Stage III Breast Cancer
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. 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 cancer physician.
Local Therapy: Surgery and Radiation
Strategies to Improve Treatment
Local Therapy: 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. For more information, go to neoadjuvant chemotherapy.
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.
A new approach for evaluating whether cancer has spread to the lymph nodes is a sentinel lymph node biopsy . The advantage to this procedure is that it 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
Research now 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 patients with stage II-III breast cancer.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.
Three 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 (see Table 1). 6
Table 1: Addition of radiation therapy to chemotherapy improves survival in the treatment of early stage breast cancer
||Chemotherapy plus radiation therapy
|Survival at 10 years
|Probability of surviving 10 years or more
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 (see Table 2).9
Table 2: Addition of radiation to hormonal therapy improves survival in the treatment of early stage breast cancer
||Hormonal therapy plus radiation
||Hormonal therapy alone
|Local-regional cancer recurrence
Systemic Therapy: Chemotherapy, Targeted Therapy, and Hormonal Therapy
Systemic therapy is treatment directed at destroying cancer cells throughout the body. 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:
- Targeted Therapy
- Hormonal Therapy
Furthermore, some patients who are not initially candidates for breast-conserving therapy may become eligible for this treatment 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.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. 12 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) appears to be more effective than paclitaxel in the treatment of patients with advanced breast cancer.14 The taxanes are typically combined with AC chemotherapy.
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 (see Table 3).15
Table 3: Taxotere-containing chemotherapy (TAC) improves survival over standard regimen (FAC)
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 committee’s guidelines are determined by an extensive review of clinical studies that evaluated neoadjuvant chemotherapy in different stages of breast cancer.
Although the long-term benefits of neoadjuvant chemotherapy are currently unknown, the results of clinical trials 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 responses than 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
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. Results from an important clinical trial indicate that 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 is also being evaluated in the treatment of early stage breast cancer.
Researchers reported in mid-2005 that 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. The researchers conducted large clinical trials involving 3,000 women who had positive lymph nodes or were considered to be high-risk despite having no cancer spread to lymph nodes, and had received no previous treatment with either anthracycline or taxane chemotherapy. Patients received chemotherapy treatment consisting of doxorubicin and paclitaxel with or without Herceptin.
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 alone26 or in combination with chemotherapy27,28,29,30 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 tamoxifen for 5 years.
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. Future progress in the treatment of stage III 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 stage III breast cancer include the following:
- New Hormonal Therapy Drugs
- Advances in Radiation Therapy
- Boost Radiation
New Hormonal Therapy Drugs
Several newer hormonal therapies, called anti-aromatase drugs, have proven to be superior to the once standard hormonal therapy drug tamoxifen for the treatment of patients with ER-positive breast cancer.37,38 The anti-aromatase drugs also appear to be associated with fewer side effects.39
Anti-aromatase drugs are a class of hormonal drugs that work by inhibiting the formation of estrogen in the body. Aromatase is the enzyme (protein) that initiates the process through which hormones in the body are converted to estrogen. Anti-aromatase drugs work by inhibiting aromatase. This activity blocks the conversion of estrogens into their active form and reduces levels of active estrogen in the body. In contrast, tamoxifen blocks estrogen from entering a cell by directly binding to the cell’s estrogen receptors.
New Approaches to Radiation
Brachytherapy: Advances in radiation therapy have led to the development of an alternative to external beam radiation therapy (EBRT) called brachytherapy. Brachytherapy is a technique for delivering radiation internally by implanting a radioactive material directly into or near the cancer. Brachytherapy does not involve daily visits to a radiation facility, as the implants (also called seeds) are left in the body for the duration of treatment. In addition, the total delivery time, or exposure to radiation, is reduced with brachytherapy (several days) compared to standard external-beam radiation therapy (several weeks).
A clinical trial published in the Journal of the National Cancer Institute shows that brachytherapy appears to be just as effective and more convenient than EBRT for patients with early stage breast cancer. Five years following administration of brachytherapy to 199 women with early stage breast cancer, 1% of the patients had a local cancer recurrence and 1% had a regional recurrence. Cancer spread to distant sites in the body occurred in 5% of patients and approximately 3% of patients had died from breast cancer. These results were similar to data from a similar group of patients who underwent EBRT.40
Radiation “boost” therapy: Standard radiation therapy following a lumpectomy consists of a limited dose of radiation (50 Gy) to the entire affected breast. While this treatment leads to long-term outcomes similar to those from mastectomy, women under age 50 experience higher rates of local recurrences following this treatment regimen compared to their elder counterparts. Researchers have theorized that an additional boost of radiation aimed only at the area from which the cancer was removed could reduce the rates of local recurrences, especially in younger patients.
The European Organization for Research and Treatment of Cancer has reported that an additional dose of radiation to the site of the removed cancer reduces local recurrence by nearly 50% among women with stage I or II breast cancer. The 5,318 women involved in this trial had undergone a lumpectomy followed by the standard dose of radiation. Approximately half of the patients were given an additional small dose of radiation to the area where the cancer had been located, while the other half received no additional treatment. The researchers followed the women for an average of 5.2 years. Women 40 years old and younger exhibited the largest benefit; in this group, local recurrences occurred in only 10.2% of patients receiving additional radiation, compared to 19.5% of those receiving standard treatment. Overall survival rates and the development of distant metastases were similar whether women received an additional boost of radiation or standard therapy. Side effects including cosmetic results and fibrosis (formation of scar tissue) were not affected by the additional radiation.41
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.N Engl J Med. 2002;347:1233-1241.
2 Lichter AS, Lippman ME, Jr Danforth DN, et al. Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. Journal of Clinical Oncology, Classic Papers and Current Comments. 1996;1:2-10.
3 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.
4 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.
5 Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546-553.
6 Overgaard M, Hansen PS, Overgaard J, et al. Postoperative Radiothearpy in High-Risk Premenopausal Women with Breast Cancer who Receive Adjuvant Chemotherapy. N Engl J Med. 1997;337(14):949-955.
7 Ragaz J, Stewart MJ, Nhu L, et al. Adjuvant Radiotherapy and Chemotherapy in Node-Positive Premenopausal Women with Breast Cancer. N Engl J Med. 1997;337(14):956-962.
8 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.
9 Overgaard M, Jensen M-B, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999;353:1641-1648.
10 Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1992;339:1-15.
11 Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405-410.
12 Cummings SR, Norton L, Eckert S, et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in post-menopausal women. Two-year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial. Proceedings of American Society of Clinical Oncology 1998;17:Abstract #3.
13 Nabholtz J-M, Pienkowski T, Mackey J, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proceedings from the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract #141.
14 Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer: Results of the North American Breast Cancer Intergroup Trial E1199. Program and abstracts of the 28th Annual San Antonio Breast Cancer Symposium. 2005;Abstract #48.
15 Martin M, Pienkowski T, John Mackey, et al. Adjuvant Docetaxel for Node-Positive Breast Cancer. New England Journal of Medicine. 2005;352(22):2302-2313.
16 Jones S, Savin M, Holmes F, et al. Final analysis: TC (docetaxel/cyclophosphamide, 4 cycles) has a superior disease-free survival compared to standard AC (doxorubicin/cyclophosphamide) in 1016 women with early breast cancer. Proceedings from the 28th San Antonio Breast Cancer Symposium. December 2005;Abstract #40.
17 Citron ML, Berry DA, Cirrincione C, Hudis C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C9741/Cancer and Leukemia Group B trial 9741. Journal of Clinical Oncology. 2003;21:1431-9.
18 Schwartz GF, Hortobagyi GN and the Consensus Conference Committee. Proceedings of the Consensus Conference on Neoadjuvant Chemotherapy in Carcinoma of the Breast, Philadelphia PA. Cancer. 2004;100:2512-2532.
19 Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. Journal of Clinical Oncology. 1997;15:2483-2493.
20 Bear HD, Anderson S, Brown A, et al. The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Cyclophosphamide: Preliminary Results From National Surgical Adjuvant Breast And Bowel Project Protocol B-27. Journal of Clinical Oncology. 2003;21:4165-4174.
21 Pietras RJ, Fendly BM, Chazin VR, et al: Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene. 1994;9:1829-1838.
22 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. N Engl J Med 2001;344:783-792.
23 Romond E, Perez E, Bryant J, et al. Doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab as adjuvant therapy for patients with HER-2 positive operable breast cancer. Combined analysis of NSABP B13/NCCTG N931. Proceedings from the 41st annual meeting of the American Society of Clinical Oncology, Orlando FL. 2005; Late breaking abstract available at: http://www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-005817-00_21-001,00.asp.
24 Goss P, Ingle J, Martino S, et al. Updated analysis of the NCIC CTC MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. New Orleans LA. 2004; Abstract #847.
25 Goss, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. Proceedings from the 2003 San Antonio Breast Cancer Symposium. 2003.
26 Muss HB. Role of adjuvant endocrine therapy in early-stage breast cancer. Seminars in Oncology. 2001;28:313-321.
27 Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet. 1996;348: 1189-1196.
28 Fisher B, Redmond C, Legault-Poisson S, et al. Postoperative chemotherapy and Nolvadex® compared with Nolvadex® alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to Nolvadex®: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. Classic Papers and Current Comments. 1996;1:71-84.
29 International Breast Cancer Study Group. Effectiveness of adjuvant chemotherapy in combination with Nolvadex® for node-positive postmenopausal breast cancer patients. J Clin Oncol. 1997;15:1385-1394.
30 Fisher B, Dignam J, DeCillis A, et al. The worth of chemotherapy and Nolvadex® (TAM) over TAM alone in node-negative patients with estrogen-receptor (ER) positive invasive breast cancer (BC): first results from NSABP B-20. Proceedings of American Society of Clinical Oncology. 1997;16:Abstract #1.
31 Li CI, Malone KE, Weiss NS. Nolvadex® therapy for primary breast cancer and risk of contralateral breast cancer. Journal of the National Cancer Institute. 2001;13:963-965.
32 Baum M, on behalf of the ATAC Trialists’ Group. The ATAC (Arimidex, Nolvadex, alone or in combination) adjuvant breast cancer trial in post-menopausal women. 24th annual San Antonio Breast Cancer Symposium. 2001.
33 The ATAC (Arimidex, tamoxifen alone or in combination) trialists’ group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer. Cancer. 2003;98 (9):1802-1810.
34 Boccardo F, Rubagotti A, Amoroso D, et al. Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Proceedings from the 2003 San Antonio Breast Cancer Symposium, 2003;Abstract #3.
35 Goss P, Ingle J, Martino S, et al. Updated analysis of the NCIC CTC MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology “Best of oncology symposium”, New Orleans, LA. 2004; Abstract #847.
36 Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med. 1996;334:1356-1361.
37 Mouridsen H, Gershanovich M, Sun Y, et al. Phase III Study of Letrozole Versus Tamoxifen as First-Line Therapy of Advanced Breast Cancer in Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group. Journal of Clinical Oncology. 2003;21:2101-2109.
38 Bonneterre J, Buzdar A, Nabholtz J-M A, et al.: Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma: Results of two randomized trials designed for combined analysis. Cancer. 2001;92:2247-2258.
39 The ATAC (Arimidex, tamoxifen alone or in combination) trialists’ group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer. Cancer. 2003;98 (9):1802-1810.
40 Vicini F, Kestin L, Chen P, et al. Limited field radiation therapy in the management of early-stage breast cancer. Journal of the National Cancer Institute. 2003;95:1205-1211.
41 Bartelink H, Horiot J-C, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med. 2001;345:1378-1387.