Stages of Breast Cancer

Stage I Breast Cancer

Overview

Patients diagnosed with Stage I invasive breast cancer have a single location of cancer less than 2 cm (3/4 inch) in size that has not spread to the axillary lymph nodes or sites distant from the breast. Although the majority of women with Stage I breast cancer are cured following treatment with surgery and radiation, some patients may benefit from additional treatment with chemotherapy and/or hormonal therapy. Treatment after surgery is called adjuvant therapy and it may further decrease the risk of cancer recurrence.

The following is a general overview of treatment for Stage I breast cancer. Treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

• Primary Treatment of Stage I Breast Cancer: Surgery and Radiation
  • Surgery
  • Radiation Therapy
• Adjuvant Therapy of Stage I Breast Cancer
  • Adjuvant chemotherapy
  • Adjuvant hormonal therapy
  • Adjuvant chemotherapy plus hormonal therapy
  • Targeted therapy – Herceptin^®
• The Era of Personalized Medicine
  • Genomic testing – Oncotype DX
• Strategies to Improve Treatment
  • Additional Approaches to Personalized Medicine
    • Pharmacogenomics – Who Benefits from Tamoxifen
  • New Chemotherapy Regimens
  • Neoadjuvant Therapy
  • Adjuvant Bisphosphonate Therapy
  • New Approaches to Radiation Therapy
  • Radiofrequency Ablation

Primary treatment of stage I breast cancer: surgery and radiation

The primary treatment of Stage I breast cancer typically consists of surgery with or without radiation therapy. Surgery and radiation are considered local therapies because they can prevent cancer recurrence in the affected breast and surrounding area, but cannot treat cancer that has already spread to other locations in the body. Systemic treatments, such as chemotherapy and hormonal therapy, can treat cancer that has spread throughout the body and may be administered as adjuvant treatment (after primary treatment) for Stage I breast cancer.

Surgery: Surgery for Stage I 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. The combination of lumpectomy and radiation 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

Mastectomy and breast-conserving therapy are the current standard of care for the local treatment of Stage I breast cancers and both are considered acceptable options. Furthermore, breast-conserving therapy and mastectomy have been shown to produce similar long-term survival.³

Surgery for early-stage breast cancer may also involve the evaluation of underarm (axillary) lymph nodes in order to determine whether cancer has spread outside the breast and establish the stage of the cancer. This is important to determine whether additional treatments beyond local therapies, such as chemotherapy, are required. 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 newer 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 only a small number of nodes (or even a single node), called the sentinel nodes, which are the first nodes to which cancer is likely to spread. 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(s). The nodes containing the dye are 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 lymph nodes in women with localized breast cancer.⁴

Research now indicates that sentinel node biopsy appears to be just as effective in determining cancer spread to axillary lymph nodes as an axillary lymph node dissection, and results in fewer side effects in patients with early-stage breast cancer.⁵

Radiation therapy: If a patient elects to have a mastectomy, radiation therapy is not typically administered; however, patients who undergo a lumpectomy typically receive radiation. Radiation therapy is usually administered using a machine that delivers a beam of radiation deep into the body where the cancer resides, a technique called external beam radiation therapy (EBRT). Radiation treatments are typically administered five days per week for five to six weeks.

Research indicates that radiation reduces the risk of a cancer recurrence in women ages 50 and older when administered after lumpectomy and hormone therapy. This trial included 636 women who were aged 50 years or older. All were treated with a lumpectomy plus the hormone therapy drug tamoxifen. Approximately half of the patients were also treated with radiation therapy to the breast, while the other half did not receive radiation therapy. Women aged 50 to 59 years appeared to benefit the most from the addition of radiation.

Adjuvant therapy

Adjuvant therapy is additional treatment administered after initial surgery and radiation therapy. The goal of adjuvant therapy is to eliminate any cancer that remains after surgery or radiation therapy, thereby reducing the risk of cancer recurrence.

Despite undergoing surgery and radiation, some patients already have small amounts of cancer that have spread outside the breast. These cancer cells are referred to as micrometastases and cannot be detected with any of the currently available tests. The presence of micrometastases causes breast cancer recurrence following local treatment with surgery and/or radiation therapy. An effective treatment is needed to cleanse the body of micrometastases in order to improve a patient’s duration of survival and potential for cure.

Adjuvant therapy for early-stage breast cancer may include chemotherapy, hormonal therapy, and/or biologic therapy. In 1990, the National Institutes of Health issued a statement indicating that all women with node-negative breast cancer have a risk of cancer recurrence and treatment with adjuvant chemotherapy and hormonal therapy should be considered on an individual basis following a discussion of the potential risks and benefits of treatment with their physician.

Clinical trials have demonstrated that treatment of early-stage breast cancer with adjuvant therapy reduces the risk of recurrence and improves survival.⁶,⁷,⁸ Patients that have been identified as having a poorer prognosis are most likely to benefit from adjuvant therapy and should work closely with their doctor to select their optimal adjuvant therapy. This section is a discussion of the potential benefits, as demonstrated in clinical trials, of the following types of adjuvant therapy:

Adjuvant Chemotherapy

Chemotherapy is any treatment involving the use of drugs to kill cancer cells and is a standard adjuvant therapy for 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.

A National Cancer Institute sponsored clinical trial initiated in 1981 illustrates the benefit of adjuvant chemotherapy treatment of women with node-negative breast cancer. In this study, 536 women with node negative breast cancer were treated with surgical mastectomy alone or with surgical mastectomy plus adjuvant chemotherapy. Ten years following treatment, 73% of women treated with mastectomy and adjuvant chemotherapy were alive without evidence of cancer recurrence, compared to only 58% of women treated with mastectomy alone. Chemotherapy reduced the risk of recurrence by 37% and the chance of dying from breast cancer by 34%.⁹

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 node-negative 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.¹⁰ Some clinical studies in women with more advanced breast cancer have suggested that including the chemotherapy drug doxorubicin in chemotherapy regimens may improve an individual’s outcome with breast cancer.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 use in node-negative breast cancer; however, these regimens are associated with more side effects than CMF.¹¹

The taxanes are a class of chemotherapy drug that have been shown to improve cancer-free survival of women with Stage II-III breast cancer and are typically combined with AC chemotherapy in the treatment of breast cancer.¹² They may also provide benefit in the adjuvant treatment of node-negative disease. Of the taxanes that are used in the treatment of breast cancer, Taxotere^® (docetaxel) appears to be more effective than Taxol^® (paclitaxel) in the treatment of patients with advanced breast cancer¹³ and is FDA-approved for the treatment of patients with locally advanced (Stage II and III) and metastatic (Stage IV) breast cancer.¹⁴

Adjuvant Hormonal Therapy

The objective of hormonal therapy is to reduce the amount of estrogen in a woman’s 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 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.

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 can lead to decreased bone density and heart disease.

Researchers associated with the National Surgical Adjuvant Breast and Bowel Projects (NSABP) have reported that adjuvant hormonal therapy appears to benefit women with ER-positive, node-negative breast cancer. Following the surgical removal of cancer, approximately half of the 2,892 patients involved in this study were treated with 5 years of the anti-estrogen drug tamoxifen and the other half of patients received placebo (inactive substitute). Results showed that, 15 years after treatment, women treated with hormonal therapy lived longer and experienced fewer cancer recurrences (see Table 1).¹⁵

Table 1: Adjuvant hormonal therapy vs. placebo in the treatment of ER-positive, node-negative breast cancer

 
Another benefit of adjuvant hormonal therapy is the potential for prevention of new cancers in the opposite breast. Research indicates that the use of hormonal therapy is associated with a reduction of breast cancer in the opposite breast in approximately half of patients with ER-positive and ER-unknown cancers.¹⁶ Women with ER-negative breast cancer should discuss with their physician the risks and benefits of hormonal therapy for prevention of a second breast cancer.¹⁷

Several newer hormonal therapies, called aromatase inhibitors, have proven to be superior to tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer.¹⁸,¹⁹ Aromatase inhibitors also appear to be associated with fewer side effects.²⁰

Adjuvant Chemotherapy plus Hormonal Therapy

Researchers with the National Surgical Adjuvant Breast and Bowel Project (NSABP) have reported that the combination of adjuvant chemotherapy and hormonal therapy appears to increase survival over adjuvant hormonal therapy alone and may be the optimal treatment for women with node-negative, ER-positive breast cancer.

In a clinical trial involving over 1,500 women with node-negative, ER-positive breast cancer, patients underwent surgical removal of the cancer and half of the patients then received 5 years of hormonal therapy and the other half received 5 years of hormonal therapy plus chemotherapy. More of the women who were treated with the combination of chemotherapy and hormonal therapy lived cancer-free for 12 years or more (see Table 2).

Table 2: Adjuvant hormonal therapy and chemotherapy in the treatment of women with node-negative ER-positive breast cancer

 
Women aged 49 years or younger derived the most benefit in terms of cancer-free and overall survival from the addition of chemotherapy, while women over the age of 60 did not achieve a benefit from the addition of chemotherapy. The study results also suggested that women with a lower degree of estrogen receptor expression benefited more from chemotherapy than those with higher receptor expression.²¹

Targeted Therapy

Herceptin^® (trastuzumab): Herceptin is a targeted therapy that binds to a protein known as HER2. Twenty to thirty percent of breast cancers overexpress (make too much of) HER2, and could potentially respond to treatment with Herceptin. Results from an important clinical trial indicate that adding Herceptin to chemotherapy improves survival for patients with advanced HER2-positive breast cancer.²² Herceptin has also been shown to improve survival among women with early-stage HER2-positive breast cancer that is node-positive or high-risk node-negative.²³ Among women with early-stage breast cancer, Herceptin is part of a treatment regimen that also includes chemotherapy.

The era of personalized medicine

An important advance in the treatment of cancer is the development of more individualized cancer therapy. Information provided by genomic tests or from analysis of other characteristics of cancer cells can often help guide the selection of treatments that have the best chance of success for a particular patient.

In the case of node-negative breast cancer, adjuvant hormonal therapy and/or chemotherapy has been shown to benefit many, but the extent of the benefit varies by the likelihood of cancer recurrence. Women with very small node-negative breast cancers, for example, have a low risk of recurrence and may not require adjuvant therapy to further reduce recurrence risk. In contrast, women with larger tumors – or other poor prognostic factors, such as high tumor grade – are more likely to benefit from adjuvant therapy.

Although factors such as tumor size can help guide decisions about the need for adjuvant therapy in women with node-negative breast cancer, researchers have been interested in developing more accurate approaches to the assessment of recurrence risk. One such approach involves genomic testing of tumor tissue. The expression, or activity, of certain genes has been linked with the likelihood of cancer recurrence; testing tumor tissue for the expression of these genes may provide important information about prognosis and likely response to treatment.

Oncotype DX is a test that measures the expression of 21 genes in a sample of early-stage breast cancer cells. The test is used to calculate a Recurrence Score^TM, which indicates the likelihood of cancer recurrence. Studies have reported that among women with node-negative, estrogen receptor-positive breast cancer treated with tamoxifen, the Recurrence Score^TM is a better predictor of recurrence than standard measures such as patient age, tumor size, and tumor grade.²⁴ The Recurrence Score was also linked with the response to chemotherapy among women with node-negative, hormone receptor-positive breast cancer,²⁵ and can help guide decisions about the need for chemotherapy.

Deciding whether adjuvant therapy is right for you: Before deciding to receive adjuvant treatment, patients should ensure they understand whether the benefits outweigh the risks for their particular cancer and circumstances. Understanding the answers to 3 questions will help determine if adjuvant therapy is a viable option:

1. What is my prognosis (risk of cancer recurrence) without adjuvant treatment?
2. How will my prognosis be improved with adjuvant treatment?
3. What are the risks of adjuvant treatment?

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 I 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 I breast cancer include the following:

• Additional Approaches to Personalized Medicine
  • Pharmacogenomics – Who Benefits from Tamoxifen?
• New Chemotherapy Regimens
• Neoadjuvant Chemotherapy
• Adjuvant Bisphosphonate Therapy
• New Approaches to Radiation Therapy
  • Brachytherapy
  • Radiation “boost” therapy
  • Hypofractionation
• Radiofrequency Ablation

Additional Approaches to Personalized Medicine

Pharmacogenomics: Pharmacogenomics refers to the study of how inherited genetic variation influences drug response. As this field progresses, it is likely to lead to more individualized cancer therapy. For example, a gene known as CYP2D6 plays a role in tamoxifen metabolism (the processing of tamoxifen by the body). Most people have two functional versions of this gene and are able to effectively process tamoxifen. Some people, however, have versions of this gene that are less effective at processing tamoxifen. Testing patients for these gene variants could eventually help doctors identify patients who are less likely to respond to tamoxifen.²⁶

New Chemotherapy Regimens

Several new chemotherapy drugs show promising activity for the treatment of breast cancer. Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies for use as adjuvant treatment is an active area of clinical research. Research is ongoing to evaluate the incorporation of the chemotherapy drugs Taxotere^® and Taxol^® into the adjuvant treatment of high-risk breast cancer.²⁷,²⁸,²⁹

Neoadjuvant Chemotherapy

Neoadjuvant therapy is treatment administered before surgery. The purpose of neoadjuvant chemotherapy is to treat the cancer immediately and shrink the tumor in order to increase the likelihood that the cancer may be completely removed with surgery. Patients with large Stage I breast cancer may benefit most from neoadjuvant chemotherapy.
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 plus adjuvant Taxotere^®. This trial involved over 2,000 women who were randomly assigned to three different groups and treated with one of the following:

• AC (doxorubicin plus cyclophosphamide) before surgery
• AC (doxorubicin plus cyclophosphamide) plus Taxotere^® before surgery
• AC (doxorubicin plus cyclophosphamide) before surgery plus Taxotere^® after surgery

Approximately 91% of the patients treated with neoadjuvant chemotherapy including Taxotere^® had an anti-cancer response, compared to 85% of patients in the other two groups.³⁰ A later report from this same study, however, indicated that the addition of Taxotere did not improve overall survival .³¹

Adjuvant Bisphosphonate Therapy

Bisphosphonates are a class of drugs that inhibit bone resorption. They are used to treat osteoporosis, as well as hypercalcemia (high levels of calcium in the blood) and bone metastases in patients with cancer.

Recent research suggests that the bisphosphonate drug Zometa^® (zoledronic acid) may also have a role in improving outcomes among women with early-stage breast cancer.³² A phase III clinical trial by the Austrian Breast Cancer Study Group enrolled 1,803 premenopausal women with Stages I-II, hormone receptor-positive breast cancer. Following surgery, all patients were treated with hormonal therapy; this consisted of Zoladex^® (goserelin) for ovarian suppression, plus tamoxifen or Arimidex^® (anastrozole). In addition to hormonal therapy, some patients were also treated with Zometa.

Compared with hormonal therapy alone, the combination of hormonal therapy and Zometa reduced the risk of cancer recurrence by 35%. The researchers concluded that the addition of Zometa to hormone therapy among premenopausal women with hormone receptor-positive breast cancer may improve recurrence-free survival.

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 less with brachytherapy (several days) than with 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.³³

MammoSite radiation therapy system is a type of brachytherapy and utilizes a device consisting of a hollow tube (catheter) with an inflatable balloon attached. The device is implanted in the breast near the site of the lumpectomy. Radiation is passed through the catheter and into the balloon, focusing the radiation in the area where a cancer recurrence is most likely. Typically, the procedure is repeated over several days. Upon completion, the catheter and balloon are removed. The MammoSite device was FDA-approved in mid-2002 for the treatment of women with early-stage breast cancer. However, the FDA warns that the safety and effectiveness of MammoSite has not been compared to whole breast irradiation.³⁴

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 would reduce the rates of local recurrences, especially in younger patients.³⁵

To evaluate the benefits and side effects of boost radiation, researchers affiliated with the European Organisation for Research and Treatment of Cancer (EORTC) conducted a study among 5,318 women with early breast cancer.³⁶ After breast-conserving surgery, all patients received 50 Gy of radiation to the entire breast. Half the patients also received a 16 Gy radiation boost to the area of the cancer. The remaining patients received no further radiation therapy.

• Ten-year survival was 82% in both study groups (the group that received boost radiation and the group that did not receive boost radiation).
• The ten-year risk of cancer recurrence within the breast was 6.2% in patients who received boost radiation and 10.2% in patients who did not receive boost radiation.
• Young women (those under the age of 40) experienced the greatest reduction in recurrence risk following boost radiation.
• Severe fibrosis occurred in 4.4% of patients treated with boost radiation, compared with only 1.6% of patients who did not receive boost radiation.

The researchers concluded that the addition of boost radiation reduced the risk of cancer recurrence within the breast, particularly in younger patients, but did not improve 10-year survival.

Hypofractionation: The current approach to radiation therapy involves several consecutive weeks of daily treatment. For many women, particularly those who have to travel long distances to reach a radiation therapy facility, this can interfere greatly with work and other activities of daily life.

A possible alternative approach is hypofractionated radiation therapy. Hypofractionation involves fewer radiation treatments with a higher dose of radiation at each treatment. Hypofractionated radiation therapy was compared to conventional radiation therapy in two clinical trials conducted in the U.K.³⁷ Women treated with hypofractionated radiation therapy received a total radiation dose of 39 to 41.6 Gy administered over 13 to 15 visits. Women treated with conventional radiation therapy received a total radiation dose of 50 Gy administered over 25 visits. Risk of cancer recurrence was low with both approaches, and there was a suggestion that hypofractionation may result in better breast appearance. The long-term effects of hypofractionation remain unknown, however.

Radiofrequency Ablation

Radiofrequency ablation (RFA) involves the use of high-energy radio waves that can be administered through the skin using a probe that is about the size of a needle. During RFA, a physician uses an imaging technique to visualize the cancer, such as an ultrasound or a computerized tomography (CT) scan. The physician then guides the probe to the correct spot(s) in the breast to deliver the high-energy radio waves that heat and ultimately destroy the cancer cells. The radio waves can also be delivered into the cancer during a surgical procedure. Researchers have been investigating RFA in liver cancer and have now extended the investigation of this technique to small breast cancers.

Researchers from Italy and the MD Anderson Cancer Center have conducted two clinical trials evaluating RFA in patients with early-stage breast cancer and have found the technique to be safe and effective.

The first trial involved 26 patients with either Stage I or II breast cancer that was 1.8 centimeters in diameter or smaller³⁸ and the second trial included 20 patients with breast cancer that was 2 centimeters or smaller in diameter.³⁹ RFA was performed for 15 minutes to destroy the breast cancer, then patients immediately underwent surgery to remove the treated tissue in order to determine whether all cancer cells had been destroyed. The cancer was completely destroyed in 45 of the 46 patients involved in both studies. Only a microscopic amount of cancer cells were left in one patient involved in the first trial and only one patient had any complications from RFA: a burn of the skin directly over the cancer site.

Researchers have initiated a clinical trial in Europe further evaluating RFA in early-stage breast cancer patients. However, long-term outcomes will be necessary to truly determine the efficacy of RFA compared to standard treatment.

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35 Bartelink H, Horiot J-C, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. New England Journal of Medicine. 2001;345:1378-1387.

36 Bartelink H, Horiot J, Poortmans P, et al. Impact of radiation dose on local control, fibrosis and survival after breast conserving treatment: 10-year results of the EORTC trial 22881-10882. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. Oral presentation December 14, 2006. Abstract #10.

37 Dewar JA, Haviland JS, Agrawal RK et al. Hypofractionation for early breast cancer: First results of the UK standardization of breast radiotherapy (START) trials. Proceedings of the 43^rd Annual Meeting of the American Society of Clinical Oncology. Chicago, IL. June 1-5, 2007. Abstract #LBA518.

38 Izzo F, Thomas R, Delrio P, et al. Radiofrequency ablation in patients with primary breast carcinoma: A pilot study in 26 patients. Cancer. 2001;92:2036-2044.

39 Bruno F, Sneige N, Ross M, et al. Small ( 2-cm) Breast Cancer Treated with US-guided Radiofrequency Ablation: Feasibility Study 1. Radiology. 2004; 231:215-224.

Stage II Breast Cancer

Overview

Patients diagnosed with stage II breast cancer have a primary cancer that either involves axillary lymph nodes and is less than five centimeters (two inches) in size, or is greater than two centimeters (3/4 inch) in size and does not involve any axillary lymph nodes. Stage II breast cancers are curable with current multi-modality treatment consisting of surgery, chemotherapy, radiation therapy and hormonal therapy.

Effective treatment of stage II 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, targeted therapy, or hormonal therapy. Systemic therapy is often administered as adjuvant therapy, which means treatment after surgery.

The following is a general overview of treatment for stage II 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
• Systemic Therapy
  • Chemotherapy
  • Targeted Therapy
  • Hormonal Therapy
• 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: Surgery for stage II 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

Mastectomy and breast-conserving therapy are the current standard of care for the local treatment of stage II breast cancers and both are considered acceptable options. Furthermore, breast conserving therapy and mastectomy have been shown to produce identical long-term survival. ³

Surgery for early stage breast cancer may also involve the evaluation of axillary (underarm) lymph nodes in order to determine whether cancer has spread outside the breast and establish the stage of the cancer. This is important to determine whether additional treatments beyond local therapies, such as chemotherapy, are required. 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

Researcher now indicates that sentinel node biopsy appears to be just as effective in determining cancer spread to axillary lymph nodes as an axillary lymph node dissection and results in fewer side effects in patients with early stage breast cancer. ⁵

Systemic therapy: chemotherapy, targeted therapy, and hormonal therapy

Systemic therapy is treatment directed at destroying cancer cells throughout the body. Some patients with stage II 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 are referred to as micrometastases and cannot be detected with any of the currently available tests. 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.

Historically, systemic therapy is administered after surgery and was referred to as adjuvant therapy. Clinical trials have shown that adjuvant chemotherapy for the treatment of stage II breast cancer improves a patient’s chance of survival and decreases the risk of cancer recurrence compared to local therapy alone. ⁶

Examples of systemic therapy include:

• Chemotherapy
• Targeted Therapy
• Hormonal Therapy

Chemotherapy

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.

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 six cycles over a period of approximately four to six months. ⁷

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. ⁸ 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. ⁹ Taxotere^® (docetaxel) appears to be more effective than paclitaxel in the treatment of patients with advanced breast cancer. ¹⁰ The taxanes are typically combined with AC chemotherapy.

TAC: According to results of a clinical trial that presented at the 2003 San Antonio Breast Cancer Symposium, patients treated with TAC (Taxotere, doxorubicin, cyclophosphamide) 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 1 ). ¹¹

Table 1
Taxotere-containing chemotherapy (TAC) improves survival over standard regimen (FAC)

 
In 2004, the U.S. Food and Drug Administration (FDA) approved Taxotere for the treatment of early stage breast cancer. ¹²

Dose-dense chemotherapy: AC, TAC, CMF, and other chemotherapy regimens are typically administered every three weeks. Dose-dense chemotherapy refers to chemotherapy treatment that is administered more frequently. Dose-dense treatment is given every two weeks rather than at the conventional three-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 three weeks (conventional treatment) or every two weeks (dose-dense). Four years after treatment, 82% of patients treated with dose-dense therapy were disease-free, compared to 75% of those treated with conventional chemotherapy. ¹³

Targeted therapy

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. ¹⁴

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. ¹⁵ 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 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. ¹⁶

Hormonal therapy

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:

• Tamoxifen
• Anti-aromatase drugs

Furthermore, there is some evidence that patients who have been treated with tamoxifen for two to five years may benefit from switching to an anti-aromatase drug . ¹⁷, ¹⁸

Tamoxifen for Early Stage Breast Cancer

The results of several clinical studies indicate that hormonal treatment with tamoxifen, either alone ¹⁹ or in combination with chemotherapy ²⁰, ²¹, ²², ²³ 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. ²⁴

It is currently recommended that tamoxifen be administered 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 two and a half 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. ²⁵

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. ²⁶

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 400 postmenopausal women with ER-positive breast cancer who had already been treated with tamoxifen for at least two years. Patients either continued with tamoxifen for up to five years or switched to Arimidex for a comparable amount of time. ²⁷ 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 five years. Research is ongoing to determine if patients can benefit from more than five years of hormonal therapy.

Femara has been shown to provide a reduced risk of death and cancer recurrence when used after five years of tamoxifen. Over 5,000 postmenopausal women who had completed five 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). Women treated with Femara had an 18% reduced risk of death and a 40% reduced risk of cancer recurrence compared to those who received placebo. Women with cancer that had spread to the lymph nodes (node-positive) experienced an even greater benefit from Femara, with a 39% reduced risk of death compared to 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. ²⁸

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. ²⁹

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 II 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 II breast cancer include the following:

• Neoadjuvant Chemotherapy
• New Hormonal Therapy Drugs
• New Approaches to Radiation Therapy

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. ³⁰ The committee’s guidelines are determined by an extensive review of clinical studies that evaluated neoadjuvant chemotherapy in different stages of breast cancer.

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 plus adjuvant Taxotere. This trial involved over 2,000 women who were randomly assigned to receive one of the following treatments:

• AC (doxorubicin plus cyclophosphamide) before surgery
• AC plus Taxotere before surgery
• AC before surgery 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. ³¹

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. ³², ³³ The anti-aromatase drugs also appear to be associated with fewer side effects. ³⁴

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 Therapy

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. ³⁵

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. ³⁶

References

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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.

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27 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. December 2003. Abstract #3.

28 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).

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31 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.

32 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.

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36 Bartelink H, Horiot J-C, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. New England Journal of Medicine. 2001;345:1378-1387.

Stage III Breast Cancer

Overview

Stage III breast cancer is characterized by one of the following:

1. 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
2. A primary cancer that is greater than 5 cm (2 inches) in size and involves axillary lymph nodes
3. 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

Systemic Therapy

• Chemotherapy
• Targeted Therapy
• Hormonal Therapy

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

 
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

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:

• Chemotherapy
• 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

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

Targeted therapy

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

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:

• Tamoxifen
• 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
  • Brachytherapy
  • 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

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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.

Treatment of Stage IV – Metastatic Breast Cancer

When breast cancer spreads away from the breast to the bones, lungs, liver, brain, skin, or other organs it is said to be metastatic. The treatment goals for metastatic breast cancer are to prolong the duration and quality of life. Some women with metastatic disease have their cancer controlled with newer treatments for 10-20 years. Treatment for metastatic breast cancer depends on prior treatment, hormonal and menopausal status, location of the recurrence, and whether a precision medicine can be used.

Researchers continue to make great strides in treating breast cancer and in making cancer treatment more tolerable, both physically and emotionally. The greatest recent advances and focus of ongoing research are in Precision Cancer Medicines and Immunotherapy Standard chemotherapy typically destroys both normal and cancerous rapidly dividing cells in a wide range of tissues, often causing side effects by damaging normal cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.

Breast cancers that are confined to the breast or area immediately surrounding the breast, are called local-regional recurrences, and are typically treated with surgery with or without radiation therapy. Most patients who experience a recurrence of breast cancer however have disease that has metastasized or spread to other locations in the body. These patients require systemic treatment that can reach the cancer anywhere in the body. Systemic therapy may consist of chemotherapy, hormonal therapy, precision cancer medicines or immunotherapy used alone or in combination.¹,² In general treatment for metastatic breast cancer falls into the following groups.

• Hormone Receptor Positive Cancers
• HER2 Positive Cancers and Other "Targetable Mutations"
• Triple Negative Breast Cancer
• Bone Metastases

Treatment of hormone receptor positive cancer

Endocrine or “hormone” therapy is usually the first treatment for hormone receptor positive metastatic breast cancer and chemotherapy is reserved for the treatment of cancers that no longer respond to endocrine therapy, hormone receptor negative cancers, or individuals requiring immediate shrinkage of the 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 contain estrogen receptors and 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 some breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of endocrine therapy.

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, aromatase inhibitors, and most recently cyclin-dependent kinase inhibitors (CDK).

Treatment for hormone receptor positive breast cancer

Recommendations set forth by a convening Expert Panel specifically for women with HR-positive, metastatic breast cancer included the following.¹⁰ A combination of a CDK4/6 inhibitor and endocrine therapy is currently the first choice because the addition of CDK 4/6 inhibitors to endocrine therapy is associated with improved survival and maintained or improved quality of life compared to other endocrine therapies.³,⁴,⁵,⁶,⁷,⁸,⁹

• Patients whose cancer cells express any level of HR-positivity should be offered endocrine therapy as initial therapy.
• Sequential endocrine therapy (using one endocrine agent until the patient’s cancer progresses, then switching to a different endocrine agent until the cancer progresses again, etc.) is the preferred treatment of choice.
• Among postmenopausal women, aromatase inhibitors (AIs) are the initial treatment of choice, with or without the addition of the CDK inhibitor.¹¹,¹²,¹³,¹⁴ For example a CDK inhibitor combined with an AI demonstrated a greater than 28-month median progression-free survival as initial endocrine-based therapy for metastatic disease compared to 14.8 months for treatment with an AI alone.
• If the cancer starts to progress on AIs, Faslodex^® (fulvestrant) or combination therapy with a CDK inhibitor and an AI can further prolong survival. The CDK inhibitor Ibrance (palbociclib) when combined with Faslodex nearly doubles the duration of survival when compared to an AI alone.¹²
• Among premenopausal women, ovarian suppression or ablation should be included in the treatment strategy. The CDK inhibitor Kisqali in combination with tamoxifen or an AI plus goserelin improve time of survival without cancer progression to 23.8 months compared to 13 months for tamoxifen or an AI plus goserelin.¹⁵

Precision cancer medicines

Not all breast cancer cells are alike. They may differ from one another based on what genes have mutations. Through genomic-biomarker testing performed on a biopsy of the cancer or from a blood sample doctors are increasingly able to define the genomic alterations in a cancers DNA that is driving the growth of a specific cancer. Once a genetic abnormality is identified, a precision medicine can be designed to target a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.

Laboratory evaluation for targetable mutations can be performed on tissue and in the blood and is evolving rapidly. It is not uncommon to get different test results from different laboratories so patients should consider having their testing reviewed and perhaps repeated by a breast cancer expert with expertise in NGS testing for breast cancer.

HER2 Positive Cancers – Twenty to thirty percent of breast cancers over express (make too much of) a protein known as HER2. Over expression of this protein leads to increased growth of cancer cells. There are several precision medicines that specifically target HER2-positive cells, and these have significantly improved outcomes among women with HER2-positive breast cancers. Optimal sequencing of these medications is increasingly complicated and new anti-HER2 therapies continue to become available leading to improved outcomes. Currently the NCCN recommends the following treatments.

• Herceptin^® (trastuzumab) recognizes and binds to HER2-positive cells and was the first precision medicine developed for the treatment of breast cancer. Among women with HER2-positive breast cancer, Herceptin is often used in combination with Perjeta as the initial treatment for metastatic disease.¹⁶,¹⁷,¹⁸,¹⁹,²⁰
• Perjeta (perjeta) targets a different part of the HER2 protein than Herceptin. Since the two drugs target different regions of HER2, they are believed to work in a way that is complementary to each other. In a comparative clinical study called the CLEOPATRA trial, the combination of Herceptin and Perjeta plus chemotherapy improved survival compared to treatment with Herceptin alone and this combination is often the initial therapy for metastatic disease.²⁹,³⁰

If cancer returns after initial treatment, there are several additional medications available that specifically target HER2 and others being evaluated in clinical trials. The presence of cancer spread to the brain is a key determinant in subsequent therapy and patients should discuss whether a MRI of the brain is necessary – 15% of patients will have asymptomatic brain metastases.

• Tukysa (tucatinib) is a highly selective oral tyrosine kinase inhibitor that targets HER2 and appears to have the best activity against brain metastases. The HER2CLIMB clinical trial demonstrated that Tukysa added to Herceptin and Xeloda reduced the risk of disease progression and improved survival, even in women with brain metastases. The Tukysa regimen is well tolerated and associated with minimal hair loss.²⁶,²⁷,²⁸
• Kadcyla (ado-trastuzumab emtansine, formerly known as T-DM1) is an antibody-drug conjugate that combines Herceptin and a chemotherapy drug (DM1) that interferes with cancer cell growth. Kadcyla delivers Herceptin and DM1 directly to HER2-positive cells, and limits exposure of the rest of the body to the chemotherapy. Kadcyla has been demonstrated to delay cancer progression and prolong survival compared to Tykerb plus Xeloda (capecitabine) and Herceptin plus docetaxel in women with recurrent metastatic, HER2-over expressed breast cancer. Kadcyla has also been evaluated as the initial treatment for metastatic HER2 + breast cancer and found to produce similar outcomes as Herceptin plus taxane or T-DM1 plus Perjeta.²¹,²²,²³,²⁴,²⁵ Kadcyla may cause interstitial lung disease and patients should discuss the potential complication with their physician.
• Neratinib targets several other HER2 proteins in addition to HER2 and can often be helpful when resistance to HER2 targeted therapies occurs.
• Tykerb (lapatinib) also targets HER2 as well as a related protein known as the epidermal growth factor receptor (EGFR).¹⁹,²⁰

BRCA Mutations – About 3% of breast cancers are in people who inherited BRCA mutations. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. Mutations in the BRCA gene raise the risk of cancer because they make the body less likely to repair damage to its DNA, making the mutations that lead to cancer more likely. Poly ADP-ribose polymerase (PARP) inhibitors block enzymes involved in repairing damaged DNA. By disrupting a cancer cells’ ability to repair itself PARP inhibitors slow uncontrolled growth and replication of cancer cells.³¹,³² There are several PARP inhibitors in development.

• Lynparza (olaparib) is the first PARP inhibitor approved for use in breast cancer. Lynparza was demonstrated to be superior to chemotherapy for treatment of HER2-negative advanced breast cancer patients who have a BRCA mutation.³¹
  • Women with BRCA positive breast cancers have hereditary breast cancers and related individuals may be at increased risk of breast cancer and should be evaluated.

Hormone Receptor–Negative Breast Cancer

The treatment for hormone receptor–negative breast cancer consists of systemic therapy with chemotherapy and/or immunotherapy. 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 also benefit from treatment with chemotherapy.

There are currently several standard chemotherapy drugs and treatment regimens available, and approximately 25% of patients who undergo chemotherapy will experience a complete remission of their cancer. Patients should discuss their goals of treatment with their physician and consider participation in a clinical study as their initial treatment.

• Taxanes 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 non-taxane chemotherapy for the treatment of metastatic breast cancer.
• 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. With Abraxane 50% more drug can be administered, more active drug is transported into the cancer cells, and patients experience fewer side effects.³³
• Xeloda (capecitabine) is a well-tolerated, oral chemotherapy drug that can be taken at home for treatment of breast cancer. Research indicates that 20-30% of patients experience a measurable shrinkage of their cancer following treatment with Xeloda. Xeloda is well-tolerated, and the average duration of survival of patients treated with Xeloda is almost 13 months.

Triple negative breast cancer (TNBC)

Approximately 12-15% of all breast cancers are triple negative, meaning that they are estrogen and progesterone-receptor negative, and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones, estrogen or progesterone, nor through an overactive HER2 pathway.

• Trodelvy (sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate comprised of an antibody that attaches to specific receptors called Trop-2 receptors and delivers an attached drug that kills cancer cells, called SN-38. By targeting Trop-2 receptors, larger amounts of chemotherapy can be delivered to the cancer cells because healthy cells are largely spared from the cancer-killing effects of the treatment. Trodelv was approved by the U.S. FDA for the treatment of patients with TNBC on April 5th, 2020.³⁹

Immunotherapy

Checkpoint Inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 receptor these drugs restore an immune cells’ ability to recognize and fight the breast cancer cells. A diagnostic test to measure the level of PD-L1 is available.

• Tecentriq (atezolizumb) The combination of Tecentriq and Abraxane improved average survival duration from 15.5 months among patients with PD-L1–positive tumors to 25 months leading to accelerated FDA approval in 2020.³⁴,³⁵,³⁶
• Keytruda (pembroluzumab) Patients were treated with Keytruda plus chemotherapy or chemotherapy alone and directly compared. In patients with the highest CPS of 10 or greater the addition of Keytruda to chemotherapy significantly prolonged survival without cancer progression.³⁸

Managing bone metastases

Recurrent breast cancer often includes cancer that has spread to the bones, 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 RANK ligand inhibitor or a bisphosphonate drug, and the use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.³⁹,⁴⁰,⁴¹,⁴²

• XGEVA (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from breast cancer.³⁹,⁴⁰
• Bisphosphonates are a class of drugs that decrease the rate of bone destruction in patients with cancer. Clinical studies have shown that bisphosphonate therapy can prevent or delay bone destruction, including fractures and related pain, in women with breast cancer that has spread to the bone.⁴¹,⁴²
• Strontium89 is a radionuclide therapy that is used to alleviate pain caused by bone metastases. Strontium89 delivers radiation directly to the boney cancerous sites and has been shown to provide pain relief from bone with a single injection.⁴³

Treatment of locally recurrent breast cancer

Recurrent breast cancers that are confined to the breast or area immediately surrounding the breast, called local-regional recurrences, are typically treated with surgery with or without radiation therapy.⁴⁶,⁴⁷

Surgery may be indicated for certain situations

For example, patients may need surgery if the following issues occur:

• Fungating/painful breast lesions (mastectomy).
• Brain or vertebral metastases with spinal cord compression.
• Isolated lung metastases.
• Pathologic (or impending) fractures.
• Pleural or pericardial effusions.

Radiation therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications for external-beam radiation therapy include the following:

• Painful bony metastases.
• Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
• Bronchial obstruction.
• Fungating/painful breast or chest wall lesions.
• After surgery for decompression of intracranial or spinal cord metastases.
• After fixation of pathologic fractures.

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