Treatment of Stage IV Breast Cancer

Cancer Connect

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 10/2018

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 the diagnosis and treatment of stage IV breast cancer. Recent advances in treatment have resulted in new treatment options that reduce symptoms and improve survival. Each person with stage IV breast cancer is different, and the specific characteristics of your condition will determine how it is managed. The information on this Web site is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.

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 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.


The taxane chemotherapy drugs are 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.[1]

Results from a large clinical trial indicate that Taxotere produces higher anti-cancer response rates, progression-free survival, and overall survival compared to Taxol.[2]

Abraxane™ (nanoparticle albumin-bound paclitaxel): A technique for delivering anti-cancer drugs is 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.[3],[4]

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 life cycle. 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.

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 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 chemotherapy treatment consisting of fluorouracil, doxorubicin, and cyclophosphamide (FAC)[5],[6]

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.[7]

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.

Precision Cancer Medicine

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 over express (make too much of) a protein known as HER2.[12] Over expression 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.

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. 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).[9],[10],[11]

Learn More About Hormonal Therapy for Breast Cancer.

Management of 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 Xgeva or a bisphosphonate drug.

Xgeva (Denosumab) targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Xgeva has shown promising results in the management of patients with bone metastases as well as the management of bone loss due to cancer treatment. When directly compared with the bisphosphonate drug Zometa in a clinical trial that enrolled more than 2,000 breast cancer patients with bone metastases Xgeva 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]

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Areas of active investigation aimed at improving the treatment of metastatic breast cancer include the following:

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.

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%).[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] 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.

[2] 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.

[3] 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.

[4] 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.

[5] 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.

[6] 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.

[7] 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.

[8] 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.

[9] Food and Drug Administration. FDA oncology tools approval summary for Femara® for treatment of advanced breast cancer in postmenopausal women. Accessed March 29, 2002.

[10] 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.

[11] 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.

[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 EnglandJournal 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: 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: 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).