Stage IV Breast Cancer
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. 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 Web site 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
- Targeted Therapy
- Management of Bone Metastases
- Strategies to Improve Treatment
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. These drugs include tamoxifen as well as a newer class of drugs known as 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 3Hormonal Therapy for 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 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.
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.4
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).5
Table 1: Taxotere versus Taxol in the treatment of breast cancer
|Progression-free survival||5.7 months||3.6 months|
|Overall survival||15.4 months||12.7 months|
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.6 7 (see table 2).
Table 2: Abraxane improves outcomes compared to Taxol
|Time to cancer progression||23.0 weeks||16.9 weeks|
|Overall survival||65 weeks||55.7 weeks|
|Grade 4 neutropenia
(low white blood cell count)
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)8 9 (see table 3).
Table 3: AT versus FAC in the treatment of metastatic breast cancer
|Time to cancer recurrence (2001)||8.3 months||6.2 months|
|Average survival (2001)||23.3 months||18.3 months|
|Time to cancer progression (2003)||8.1 months||6.6 months|
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.10
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).11
Table 4: Survival benefit of Gemzar and Taxol over Taxol alone
|Gemzar and Taxol||Taxol alone|
|Overall survival||18.5 months||15.8 months|
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 therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target,” targeted therapies may slow cancer cell growth or increase cancer cell death.
HER2-targeted therapy: Twenty to thirty percent of breast cancers overexpress (make too much of) a protein known as HER2.12 Overexpression of this protein leads to increased growth of cancer cells. Fortunately, the development of treatments that specifically target HER2-positive cells has improved outcomes among women with HER2-positive breast cancer.
- Herceptin® (trastuzumab): Herceptin is an agent that recognizes and binds to HER2-positive cells. The effects of Herceptin are thought to include decreased cell growth and increased cell death.13 Results from an important clinical trial indicate that adding Herceptin to chemotherapy improves survival for patients with advanced HER2-positive breast cancer.14
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.15 The addition of Avastin did not, however, significantly improve overall survival.
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.
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:
- New Approaches to Managing Bone Metastases
- Targeted Therapy
- Epidermal Growth Factor Receptor (EGFR) Inhibitors
- Advances in Hormonal Therapy
Denosumab is an investigational drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Denosumab has shown promising results in the management of patients with bone metastases as well as the management of bone loss due to cancer treatment.
Denosumab was directly compared with the bisphosphonate drug Zometa in a Phase III clinical trial that enrolled more than 2,000 breast cancer patients with bone metastases. The results indicated that denosumab was more effective than Zometa at delaying skeletal complications such as fracture, spinal cord compression, surgery to the bone, and radiation to the bone.16
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.
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.
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%).17 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.18
1 Food and Drug Administration. FDA oncology tools approval summary for Femara® for treatment of advanced breast cancer in postmenopausal women. Accessed March 29, 2002.
2 Food and Drug Administration. FDA oncology tools approval summary for Arimidex® for treatment of advanced breast cancer in postmenopausal women with disease progression following Nolvadex® therapy. Accessed March 29, 2002.
3 Food and Drug Administration. FDA oncology tools approval summary for Aromasin® for treatment of advance breast cancer in postmenopausal women whose disease has progressed following Nolvadex® therapy. Accessed March 29, 2002.
4 Seidman D, Berry C, Cirrincione C, et al. CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (s) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. New Orleans LA. 2004; Abstract #512.
5 Jones SE, Overmoyer EB, Budd GT, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal of Clinical Oncology. 2005;23:5542-5551.
6 O’Shaughnessy J, Tjulandin S, Davidson N, et al. ABI-007 (Abraxane®), a nanoparticle albumin-bound paclittaxel demonstrates superior efficacy vs. taxol in MBC: a phase III trial (Abstract #44). Proceedings from the 26th annual San Antonio Breast Cancer Symposium ( 12/3/03 ), Abstract #44.
7 New Antitubulin Agents. Proceedings from the 22nd annual Miami Breast Cancer Conference. Presented by Dr. Perez. Friday February 25, 2005. 2:45 pm. Miami, Florida.
8 Jassem J, Pienkowski T, Pluzanska A, et al. Doxorubicin and Paclitaxel Versus Fluorouracil, Doxorubicin, and Cyclophosphamide as First-Line Therapy for Women With Metastatic Breast Cancer: Final Results of a Randomized Phase III Multicenter Trial. Journal of Clinical Oncology. 2001;19(6):1707-1715.
9 Bontenbal M, Braun JJ, Creemers GJ, de Boer AC, et al. Phase III study comparing AT (Adriamycin, Docetaxel) to FAC (Fluorouracil, Adriamycin, Cyclophosphamide) as first-line chemotherapy (CT) in patients with metastatic breast cancer (MBC). Proceedings from the 12th European Conference on Clinical Oncology, 2003; Copenhagen , Denmark.
10 Nabholtz JM, Mackey JR, Smylie M, et al. Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Journal of Clinical Oncology. 2001;19:314-321.
11 Albain KS , Nag S, Calderillo-Ruiz G, Jordaan JP, et al. Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology held in New Orleans LA , June 4-8, 2004, Abstract #510.
12 Howlader N, Altekruse SF, Li Ci, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014 Apr 28;106(5).
13 Hobday TJ, Perez EA. Molecularly targeted therapies for breast cancer. Cancer Control. 2005;73-81.
14 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine. 2001;344:783-792.
15 Genentech. FDA Grants Accelerated Approval of Avastin in Combination With Paclitaxel Chemotherapy for First-Line Treatment of Advanced HER2-Negative Breast Cancer. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11027. Accessed February 2008.
16 Amgen press release. Denosumab demonstrates superiority over Zometa in pivotal phase 3 head-to-head trial in breast cancer patients with bone metastases. Available at: http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2009&releaseID=1305355 Accessed July 8, 2009.
17 Paridaens L, Dirix C, Lohrisch L, et al. Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Annals of Oncology. 2003;14:1391-1398.
18 John F, Robertson A, Howell P, et al. Faslodex versus Nolvadex for the first-line treatment of advanced breast cancer (ABC) in postmenopausal women. Annals of Oncology. 2002;13:46 (Abstract #164).
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