly overexpressed, or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell. Several drugs that inhibit EGFR have been developed and are currently being evaluated in the treatment of breast cancer.

Tarceva (erlotinib) is an EGFR inhibitor that is approved for the treatment of advanced non-small cell lung cancer and is being evaluated in the treatment of other cancers, including advanced breast cancer.

Tipifarnib (Zarnestra™): Tipifarnib is a drug designed to block a key enzyme (protein) involved in a genetic abnormality that is common in many cancers. Tipifarnib slows down or stops the excessive replication of cancer cells that results from this mutation. Researchers from England have found that Tipifarnib has some anti-cancer activity in patients with advanced breast cancer.[20]

Vaccines: One strategy for stimulating the immune system to attack cancer cells is the use of vaccines. Cancer cells often display certain small proteins and/or carbohydrates (antigens) on their surface that are not displayed by healthy cells. Vaccines are often comprised of these specific antigens, which can be taken directly from the patient’s cancer cells, other patient’s cells, or produced in a laboratory. If these antigens are injected into the patient, the immune system recognizes them as “foreign” and will attack the cancer cells displaying the antigens. Researchers are now evaluating various strategies to enhance the immune response against the injected antigens, including combining the patient’s own immune cells with the specific antigens in a laboratory prior to injection.

Advances in Hormonal Therapy

Researchers continue to evaluate ways to improve hormonal therapy for breast cancer by evaluating new agents or different ways to administer drugs that are already in use. Aromasin and Faslodex® (fulvestrant) are approved for treatment of women with metastatic breast cancer that has stopped responding to tamoxifen, but not as initial treatment. However, research now indicates that these two anti-estrogen agents appear to be superior to tamoxifen as initial treatment of metastatic disease. Anti-cancer responses were three times more prevalent among patients treated with Aromasin compared to patients treated with tamoxifen (41% versus 17%).[21] Treatment with Faslodex also resulted in more anti-cancer responses than tamoxifen, and patients who received Faslodex experienced a longer time before their cancer progressed.[22]

Advances in Chemotherapy

New chemotherapy regimens: Evaluation of new multi-drug chemotherapy regimens including the taxanes, Gemzar and Xeloda® (capecitabine) (with and without a platinum drug), is ongoing.

Dose dense treatment: A large clinical trial performed in early-stage breast cancer demonstrated that rapid administration of single chemotherapy agents reduced the number of cancer relapses compared to standard multi-agent multi-cycle chemotherapy.[23] Doctors believe that by rapidly administering several different single chemotherapy agents, cancer cells responsible for recurrence may be destroyed before they develop resistance.

High-dose chemotherapy and autologous stem cell transplant: Since conventional doses of chemotherapy appear to cure a number of women, some doctors believe that very high doses of chemotherapy can cure even more cases of breast cancer. Additionally, more chemotherapy has been shown to kill more cancer cells. However, high-dose chemotherapy kills critical red and white blood cells; therefore, to combat this side effect, this treatment is coupled with the administration of the patient’s own stem cells to grow new blood cells.

Some research suggests that high-dose chemotherapy does not produce worse outcomes and may cure some patients. Based on an evaluation of outcomes of approximately 1,000 patients with metastatic breast cancer, researchers estimate that those receiving high-dose chemotherapy with stem cell transplantation are likely to live at least three to five years longer after treatment than those treated with conventional dose.[24] A small study that evaluated high-dose chemotherapy with autologous stem cell transplantation indicates that cure may be possible with this approach. Among 22 women who underwent treatment for metastatic breast cancer, 14% lived 10 years or more without a relapse of their cancer and appeared cured of their disease.[25] High-dose chemotherapy appears to produce the best results in the treatment of patients with minimal cancer. Among 40 patients who had their Stage IV cancer surgically removed and/or irradiated to eliminate all obvious cancer, followed by high-dose chemotherapy with autologous stem cell transplant, more than half (55 percent) survived without evidence of recurrent cancer.[26]

Other studies have not demonstrated an improvement in patients treated with high-dose chemotherapy. Ongoing trials will ultimately determine whether certain patients can benefit from this treatment strategy.

New Bisphosphonate Drugs

Boniva™ (ibandronate) is a bisphosphonate that may be administered into a vein (intravenous) or orally. Both Zometa and Aredia are bisphosphonates that can only be administered intravenously. Oral administration makes treatment more convenient for patients and health care providers. Currently, Boniva is approved for the prevention and treatment of post-menopausal osteoporosis.

Researchers from Europe have found that Boniva reduces bone complications, including bone fractures and spinal cord compression, and reduces the need for radiation or surgery more so than placebo in the treatment of patients with bone metastasis from breast cancer.[27]

References:

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