Recurrent Breast Cancer
Recurrent breast cancer is cancer that progresses during treatment or recurs after a remission. Although breast cancer may recur almost anywhere in the body, common locations include the liver, bones, lungs, brain, and skin. Treatment for recurrent breast cancer depends on which treatments the patient has already received and where the cancer has recurred.
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. Most patients who experience a recurrence of their cancer have disease that has metastasized, or spread, throughout the body. These patients require systemic treatment that can reach the cancer anywhere in the body; this includes chemotherapy, hormonal therapy, or targeted therapy
The following is a general overview of treatment for recurrent 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 treating cancer physician.
Treatment of Local–Regional Recurrence of Breast Cancer
Following primary surgical treatment of breast cancer with mastectomy or breast-conserving surgery (lumpectomy plus radiation), patients may experience a local recurrence, which is defined as cancer recurring within the previously affected breast, chest wall, or skin over the breast. Patients may also experience a regional recurrence of cancer, which is defined as cancer involving the supraclavicular, internal mammary, or axillary lymph nodes.
Recurrence after mastectomy: Local recurrence of breast cancer following initial treatment with mastectomy may be effectively controlled with additional radiation treatment. Surgery prior to radiation therapy may also be beneficial in selected circumstances. Additional local recurrences may be preventable depending on the size of the cancer, the amount of radiation delivered, and the size of the radiation field (the amount of tissue irradiated).1
Despite effective local control with surgery and radiation, the majority of patients experiencing a local recurrence ultimately develop systemic recurrence of their cancer. For this reason, many doctors believe additional treatment with chemotherapy or hormonal therapy may be useful.
Recurrence after breast-conserving surgery: A recurrence following breast-conserving therapy that is limited to the local–regional area around the original cancer is typically treated with a mastectomy. With this approach, approximately 60-75% of patients are likely to survive five years or longer without another cancer recurrence. Mastectomy may be followed by radiation in some circumstances. Patients with regionally recurrent breast cancer are at a higher risk of a future systemic relapse2and may benefit most from the addition of radiation therapy or another treatment.
Systemic Therapy for Recurrent Breast Cancer
Targeted therapies are treatments that can selectively target cancer cells and minimize damage to normal, healthy cells. This means that side effects of targeted therapy are generally less severe. Targeted therapies can be easily combined with chemotherapy. Advances in science and technology have led to the development of several different types of targeted therapies.
Human Epidermal Growth Factor Receptor-2 (HER2): Twenty to thirty percent of breast cancers overexpress (make too much of) a protein known as HER2.3 Overexpression of this protein leads to increased growth of cancer cells. Fortunately, the development of treatments that specifically target HER2-positive cells has improved outcomes among women with HER2-positive breast cancer.
- Herceptin® (trastuzumab): Herceptin is an agent that recognizes and binds to HER2-positive cells. The effects of Herceptin are thought to include decreased cell growth and increased cell death.4 Among women with HER2-positive breast cancer, Herceptin in combination with chemotherapy has been shown to increase response rates and prolong survival compared to treatment with either Herceptin or chemotherapy alone.567 For women who have relapsed after prior chemotherapy for metastatic breast cancer, Herceptin can also be used alone. A study among women who had received extensive prior therapy for metastatic breast cancer reported that treatment with Herceptin alone resulted in a partial or complete disappearance of detectable cancer in 15% of the women.8
- Tykerb® (lapatinib): Tykerb targets HER2 as well as a related protein known as the epidermal growth factor receptor (EGFR). According to the results of a phase III clinical trial, the combination of Tykerb with the chemotherapy drug Xeloda® (capecitabine) resulted in a longer time to cancer progression than Xeloda alone among women with HER2-positive, refractory advanced or metastatic breast cancer.9 Tykerb is approved for use in combination with Xeloda for the treatment of HER2-positive advanced or metastatic breast cancer that has progressed following prior therapy with an anthracycline, a taxane, and Herceptin.
Avastin® (bevacizumab): Avastin, a new type of targeted therapy that inhibits the development of new blood vessels, utilizes a process called angiogenesis. Cancer cells require food, oxygen, and proteins in order to grow and spread. New blood vessels are necessary to deliver these essential components of cellular growth. Avastin produces its anti-angiogenic effects by binding to a protein called vascular endothelial growth factor (VEGF). VEGF causes endothelial cells (cells comprising the innermost layer of blood vessels) to replicate and migrate from existing blood vessels to the cancer. The binding of Avastin to VEGF reduces this activity.
Research indicates that the addition of Avastin to chemotherapy in the treatment of patients with advanced breast cancer produces more anti-cancer responses and longer cancer-free survival than chemotherapy alone (see table 1). This clinical trial included over 700 women with locally advanced or metastatic breast cancer who were in good physical condition and had no cancer spread to the nervous system (brain). The majority of the patients had HER2-negative disease. Patients received either Taxol plus Avastin or Taxol® alone.10
Table: Addition of Avastin to Taxol chemotherapy in the treatment of breast cancer
|Taxol plus Avastin||Taxol alone|
|Progression-free survival||10.9 months||6.11 months|
Chemotherapy for Recurrent Breast Cancer
Patients with recurrent cancer have typically already received chemotherapy as their initial treatment. The first chemotherapy treatment is called “first-line” and additional chemotherapy for cancer that has recurred is referred to as “second-line.” With the exception of instances where initial treatment may have been inadequate, second-line chemotherapy is typically associated with lower response rates and a shorter duration of remission than first-line therapy. Thus, the goal of second-line chemotherapy is to reduce symptoms, improve a patient’s quality of life, and possibly increase survival.
The type of second-line therapy that is selected and its effectiveness depends on which first-line chemotherapy the patient received. In particular, whether or not a patient’s previous treatment contained doxorubicin or a taxane helps determine options for second-line treatment. Patients typically develop resistance to drugs that were previously used to treat their cancer.
Patients previously treated with a taxane: Abraxane®, a new way to deliver paclitaxel, Gemzar® (gemcitabine), or the oral chemotherapy drug Xeloda® (capecitabine) are treatment options for patients who have already been treated with a taxane.
- Abraxane™ (nanoparticle albumin-bound paclitaxel): Abraxane employs a new technique for delivering the anti-cancer drug, paclitaxel. It utilizes albumin, the most abundant protein in the body, to deliver the paclitaxel directly to cancer cells. Albumin is a blood protein that is used by the body to transport nutrients and energy to tissues throughout the body. Once the albumin reaches the tissues of the body, it binds to receptors on the surface of the blood vessel and is taken into the tissues, where it delivers its cargo to the surrounding cells. In the case of Abraxane, that cargo is the anti-cancer drug, paclitaxel.
Results of a clinical trial indicate patients with breast cancer that has progressed with taxanes may respond to treatment with Abraxane. Among 75 patients with taxane-refractory disease, half experienced anti-cancer responses with Abraxane treatment. The cancer was stabilized, meaning it didn’t progress, in 40% of patients. While some patients experienced side effects of treatment, three-quarters were able to receive full doses of Abraxane. Severe loss of sensation in hands and feet occurred in 17% of patients, but this condition did not halt treatment for these patients; 77% were able to continue treatment with lower doses of Abraxane.11
- Gemzar® (gemcitabine): Clinical studies indicate that Gemzar is an active anti-cancer agent in the treatment of patients with recurrent breast cancer that has previously been treated with a taxane. In clinical trials that have evaluated Gemzar as a second-line treatment for breast cancer, approximately one-third of patients had an anti-cancer response. These patients survived an average of 12-18 months.1213
- Xeloda® (capecitabine): Xeloda 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.14
Patients not previously treated with a taxane: For patients not previously treated with docetaxel (Taxotere®) or paclitaxel (Taxol®), clinical studies suggest that treatment with one of these drugs, either as a single agent or in combination with other chemotherapy drugs, can reduce cancer symptoms and prolong a patient’s survival compared to other treatments.
Patients with anthracycline-resistant disease: Patients who have stopped responding to anthracyclines, a class of drugs that includes doxorubicin, are said to be anthracycline-resistant. Treatment options for these patients typically include a taxane alone or in combination with another chemotherapy drug.
- Abraxane: A clinical trial that directly compared Abraxane to Taxol in the treatment of 460 patients with metastatic breast cancer, more than three-quarters of whom had received prior therapy that included an anthracycline, demonstrated improved outcomes with Abraxane. Abraxane doubled anti-cancer response rates and significantly delayed disease progression with fewer side effects (see table 4).15 The group of patients who had received prior therapy experienced the greatest improvement, living 10 weeks longer than those treated with paclitaxel (56 weeks versus 46 weeks).16
Table: Abraxane improves outcomes and reduces risk of infection compared to Taxol
|Time to cancer progression||21.9 weeks||16.1 weeks|
|Grade 4 neutropenia(low white blood cell count)||7%||19%|
- Taxotere: Results from a large clinical trial indicate that Taxotere produces longer progression-free and overall survival, and more anti-cancer responses compared to Taxol in the treatment of recurrent breast cancer (see table).17
Table: Taxotere superior to Taxol in the treatment of recurrent breast cancer
|Progression-free survival||5.7 months||3.6 months|
|Overall survival||15.4 months||12.7 months|
Taxotere also appears to be as effective as 5-FU/Navelbine, while producing fewer side effects, in the treatment of patients with metastatic breast cancer whose cancer has progressed following anthracycline-based therapy. 18
- Taxotere/Paraplatin: Results of a clinical trial indicate that 61% of patients with anthracycline-resistant disease treated with Taxotere/Paraplatin responded to treatment, and 66% lived one year or more. On average, the cancer progressed 10 months after treatment.19
- Taxotere/Xeloda: Results of a clinical trial indicate that patients who received Taxotere plus Xeloda treatment had more anti-cancer responses, lived longer, and experienced a longer time before their cancer progressed compared to patients who were treated with Taxotere alone (see Table 2 ).20
Table: Taxotere plus Xeloda vs. Taxotere alone in the second-line treatment of advanced breast cancer
|Time to cancer progression||6.1 months||4.2 months|
|Average survival||14.5 months||11.5 months|
The results from this trial prompted the Food and Drug Administration (FDA) to approve the combination of Taxotere plus Xeloda for the treatment of metastatic breast cancer that has stopped responding to anthracyclines.
Patients not previously treated with doxorubicin: The chemotherapy drug doxorubicin is one of the most active chemotherapy agents used for the treatment of breast cancer—most patients receive it as part of their initial treatment for breast cancer. However, an individual can only receive a limited number of doxorubicin due to the risk of damage to the heart with increased exposure.21
Doxorubicin administered alone or in combination with a taxane may be an effective second-line treatment for patients not previously treated with this drug. Patients who have been previously treated with doxorubicin can receive additional doxorubicin treatment in selected circumstances, depending upon how much prior doxorubicin therapy was administered. Because doxorubicin is known to cause damage to the heart, patients may wish to have their heart function evaluated before electing to receive continued doxorubicin therapy.22
Patients resistant to anthracyclines, taxanes, and Xeloda:The chemotherapy drug Ixempra™ (ixabepilone) has been approved as a single agent for the treatment of metastatic or locally advanced breast cancer that is resistant to anthracyclines, taxanes, and Xeloda. Ixempra is also approved in combination with Xeloda for patients who are resistant to anthracyclines and taxanes, and for patients who are resistant to taxanes and cannot tolerate further anthracycline treatment.
Two clinical trials prompted the FDA approval of Ixempra.The first trial evaluated Ixempra as a single agent. This trial included 126 patients with advanced breast cancer who had stopped responding to treatment with an anthracycline, a taxane, and Xeloda. Patients who had HER2-positive cancer had received prior therapy with Herceptin® (trastuzumab) and had stopped responding. Anticancer responses with Ixempra occurred in 12% of patients.23
The second trial compared Ixempra plus Xeloda to Xeloda alone in 752 patients who had stopped responding to anthracyclines and taxanes.24 Treatment with Ixempra plus Xeloda significantly improved progression-free survival compared with Xeloda alone in this group of patients.
Hormonal Therapy for Recurrent Breast Cancer
The growth of some breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of hormonal therapy in the treatment for breast cancer.
Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.
Estrogen can also cause some cancers to grow. The breasts, uterus, and other female organs are composed of cells that are stimulated to grow when exposed to estrogen. These cells contain estrogen receptors. Estrogen circulating in the blood binds to these receptors and stimulates growth-related activities in the cell. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER-positive) cancers.
The growth of ER-positive breast cancer cells can be prevented or slowed by reducing their exposure to estrogen. This is the goal of hormonal therapy for breast cancer. 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.
Currently, many women with estrogen receptor-positive breast cancer are initially treated with tamoxifen, a hormonal therapy drug that acts by blocking estrogen receptors.
However, a newer group of drugs, called aromatase inhibitors, have more recently been developed and appear to be more active than tamoxifen in postmenopausal women.
Aromatase Inhibitors:Aromatase inhibitors block the conversion of androgens to estrogen, and reduce estrogen levels in postmenopausal women. Currently, three anti-aromatase drugs are approved for the treatment of postmenopausal women with breast cancer: Femara® (letrozole) Arimidex® (anastrozole), and Aromasin® (exemestane).25,26,27 Femara and Arimidex are nonsteroidal aromatase inhibitors that bind reversibly to aromatase. Aromasin is a steroidal aromatase inhibitor that binds permanently to aromatase.
Patients who have experienced a recurrence of breast cancer after initial treatment with hormonal therapy are said to have ‘hormone-resistant’ disease. Therapy for recurrent, hormone-resistant breast cancer may differ based on which treatment was previously administered. Research is ongoing to determine the optimal treatment for:
Premenopausal women who have previously received tamoxifen are likely to be treated with ovarian removal or suppression.28
For postmenopausal patients with metastatic breast cancer that has stopped responding to tamoxifen, several phase III clinical trials have indicated that aromatase inhibitors produce better results than another type of hormonal therapy known as megestrol acetate.29 The question of which aromatase inhibitor to use in this setting remains uncertain, however. Femara, Arimidex, and Aromasin are all approved for advanced postmenopausal breast cancer that has stopped responding to tamoxifen.
Femara and Arimidex were compared among postmenopausal women with advanced breast cancer that had progressed following tamoxifen.30 Approximately half of the patients had hormone receptor-positive breast cancer and the other half had unknown hormone receptor status. Overall, treatment response was higher in patients treated with Femara (19.1% response rate) than in patients treated with Arimidex (12.3% response rate). Survival was similar in the two treatment groups.
The antiestrogen drug Faslodex® (fulvestrant) has also been approved for the treatment of postmenopausal, estrogen receptor-positive metastatic breast cancer that has progressed following other anti-estrogen therapy. Faslodex has been reported to be at least as effective as the aromatase inhibitor Arimidex in this setting.3132
For patients with metastatic disease that has stopped responding to non-steroidal aromatase inhibitors such as Femara and Arimidex, switching to Aromasin or Faslodex has been shown to provide some benefit.
The effects of Aromasin and Faslodex in women who have stopped responding to treatment with a non-steroidal aromatase inhibitor were assessed in a Phase III clinical trial known as the EFFECT trial.33
The study included nearly 700 postmenopausal women with hormone receptor-positive, advanced breast cancer that worsened or recurred during or shortly after treatment with a non-steroidal aromatase inhibitor. Women were treated with either Aromasin or Faslodex.
- Time to cancer progression was 3.7 months in both treatment groups.
- A reduction in detectable cancer occurred in 6.7% of patients treated with Aromasin and 7.4% of patients treated with Faslodex.
- There were no significant differences between treatment groups in treatment safety or adverse treatment effects.
The researchers concluded that either Aromasin or Faslodex may be used in postmenopausal women with hormone-positive, advanced breast cancer who have received prior treatment with a non-steroidal aromatase inhibitor.
For more in-depth information, go to Hormonal Therapy for Breast Cancer
Managing Bone Metastases
Recurrent breast cancer often includes cancer that has spread to the bones, called metastases. Cancer can spread to the bones when individual cancer cells break off from the original tumor and travel in the circulatory or lymph system until they get lodged in a small vessel in a new area. The cell then grows into another tumor. Management of bone metastases may include a bisphosphonate drug.
Bisphosphonates: Bisphosphonates are a class of drugs that decrease the rate of bone destruction in patients with cancer. Clinical studies have 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.3435
In November 2003, the American Society of Clinical Oncology recommended the use of the bisphosphonates Zometa® (zoledronic acid) or Aredia® (pamidronate) for treatment of patients with bone metastasis from breast cancer. The optimal duration of use or the optimal time to administer bisphosphonates is still being evaluated in clinical trials. Researchers are hopeful that bisphosphonates may help to prevent some patients from developing bone metastasis if they are administered prior to bone spread.
For more in depth information, go to Bone Complications and Cancer.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies are evaluated with cancer patients. Clinical trials are studies that measure the effectiveness of new drugs or treatment strategies. Future progress in the treatment of recurrent 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 recurrent breast cancer include the following:
- Targeted Therapies in Development: EGFR Inhibitors
- Advances in Chemotherapy
- Photodynamic Therapy
- Phase I Clinical Trials
Targeted Therapies in Development: EGFR Inhibitors
Epidermal growth factor receptors (EGFR) are small proteins that are found on the surface of all cells. EGFR binds exclusively to small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote controlled cellular growth. However, in many cancer cells, EGFR is either abundantly overexpressed or the EGFR biological processes that normally stimulate cell growth are constantly active; this leads to the uncontrolled and excessive growth of the cancer cell. Several drugs that inhibit EGFR have been developed and are currently being evaluated in the treatment of breast cancer.
Tarceva® (erlotinib) is an EGFR inhibitor that is approved for the treatment of advanced non-small cell lung cancer and is being evaluated in the treatment of other cancers, including advanced breast cancer.
Advances in Chemotherapy
Camptosar® (irinotecan) may be an effective treatment option for breast cancer patients resistant to taxanes and/or anthracyclines. In a clinical trial, Camptosar® was administered to 102 patients with breast cancer that had spread to distant sites in the body. Some of the patients had received two or three previous chemotherapy regimens. Patients who had stopped responding to both taxanes and anthracyclines appeared to derive most benefit; 27% responded to treatment compared to 18% for patients who had stopped responding to only one of these types of drugs. The duration of anti-cancer response was four months, and 63% of patients lived six months or more.38
Phase I Clinical Trials
New cancer treatments continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate the new therapies in order to determine the best way to administer new therapies and whether the treatments have any anti-cancer activity in patients.
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21 Buzdar AU, Marcus C, Smith TL, et al. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 1985;55:2761.
22 FDA. FDA Oncology Tools Product Label Details in Conventional Order for Doxorubicin. https://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=doxorubicin. Accessed March 29,2002.
23 Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a Phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. Journal of Clinical Oncology.2007;25:3407-3414.
24 Vahdat LT, Thomas E, Li R, et al. Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer previously treated or resistant to an anthracycline and resistant to taxanes. Proceedings from the 2007 annual meeting of the American Society of Clinical Oncology. 2007;25:abstract 1006.
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29 Altundag K, Ibrahim NK. Aromatase Inhibitors and Breast Cancer: An Overview. The Oncologist. 2006;11:553-562.
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33 Gradishar W, Chia S, Piccart-Gebhart J, et al. Fulvestrant versus exemestane following prior non-steroidal aromatase inhibitor therapy: first results from EFECT, a randomized, Phase III trial in postmenopausal women with advanced breast cancer. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. Oral presentation December 15, 2006. Abstract #12.
34 Ross JR, Saunders Y, Edmonds PM, et al. Systematic Review of Role of Bisphosphonates on Skeletal Morbidity in Metastatic Cancer. British Medical Journal. 2003;327:469-471.
35 Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000; 88(5):1082-1090.
36 Albain K, Elledge R, Gradishar W, et al. Open-label phase II, multicenter trial of ZD1839 (Iressa) in patients with advanced breast cancer. Special Issue 25th Annual San Antonio Breast Cancer Symposium 2002;76:S33. Abstract #20.
37 Robertson J, Gutteridge E, Cheung K, et al. A phase II study of ZD1839 (Iressa) in tamoxifen-resistant ER-positive and endocrine-insensitive (ER-negative) breast cancer. Special Issue 25th Issue Annual San Antonio Breast Cancer Symposium. 2002;76:S96 Abstract #357.
38 Perez E, Willham D, Mailliard J, et al. Randomized phase II study of 2 schedules of irinotecan (CPT-11) for patients (pts) with refractory metastatic breast cancer (MBC): an NCCTG Cooperative Group study. Proceedings from the 38th Annual Meeting of the American Society of Clinical Oncology 2002;21:1. Abstract #206.
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