Treatment of Stage III Breast Cancer
Medically reviewed by Dr. C.H. Weaver M.D. 2/2020
Stage III breast cancer is characterized by one of the following:
- A primary cancer that measures less than 5 cm (2 inches) in size and causes axillary (underarm) lymph nodes to be attached to each other or other structures
- A primary cancer that is greater than 5 cm (2 inches) in size and involves axillary lymph nodes
- A primary cancer that is attached to the chest wall or skin
Breast cancer that has spread to the lymph nodes is commonly referred to as node-positive disease.
Effective treatment of stage III breast cancer requires both local and systemic therapy. Local therapy consists of surgery and/or radiation and is directed at destroying any cancer cells in or near the breast. Systemic therapy is directed at destroying cancer cells throughout the body, and may include chemotherapy, hormonal therapy, or biological therapy. Systemic therapy may be administered before surgery, which is called neoadjuvant therapy.
The following is a general overview of treatment for stage III breast cancer. 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 cancer physician.
- Local Therapy: Surgery & Radiation
- Systemic Therapy
- Precision Medicines-Targeted Therapy
- Hormonal Therapy
- Strategies to Improve Treatment
Surgery and Radiation
Surgery and radiation are considered local therapies because they can treat the cancer in the breast and prevent cancer recurrence in the affected breast and surrounding area, but cannot treat cancer that has already spread to other locations in the body.
Surgery: Doctors currently recommend that all patients with stage III breast cancer undergo surgical removal of the primary breast cancer. Surgery for stage III breast cancers may consist of mastectomy or lumpectomy. A mastectomy involves removal of the entire breast, whereas a lumpectomy involves removal of the cancer and a portion of surrounding tissue. Because a lumpectomy alone is associated with a higher rate of cancer recurrence than mastectomy, patients who elect to have a lumpectomy are also treated with radiation therapy. This combination of 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 to lumpectomy alone. (1,2) Furthermore, breast-conserving therapy and mastectomy have been shown to produce identical long-term survival. (3)
Some patients who are not initially candidates for breast-conserving therapy may become eligible for breast-conserving therapy after undergoing chemotherapy. Systemic treatment before surgery is called neoadjuvant therapy. Neoadjuvant chemotherapy is a recommended treatment for some women with stage III breast cancer.
Surgery for early stage breast cancer may also involve the evaluation of axillary (underarm) lymph nodes to determine the stage of disease and whether cancer has spread outside the breast. For over 30 years, the standard of practice for breast cancer staging has included the removal of approximately 10-25 axillary lymph nodes to help determine whether the cancer has spread. This procedure, called an axillary lymph node dissection, can be associated with chronic side effects, including pain, limited shoulder motion, numbness, and swelling.
Sentinel lymph node biopsy involves the removal of a single lymph node, called the sentinel node, which is the first lymph node to collect excess fluid surrounding the cancer. Prior to surgery, blue dye 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 evaluated under a microscope to determine whether cancer has spread. Sentinel lymph node biopsy is becoming the standard approach for determining whether cancer has spread to the axillary lymph nodes. (4,5)
For more detailed information, go to Surgery for Breast Cancer.
Radiation therapy: It is recommended that patients with stage III breast cancers treated with lumpectomy (breast-conserving surgery) receive additional treatment with radiation therapy. The addition of radiation therapy decreases the risk of local cancer recurrence and improves survival.
Studies have shown that the addition of radiation therapy to mastectomy and chemotherapy reduces cancer recurrences and increases survival among women with stage II-III breast cancer. In a clinical study involving 1,708 women with stage II-III breast cancer, researchers from Denmark reported a reduction in local regional recurrence, an increase in survival, and an increased probability of surviving 10 years or more with radiation therapy. (6)
Canadian researchers reported that, among 319 women with node-positive breast cancer that were randomized to receive chemotherapy plus radiation or chemotherapy alone, 29% fewer patients died and cancer recurrences were reduced by 33% with the addition of radiation therapy. (7)
Finally, researchers from M.D. Anderson have reported that radiation therapy following a mastectomy in patients with node-positive breast cancer appears to drastically reduce the rate of local-regional recurrences. These findings were based on evaluation of the results from 5 clinical trials involving approximately 1,500 women. The outcomes of 469 women who received radiation therapy following a mastectomy were compared to the outcomes of 1,031 women who did not receive additional radiation therapy following a mastectomy. All patients were treated with Adriamycin® (doxorubicin)-based chemotherapy. Women with increasing lymph node involvement or cancer cells near the edge of the surgically removed tissue appear to benefit most from post-mastectomy radiation. (8)
Radiation therapy has also been shown to benefit postmenopausal women with stage II-III breast cancer that receive hormonal therapy. The 1,375 women involved in this study were randomly assigned to receive hormonal therapy for one year alone (689) or hormonal therapy with postoperative radiotherapy to the chest wall and regional lymph nodes (686). Results showed a significant reduction in local regional recurrence and improvement in disease-free survival and survival of 10 years or more for patients who received radiation therapy. (9,10)
Chemotherapy, Targeted Therapy, and Hormonal Therapy
Systemic therapy is treatment directed at destroying cancer cells throughout the body and is typically added to local therapy for the treatment of stage III breast cancer. Some patients with stage III breast cancer already have small amounts of cancer that have spread outside the breast that the surgery or radiation does not treat. These cancer cells cannot be detected with any of the currently available tests and are referred to as micrometastases. The presence of micrometastases causes breast cancer recurrence following local treatment with surgery and/or radiation therapy alone. An effective systemic treatment is needed to cleanse the body of micrometastases in order to improve a patient’s duration of survival and potential for cure.
Examples of systemic therapies that are commonly used in the treatment of stage III breast cancer include:
- Hormonal Therapy
- Targeted Therapy with Precision Cancer Medicines or Immunotherapy
Furthermore, some patients who are not initially candidates for breast-conserving therapy may become eligible for breast conservation after undergoing chemotherapy. Systemic treatment before surgery is called neoadjuvant therapy. Neoadjuvant chemotherapy is the recommended systemic therapy for many women with stage III breast cancer.
Chemotherapy is any treatment involving the use of drugs to kill cancer cells and is a standard adjuvant therapy for the treatment of early stage breast cancer. Cancer chemotherapy may consist of single drugs or combinations of drugs and can be administered through a vein or delivered orally in the form of a pill.
Historically, systemic therapy has been administered after surgery and is referred to as adjuvant therapy. Clinical trials have shown that adjuvant chemotherapy improves a patient’s chance of survival and decreases the risk of cancer recurrence compared to local therapy alone in the treatment of stage III breast cancer. (10)
Chemotherapy options: There are many different chemotherapy drugs and combinations of drugs (regimens). The regimen consisting of cyclophosphamide, methotrexate and fluorouracil (CMF ) was the first standard combination used to treat individuals with early stage breast cancer and has been in use for many years. CMF chemotherapy is typically administered for 6 cycles over a period of approximately 4-6 months but has largely been replace by taxane based chemotherapy regimens. (11)
Research shows that the inclusion of the chemotherapy drug doxorubicin in adjuvant chemotherapy increases the number of women that can expect to survive without evidence of cancer compared to combination chemotherapy without doxorubicin. CAF (cyclophosphamide, doxorubicin, and fluorouracil) and AC (doxorubicin and cyclophosphamide) are also considered standard chemotherapy regimens for the treatment of early stage breast cancer. However, these regimens are typically associated with more side effects than CMF.
Taxanes: The taxanes are a class of chemotherapy drug that have been shown to improve cancer-free survival in women with stage II-III breast cancer. (13) Taxotere® (docetaxel) or paclitaxel are are typically combined with AC chemotherapy. (14)
Taxotere-containing combinations: Patients treated with a combination of Taxotere, doxorubicin, and cyclophosphamide–called TAC–have been shown to live longer and are cancer-free longer than those treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide). This trial involved 1,500 women with node-positive, early (stage II-III) breast cancer. (15)
Patients treated with Taxotere and cyclophosphamide have been shown to be free of cancer for longer after treatment compared to patients treated with standard AC. Furthermore Taxotere/cyclophosphamide may be less toxic to the heart. (16)
Dose-dense chemotherapy: AC, TAC, CMF and other chemotherapy regimens are typically administered every 3 weeks. Dose-dense chemotherapy refers to chemotherapy treatment that is administered more frequently. Dose-dense treatment is given every 2 weeks rather than at the conventional 3-week interval in order to increase the total amount of chemotherapy used to treat the cancer.
Researchers have reported that patients with node-positive breast cancer treated with dose-dense chemotherapy live longer without cancer recurrence than patients treated with conventional chemotherapy. The 2,005 patients involved in one study received chemotherapy treatment with doxorubicin, paclitaxel, and cyclophosphamide either every 3 weeks (conventional treatment) or every 2 weeks (dose-dense). At 4 years, 82% of patients treated with dose-dense therapy were disease-free, compared to 75% of those treated with conventional chemotherapy. (17)
Neoadjuvant chemotherapy: Neoadjuvant therapy is treatment administered before surgery. The purpose of neoadjuvant therapy is to immediately treat and shrink the cancer in order to increase the likelihood that it may be completely removed with surgery. A committee of physicians, called The Consensus Conference Committee, has published treatment guidelines stating that neoadjuvant chemotherapy is “the treatment of choice” for patients with stage III breast cancer and is “worthy of consideration” in patients with stage IIA and IIB breast cancer. (18) The results of clinical trials also clearly demonstrate that neoadjuvant therapy increases the likelihood that patients can undergo breast-conserving surgical treatment instead of surgical mastectomy. (19)
Researchers affiliated with the National Surgical Adjuvant Breast and Bowel Project have reported that neoadjuvant chemotherapy that includes the drug Taxotere produces more anti-cancer responsesthan neoadjuvant chemotherapy without Taxotere or neoadjuvant chemotherapy combined with adjuvant Taxotere. This trial involved over 2,000 women who were randomly assigned to receive one of the following treatments:
- Neoadjuvant AC (doxorubicin plus cyclophosphamide)
- Neoadjuvant AC plus Taxotere
- Neoadjuvant AC plus Taxotere after surgery
Approximately 91% of the patients treated with Taxotere® before surgery had an anti-cancer response, compared to 85% of patients in the other two groups. (20)
Targeted Therapy With Precision Cancer Medicines
A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes.
Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing, such as blood cells and the cells lining the mouth and GI tract are also damaged. Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage. Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.
Monoclonal antibodies: Advances in science and technology have led to the development of several different types of targeted therapies. Monoclonal antibodies are a type of targeted therapy that has been used in the treatment of breast cancer. Monoclonal antibodies are comprised of proteins that can be made in the laboratory and are designed to recognize and bind to specific proteins that occur in large quantities on the surface of some cancer cells. This binding action promotes anti-cancer benefits by:
- Eliminating the cancer cell’s stimulus to grow, and
- Activating the immune system to attack and kill the cancer cells that the monoclonal antibody is bound to.
Human Epidermal Growth Factor Receptor 2 (HER2): Some breast cancers have an abundance of a protein called HER2 on their outer surface. These cancers are called HER2-positive. HER2 proteins bind exclusively with other proteins that circulate in the blood called growth factors. This binding activity leads to the uncontrolled replication and growth of the cancer cells. Approximately one out of three breast cancer patients have HER2-positive breast cancer. (21)
Herceptin®: Herceptin (trastuzumab) is a monoclonal antibody that binds to the HER2 protein and adding Herceptin to chemotherapy improves survival for patients with advanced HER2-positive breast cancer. (22) Herceptin is the first monoclonal antibody to be approved by the FDA for the treatment of advanced breast cancer and additional precision cancer medicines that target HER2 are available and more active than Herceptin.
Women with node-positive breast cancer treated with chemotherapy plus Herceptin had a significantly reduced risk of death or cancer recurrence compared to patients treated with chemotherapy alone. After two years of treatment, results indicate that patients who received Herceptin had a 33% reduced risk of dying compared to patients that received chemotherapy alone. Also, the rate of a cancer recurrence was reduced by 52% in patients treated with Herceptin. (23)
Hormonal therapy involves reducing the level of estrogen in the body. 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 have estrogen receptors on their surface. 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.
The growth of ER-positive breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of hormonal therapy for breast cancer. However, a reduction in estrogen levels can also result in side effects because estrogen is necessary for important body functions, such as bone growth and cardiovascular health. Lower estrogen levels lead to decreased bone density and heart disease.
Hormonal therapy appears to benefit all women with early stage breast cancer. The hormonal therapies that have been investigated in the treatment of early stage breast cancer are:
- Anti-aromatase drugs
Furthermore, there is some evidence that patients who have been treated with tamoxifen for 2-5 years may benefit from switching to an anti-aromatase drug. (24,25)
Tamoxifen for Early Stage Breast Cancer
The results of several clinical studies indicate that hormonal treatment with tamoxifen, either alone (26) or in combination with chemotherapy (27-29) can reduce the rate of cancer recurrence and improve the duration of survival in women with ER-positive breast cancer. Patients with ER-status-unknown breast cancer may also benefit, but tamoxifen does not appear to be a beneficial treatment for patients with ER-negative breast cancer. However, ER-negative patients are at high risk of developing a cancer in their other breast and may want to learn more about prevention of breast cancer using hormonal treatment. (31)
It is currently recommended that patients receive hormonal therapy for 5 years or longer.
Anti-Aromatase Drugs for Early Stage Breast Cancer
Anti-aromatase drugs have been shown to provide a greater reduction in the risk of cancer recurrence and appear to produce fewer side effects than tamoxifen. The anti-aromatase drugs that are approved for the treatment of early stage breast cancer include Arimidex® (anastrazole) and Femara® (letrozole).
One of the most notable studies designed to evaluate the use of an anti-aromatase drug in the management of early stage breast cancer was the Arimidex, Tamoxifen Alone or in Combination (ATAC) clinical trial. In this clinical trial, over 9,000 post-menopausal women with ER-positive or unknown receptor status, early stage breast cancer were treated with either Arimidex, tamoxifen, or both drugs as adjuvant therapy for five years and the results were then directly compared. After 2.5 years of treatment, patients treated with the anti-aromatase drug Arimidex had a 17% decrease in the risk of cancer recurrence compared to patients treated with tamoxifen. (32)
After 4 years of treatment, ER-positive and ER status unknown patients treated with Arimidex® were more likely to be alive without cancer recurrence than patients treated with tamoxifen . In addition, the rate of breast cancer in the opposite breast was reduced by half in patients treated with Arimidex compared to patients treated with tamoxifen. Patients treated with tamoxifen were more likely to develop uterine cancer, vaginal bleeding, stroke, blood clots and hot flashes, while patients treated with Arimidex experienced more musculoskeletal problems and bone fractures. (33)
Should patients switch from tamoxifen to an anti-aromatase drug?
Because the anti-aromatase agents appear to be superior to tamoxifen, physicians have conducted clinical trials to determine whether patients on tamoxifen should switch to an anti-aromatase drug. Arimidex has been shown to provide benefit following tamoxifen in the treatment of patients with early stage breast cancer. Research is ongoing to directly compare these post-tamoxifen options and determine which treatment provides the best outcomes.
Switching from tamoxifen to Arimidex has also been shown to reduce cancer recurrence. One study evaluated over 400 postmenopausal women with ER-positive breast cancer who had already been treated with tamoxifen for at least 2 years. Patients either continued with tamoxifen for up to 5 years or switched to Arimidex for a comparable amount of time. (34) The patients who switched to Arimidex had 60% fewer cancer recurrences than patients who remained on tamoxifen.
How long should patients take hormonal therapy?
Tamoxifen has been the standard drug for hormonal therapy and is typically administered for 5 years. Research is ongoing to determine if patients can benefit from more than 5 years of hormonal therapy.
Femara has been shown to provide a reduced risk of death and cancer recurrence when used after 5 years of tamoxifen. Over 5,000 postmenopausal women who had completed 5 years of treatment with tamoxifen participated in a clinical trial evaluating Femara. Approximately half of these women received Femara and the other half received a placebo (inactive substance). Overall, treatment with Femara reduced the risk of cancer recurrence by 40%. Women with node-positive disease that were treated with Femara had a 39% reduced risk of death compared to patients who received placebo.
Approximately 5% of the patients treated with Femara experienced a reduced quality of life compared to those treated with placebo. This included decreased physical function (6%), increased pain (5%), and decreased vitality (5%). However, a large proportion of patients considered the side effects to be worth the reduced risk of a cancer recurrence. This trial was stopped prematurely due to the obvious benefits of treatment with Femara compared to placebo. (35)
What is the optimal sequence of therapy?
The timing or sequence of therapy may be important. A large clinical study has addressed the question of whether radiation therapy should be given before or after chemotherapy following treatment with breast-conserving surgery. Following breast-conserving surgery, half the patients in this study were treated with chemotherapy followed by radiation and half were treated with radiation followed by chemotherapy. The patients treated with chemotherapy followed by radiation were more likely to live 5 years or more after treatment than patients treated with radiation followed by chemotherapy. Patients treated with chemotherapy first survived longer because they were less likely to experience systemic recurrence of their cancer. Patients treated with radiation first, however, were less likely to experience a local recurrence of their cancer. (36)
It is much easier to treat local recurrence of cancer than systemic recurrence of cancer and this may explain why the patients treated with chemotherapy followed by radiation had improved survival compared to patients treated with radiation followed by chemotherapy. An additional explanation is that delivering radiation therapy before chemotherapy treatment of systemic disease may adversely affect the doctor’s ability to deliver the chemotherapy treatment. Although the sequence of treatments is undergoing continued evaluation, the current data suggest that standard treatment of early stage breast cancer outside the context of a clinical study should include definitive surgery first, followed by systemic chemotherapy, and lastly, radiation. Hormone therapy can begin during or following radiation 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. Areas of active investigation aimed at improving the treatment of stage III breast cancer include the following:
Findings from the I-SPY2 clinical trial suggest that combining the precision immunotherapy medication Keytruda (pembrolizumab) with neoadjuvant chemotherapy are significantly better for patients with HER 2 -negative breast cancer than chemotherapy alone.
In the I-SPY clinical trial 181 women were treated with standard neoadjuvant chemotherapy and 69 were treated with 4 cycles of Keytruda plus weekly paclitaxel followed by adjuvant chemotherapy.
When added to standard neoadjuvant chemotherapy, Keytruda more than doubled the estimated complete response rates assessed at surgery for both HR-positive/ERBB2-negative and triple-negative breast cancer. The research suggests that adding the Keytruda checkpoint inhibitor in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to provide additional benefit and will be studied in a phase 3 comparative clinical trial. (37)
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- Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347;1227-1232.
- Edge SB, Niland JC, Bookman MA, et al. Emergence of sentinel node biopsy in breast cancer as standard-of care in academic comprehensive cancer centers. Journal of the National Cancer Institute. 2003;95:1514-1521.
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- Woodward W, Katz A, Buchholz T, et al. Patterns and predictors of locoregional recurrence in 469 patients treated with post-mastectomy radiation. International Journal of Radiation Oncology, Biology and Physics. 2002;54:91-92. Proceedings from the American Society of Therapeutic Radiation Oncology. Abstract #158.
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- JAMA Oncol. 2020 Feb 13. Epub ahead of print.