INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Every year, approximately 205,000 American women are diagnosed with breast cancer and more than 40,000 die from this disease. Early detection and treatment can improve survival by removing the breast tumor before it has a chance to spread (metastasize).
Despite early diagnosis and treatment, breast cancer can reappear at a later time (termed a recurrence or a relapse). Recurrence can occur even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. The vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor. However, 1 to 5 percent of women newly diagnosed with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapies, or some combination of these options. These treatments rarely lead to long-term survival without disease recurrence (termed relapse-free survival), although they can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life.
The choice of treatment for metastatic breast cancer depends upon many individual factors, including specific features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to the various types of therapy, treatment-related side effects, and a woman's personal preferences. Each woman should carefully discuss the many available treatment options to determine which is the best choice for her.
GENERAL TREATMENT PRINCIPLES — Some general principles of treating metastatic breast cancer can help a woman to understand the options that are available and the goals of therapy.
Confirming the diagnosis — It is important to confirm that a suspicious finding or symptom is indeed metastatic breast cancer, because other conditions may produce signs and symptoms that mimic those of breast cancer.
Metastatic breast cancer is usually confirmed by a biopsy (collection of a small sample of tissue or a body fluid for laboratory evaluation). If the biopsy reveals breast cancer, the laboratory evaluation can also help identify alterations in the cancer that may have occurred over time. These changes can impact treatment. Furthermore, the sample may also be tested for the presence of a protein called HER2, which can indicate a higher chance of responding to a specific "targeted" treatment called Herceptin (see "Herceptin (Trastuzumab)" below).
Goals of treatment — For many cancers, cure is the expected goal of treatment, particularly if the cancer is diagnosed at an early stage. However, cure is an unlikely outcome for women with metastatic breast cancer; as a result, other goals are of greater importance. These include relief of symptoms, improved QOL, longer survival, and a longer progression-free or relapse-free survival.
Cure — Breast cancer is considered cured when there is no remaining evidence of the cancer (called a remission) for a defined period of time, and a woman is able to live out a normal life span. However, it is difficult to define the period of time that must pass before a woman is considered cured of breast cancer because this disease can recur many years after initial diagnosis and treatment. For women with early breast cancer, a recurrence is most likely within the first five years after treatment, but can still occur up to 30 years later.
Cure is possible, but it is very uncommon in women with metastatic breast cancer. A few women in whom treatment leads to a complete remission may be long-term survivors. However, further tumor progression is prevented for prolonged periods (five to ten years) in only 2 to 5 percent of cases [1].
Prolonged survival — Despite the disappointing cure rate, treatment prolongs survival in women with metastatic breast cancer. The average survival duration for women treated for metastatic breast cancer has improved over the last 20 years [2,3], and is approximately 24 months, although the range extends from a few months to many years. Survival tends to be slightly longer (by months rather than years) for women whose cancers respond to treatment, compared to those who do not respond (nonresponders).
Improved QOL — Treatment can improve QOL in women with metastatic breast cancer by minimizing symptoms that are caused by the cancer. Studies suggest that chemotherapy effectively improves QOL despite its associated side effects.
Response rates — The response rate for a given treatment is a measure of that treatment's effectiveness. It refers to the proportion of women receiving a specific form of treatment who have a measurable decrease in the amount of breast cancer, either by physical examination or x-ray studies (eg, computed tomography (CT) scan or chest x-ray). Generally, the response to treatment is considered to be an objective, measurable indication of benefit from therapy. It is a commonly used endpoint in many clinical trials to assess the activity of new treatments.
Oncologists classify responses to therapy into four categories: Complete response — no further evidence of the tumor can be detected Partial response — more than 50 percent decrease in the amount of measurable breast cancer Minor response — less than 50 percent decrease in the amount of breast cancer Stable disease — no measurable decrease in the amount of tumor, but no increase in tumor size during treatment.
Sometimes, treatments that do not objectively decrease the amount of breast cancer can stabilize tumor growth; in other words, the tumor persists, but does not progress. Women with stable disease in response to a specific treatment tend to survive longer than women whose breast cancer grows despite treatment (called progressive disease), particularly if tumor size is stable for at least six months.
Clinical benefit — Although response rates in published studies usually include only the patients who have a complete or partial response to a specific therapy, patients with minor responses and stable disease also benefit from therapy, albeit to a lesser degree (see above). More recently, several clinical trials have designated a new term, "clinical benefit" to encompass complete and partial responders as well as those with minor responses and stable disease.
Both the response rate and the clinical benefit rate give an estimate of the likelihood of a woman benefiting from a specific therapy. As an example, if a treatment has a response rate of 60 percent, 60 of every 100 treated women can expect to have a measurable decrease (50 percent or greater decrease) in the amount of breast cancer, as long as treatment is administered on time and in the appropriate doses. Whenever possible, the treatment of metastatic breast cancer is aimed at achieving the highest possible response or clinical benefit rate with the least possible toxicity. When this is achieved, quality of life should be improved.
Disease progression — Even if there is a good response to initial therapy, metastatic breast cancer eventually becomes resistant to treatment and continues to grow despite therapy. This is called progressive disease, and indicates the need to switch to a different therapy. Since there are many different treatments available, it is not uncommon for women with metastatic breast cancer to receive many different therapies.
CHOOSING THE BEST TREATMENT OPTION — Multiple factors are considered when choosing among treatment options, including prognostic factors, response rates, the priorities of treatment, and the balance between the relative benefits and risks (side effects) of each therapy. An important factor is whether a woman's breast cancer makes hormone receptors (indicating that the tumor may be responsive to hormone treatments) or the protein HER2, which indicates that the targeted therapy Herceptin may be beneficial.
Several of the factors that are taken into account when selecting among the many treatment options are discussed in detail below.
Prognostic factors — As noted above, the range of survival for women with metastatic breast cancer ranges from several months to several years. Certain factors can help to determine the likely course of metastatic breast cancer over time (the prognosis). Relapse-free interval — The relapse-free interval refers to the time from initial diagnosis to the first disease recurrence. The prognosis of metastatic breast cancer is usually better when several five years have elapsed between the initial treatment and recurrence. Number of metastatic sites — Tests can help identify the number of locations affected by metastases. Women with metastases involving fewer sites usually have a better prognosis than those with many sites. Vital (visceral) organ involvement — The prognosis of metastatic breast cancer is usually better when metastases are located in the chest wall, lymph nodes, or bones rather than in organs such as the liver or lung. Hormone receptor status — Laboratory tests can determine if the breast cancer cells have hormone receptors such as estrogen receptors (ERs) or progesterone receptors (PRs). Besides indicating which tumors are likely to respond to hormone treatments, the presence of hormone receptors on breast cancer cells is also associated with a better prognosis. HER2 — Some breast cancers express high levels of a protein called HER2. Although controversial, overexpression of HER2 may be associated with a worse prognosis. More importantly, overexpression of this protein is a powerful predictor of a response to the targeted agent Herceptin (trastuzumab), which allows the physician to select those women who stand to benefit from this drug. (See "Herceptin (Trastuzumab)" below).
Predictive factors — Other factors, called predictive factors, can help predict the likelihood that breast cancer will respond to a specific type of therapy.
Hormone therapy — As noted above, the presence of hormone receptors indicates that a breast cancer may respond to hormone treatment. Hormone therapy is often recommended as the initial treatment for women with ER or PR-positive metastatic breast cancer, because it typically has fewer associated side effects than does chemotherapy. (See "Patient information: Endocrine therapy for metastatic breast cancer").
If there is a reasonable doubt that hormone therapy will be effective, then chemotherapy is often recommended as the initial systemic treatment. Several factors decrease the chances of responding to hormone therapy: A short interval between initial treatment and recurrence The presence of metastases in visceral organs like the lung or liver; women who have isolated metastases in bones or soft tissues such as lymph nodes or skin are more likely to respond to hormone therapy. A lower number of ER receptors. Between 50 and 60 percent of breast cancers with high or moderate numbers of ERs respond to hormone therapy, compared with only 10 percent of breast cancers with few ERs The absence of PR receptors
Chemotherapy — Unlike hormone therapy, there are no well-defined factors that predict whether a breast cancer will respond to chemotherapy. Chemotherapy rather than hormone therapy is chosen when a tumor lacks both ERs and PRs. Among women with metastatic breast cancer who have not previously received chemotherapy for metastatic breast cancer, between 50 and 75 percent of women will respond to the initial course of chemotherapy. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Chemotherapy may also be recommended as the initial therapy (even in women with hormone receptor-positive tumors) when the breast cancer is progressing rapidly, when metastases are present in vital organs, when a woman has many cancer-related symptoms, or when a rapid response to therapy is needed (eg, if the cancer is close to or pushing against the spinal cord). In vitro drug assays — There are laboratory tests of the sensitivity or resistance of tumor cells to chemotherapy drugs, called in vitro drug assays. In these tests, breast cancer cells, which are obtained by biopsy, are combined with a chemotherapy drug (in a laboratory, not in the patient) to determine if the drug could be of benefit.
While these tests are accurate in predicting "extreme drug resistance" (ie, if the cancer is very resistant to a certain chemotherapy drug in the laboratory, it is not likely to be effective in the patient), they do not accurately predict response (ie, if the tumor cells in the laboratory are killed by the drug, this does not always indicate whether the tumor in the patient will respond to that drug). Thus, use of these assays is controversial. Chemotherapy plus hormone therapy — Although simultaneous treatment with chemotherapy and hormone therapy improves the likelihood that hormone receptor-positive metastatic breast cancer will respond to therapy, no studies have shown that such combination therapy improves survival [4]. Furthermore, combined therapy is more likely to cause additional side effects than either treatment alone; these side effects can reduce a woman's QOL.
For these reasons, women with hormone-receptor-positive breast cancer are usually treated sequentially, with hormone therapy first, followed by chemotherapy when the patient becomes refractory to hormone treatment. Occasionally, if a patient has extensive visceral organ involvement, it is appropriate to induce a remission with chemotherapy first, and then follow this therapy with less toxic hormone therapy.
Herceptin (Trastuzumab) — As noted above, whether a breast cancer produces high levels of HER2 is a powerful predictor of benefit from treatment with Herceptin (trastuzumab). At present, Herceptin use is restricted to individuals whose tumors are strongly HER2-positive. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Herceptin alone is a reasonable choice for women with minimal symptoms and no rapidly progressing disease involving the internal organs (eg, liver, lungs). However, symptomatic women or those with internal organ involvement are often offered Herceptin in combination with a chemotherapy drug such as paclitaxel; there is evidence that both drugs work better together than either one taken alone.
Local versus systemic therapy — The treatments described above are all systemic (or bodywide) therapy; the drug is distributed throughout the body, and the benefit may be seen in metastases, no matter where they are located. In most cases, the treatments are administered into the vein, although most hormone therapies and some chemotherapy drugs (eg, Xeloda [capecitabine]) are given by mouth.
In contrast to systemic therapy, local therapy refers to surgery and/or radiation therapy that is directed specifically at areas affected by breast cancer. Such therapy benefits only the site at which the treatment is directed, and areas of disease elsewhere in the body are not affected.
Women with a breast cancer recurrence that is limited to the breast or chest wall are the most appropriate candidates for local therapy. However, surgery or radiation may also be considered for selected women with metastatic disease. In general, areas of metastatic breast cancer respond better to local rather than systemic therapies, but several factors must be taken into account when considering the need for local therapy. These include how widespread the cancer is, the location of the metastases, and the urgency of treating disease at that specific site.
As an example, if a bone metastasis is threatening a bone that is important for weight bearing, (eg, the thigh bone), surgery may be the best option to prevent a fracture. In these situations, local therapy (surgery followed by radiation) is generally accompanied by, or followed by systemic therapy.
BISPHOSPHONATE THERAPY — In addition to systemic therapy with either chemotherapy or hormone therapy, women who have breast cancer metastases to bone also benefit from therapy with bone-strengthening drugs called bisphosphonates. When combined with systemic therapy, monthly injections of a bisphosphonate (eg, pamidronate or zoledronic acid) can reduce the likelihood of complications from the bone metastases, such as bone fractures. For women with metastatic breast cancer and pain due to bone metastasis, intravenous bisphosphonate may also be of benefit to relieve pain when used in conjunction with systemic chemotherapy or hormone therapy.
MONITORING DURING THERAPY — Regular monitoring is essential for women who are receiving therapy for metastatic breast cancer. This monitoring determines the effectiveness of therapy and aids in monitoring for side effects.
Medical history and physical examination — A periodic medical history and physical examination are useful for monitoring symptoms, treatment-related side effects, and the response to treatment of any obvious signs of breast cancer, such as nodules beneath the skin. However, in 50 percent of women with metastatic breast cancer, a medical history and physical examination do not provide helpful information about the response of the cancer to treatment.
Imaging tests — Imaging tests, including x-rays, CT scans, magnetic resonance imaging scans (MRIs), bone scans, and sometimes PET scans are useful for viewing changes in the location and size of breast cancer metastases. Selected tests are often performed periodically during treatment to assess the response to therapy.
Bone scans are imaging tests that help determine if bone metastases are present, and if they are responding to treatment or progressing. However, the amount of tumor involvement on a bone scan is difficult to measure or quantitate. Thus, bone scans are not as useful as x-rays, CT scans, or MRI studies to characterize the treatment response.
Tumor markers — In women who do not have detectable outward signs of metastatic breast cancer, blood levels of tumor markers (such as CA15-3 and/or carcinoembryonic antigen [CEA]) may be used to measure the cancer's response to treatment. Blood levels of these tumor markers correlate with the course (ie, the clinical behavior) of breast cancer in 60 to 70 percent of women with metastatic breast cancer. However, treatment decisions are rarely, if ever made on the basis of a tumor marker alone, and their use is currently reserved for women with no areas of disease that can be followed to assess the response to treatment.
Circulating tumor cells — Another blood test that may be used to monitor the response to a specific treatment in women with metastatic breast cancer is an assay (the CellSearch assay) that determines the number of breast cancer cells circulating in the blood (termed circulating tumor cells). Although some studies suggest that the persistence of a larger number of tumor cells in the blood after a new treatment is started predicts that the treatment may not be effective [5], it is unknown whether changing the treatment in response to a large number of circulating tumor cells results in a better outcome. Trials are underway to answer this question. Until then, many oncologists restrict the use of the CellSearch assay to patients who lack measurable disease (eg, those with bone-only metastases), in whom the time of disease progression is particularly difficult to determine.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Greenberg, PA, Hortobagyi, GN, Smith, TL, et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14:2197.
2. Gennari, A, Conte, P, Rosso, R, et al. Survival of metastatic breast carcinoma patients over a 20-year period. Cancer 2005; 104:1742.
3. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
4. Fossati, R, Confalonieri, C, Torri, V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16:3439.
5. Cristofanilli, M, Budd, GT, Ellis, MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351:781.
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