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 (a recurrence), 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. Although the vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor, 1 to 5 percent of women with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer is usually not a curable condition. However, systemic (bodywide) treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life (QOL). Options for systemic treatment in women with metastatic breast cancer include chemotherapy, hormone therapy, and targeted agents such as Herceptin (trastuzumab).
This topic review will discuss the use of chemotherapy and Herceptin in advanced and metastatic breast cancer. General principles that guide the treatment of metastatic breast cancer and the use of hormone therapy in this situation are presented elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
General principles of treatment — As noted above, the goals of systemic treatment for metastatic breast cancer include symptom control, improved quality of life, and prolonged survival rather than cure. To quantify these benefits, oncologists use certain endpoints to measure a treatment's effectiveness. These include: Response rate — The proportion of persons who have a measurable (50 percent or more) decrease in the amount of cancer Clinical benefit rate — The proportion of patients who have measurable as well as partial or stable responses to treatment Disease progression time — The duration of time that a certain therapy is effective before an alternate treatment is required Survival — Despite the importance of response rate, clinical benefit, and disease progression, the gold standard for deciding whether one therapy is better than another is the impact the treatment has on survival. Even if one treatment has a higher response rate than another, it does not follow that survival is also better.
This is a particularly important concept when considering the sequential use of single drugs versus combination chemotherapy regimens for treatment of metastatic breast cancer. Combinations of drugs typically have a higher response rate than a drug given individually, but also have more side effects; survival benefits are modest, at best. It is possible that similar outcomes may be obtained by giving the individual drugs of the combination regimen one at a time (sequentially), rather than all at the same time (concurrently). This is a controversial area in the treatment of metastatic breast cancer, and is discussed in more detail below.
More detailed explanation about the issues surrounding assessment of treatment benefit is provided elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer").
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These cytotoxic (toxic to cells) drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.
Most chemotherapy drugs are given into the vein (IV) rather than by mouth; one exception is the drug Xeloda (capecitabine), which is given by mouth. Chemotherapy is usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines.
Many different cytotoxic drugs are effective in the treatment of metastatic breast cancer. The most commonly used include: cyclophosphamide (C), methotrexate (M), doxorubicin (often abbreviated A for its brand name Adriamycin®), epirubicin (Ellence®), 5-fluorouracil (abbreviated 5-FU, or F), capecitabine (Xeloda®), paclitaxel (Taxol®), docetaxel (Taxotere®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®).
Combination versus sequential single agent therapy — Specific combinations of these individual drugs (called regimens) have been developed to improve the likelihood of successfully shrinking tumors. As noted above, one of the most pressing and unanswered questions in chemotherapy treatment of metastatic breast cancer is whether similar outcomes can be achieved, with less toxicity, by the sequential use of active single agents, rather than combination regimens. (See "Selecting optimal therapy" below).
Many oncologists consider single-drug chemotherapy a reasonable treatment option, especially for women who have received several different types of chemotherapy for breast cancer. On the other hand, because combination therapy is often associated with a higher response rate, it may be chosen over single agent therapy if the breast cancer is growing rapidly, causing severe symptoms, or if vital organs (eg, liver, lungs) are involved in the tumor.
In the following sections, we will review the most active agents and drug combinations.
Anthracyclines and related drugs — The anthracyclines and related drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), and mitoxantrone (Novantrone®). When used alone, these drugs have a response rate of 35 to 40 percent. Doxil® is a special form of doxorubicin in which the drug is contained or encapsulated within a fat-containing substance called liposomes. This allows the drug to remain in the body for a longer period of time and may reduce the likelihood of side effects involving the heart.
Anthracyclines are often used in combination with other drugs. Common combinations include AC (doxorubicin plus cyclophosphamide), FAC or CAF (cyclophosphamide plus doxorubicin and 5-FU) and CEF (cyclophosphamide plus epirubicin and 5-FU). A good response to these combinations occurs in 20 to 60 percent of women with metastatic breast cancer who have not been previously treated for advanced disease. Side effects — The possible side effects of anthracyclines include nausea, vomiting, hair loss, and temporary loss of bone marrow function. Bone marrow suppression can lead to infections (which can occur with a low white blood cell count), anemia (which can cause fatigue and low energy) and bleeding (which can occur if the platelet count is very low).
The anthracyclines and related drugs can also damage the heart muscle and cause heart failure. Several measures can reduce the likelihood of this side effect, including limiting the total or cumulative dose of these drugs, administering them gradually (over 6 to 96 hours) or in more frequent smaller doses, simultaneously administering drugs that protect the heart muscle, or by using the liposome-encapsulated form of doxorubicin, Doxil®.
Taxanes — As a group, the taxanes (paclitaxel [Taxol®] and docetaxel [Taxotere®]) are some of the most active drugs available for the treatment of advanced breast cancer. Drugs of this class are often the first drugs chosen to treat breast cancers that do not respond to hormone therapy and those that have responded poorly to other chemotherapy drugs such as anthracyclines.
Paclitaxel (and less commonly docetaxel) can cause serious hypersensitivity (allergic) reactions in some women. Because of this, premedication with steroids and antihistamines is generally recommended prior to each treatment. A newer formulation of paclitaxel is available (Abraxane®) which is associated with significantly fewer allergic reactions. Pretreatment is not necessary, but the drug is quite a bit more expensive than conventional paclitaxel.
More frequent administration of these drugs (ie, weekly rather than every three week treatment) allows a higher total dose of chemotherapy drugs to be given, and also appears to lower the likelihood of some side effects, such as bone marrow suppression, or muscle and joint aches, but not others.
Paclitaxel — Paclitaxel may be given once every three weeks or in lower doses once per week. It produces a response in 35 to 55 percent of women with metastatic breast cancer who have not been previously treated with doxorubicin, and in about 20 percent of women whose breast cancers are resistant to doxorubicin. Side effects — Hair loss is a common side effect of paclitaxel; nausea and vomiting are less common. About 5 to 15 percent of women experience muscle and joint pain after paclitaxel treatment; the symptoms typically begin 24 to 72 hours after treatment and last two to four days. This side effect can be minimized with steroid premedication, and seems to be less common when paclitaxel is administered weekly.
Paclitaxel can also suppress the bone marrow function, temporarily lowering the blood counts. It may be possible to reduce the effects of paclitaxel on the bone marrow and nerves by using more frequent, smaller doses.
It can cause a type of nerve damage that affects the fingers and toes. This is called peripheral neuropathy, and is severe in only 10 to 15 percent of women. However, the effects are cumulative (ie, it is more common and more severe as more drug is given). Paclitaxel may be inappropriate for some women with poor liver function.
Abraxane — Abraxane® is a unique formulation of paclitaxel whose main benefit is that it causes significantly fewer allergic reactions. In addition, at least one study suggests that Abraxane may be associated with a moderately higher response rate and duration of benefit compared to paclitaxel, but it may also cause more neurologic toxicity, and is also significantly more expensive than paclitaxel. As a result, there is controversy as to whether Abraxane® should replace standard paclitaxel for the treatment of metastatic breast cancer.
Docetaxel — Like paclitaxel, docetaxel may be given once every three weeks or in lower doses once per week. Docetaxel has a response rate of 35 to 60 percent in women with metastatic breast cancer, including women with advanced disease who have been previously treated with many other types of chemotherapy. In addition, up to 25 percent of breast cancers that are resistant to paclitaxel respond to docetaxel. Side effects — Docetaxel occasionally causes nausea and vomiting and often causes hair loss. Like paclitaxel, docetaxel can also temporarily suppress bone marrow function and may cause peripheral neuropathy, which may or may not be reversible. Docetaxel may cause fluid retention, which can be prevented if steroids are given prior to docetaxel.
It is possible to reduce the side effects of docetaxel by using more frequent, smaller doses (ie, weekly therapy). However, weekly therapy is more often associated with excess tear production in the eyes and nail changes.
Taxane combinations — Paclitaxel or docetaxel may be used in combination with other chemotherapy drugs. Adding a taxane to other chemotherapy drugs increases the likelihood of response, but also increases the chance of serious side effects. Furthermore, as noted above, the increase in response rate with combination therapy has translated into only minor improvements in survival compared to sequential administration of active single agents [1-3]. As an example, in a single study, women receiving both gemcitabine plus paclitaxel had a higher response rate (41 versus 22 percent) and a slightly longer (two month) survival compared to those receiving paclitaxel alone [1]. Although the side effects were more pronounced in women receiving both gemcitabine and paclitaxel, they were not particularly severe in either group.
Although combinations of paclitaxel and doxorubicin have been associated with very high response rates, they also cause higher than expected rates of heart damage in many but not all [3] studies. While combination of docetaxel and doxorubicin do not appear to increase the risk for heart problems, they have been associated with life-threatening bone marrow suppression and associated infection.
It is not clear that the added toxicities of anthracycline/taxane combinations are justified by a greater therapeutic benefit, or that anthracycline/taxane combinations provide clear benefit over sequential administration of each agent alone [3]. A pooled analysis of seven trials comparing anthracycline/taxane regimens versus other combinations of an anthracycline/cyclophosphamide with or without 5-FU for first-line therapy came to the following conclusions [4]: Use of a taxane/anthracycline combination significantly increased the response rate, and doubled the chance of a complete response Taxane-based regimens were associated with a borderline improvement in time to tumor progression, but survival was not improved Patients treated with a taxane/anthracycline regimen were nearly three times more likely to require hospitalization for fever in the setting of low blood counts
Alkylating drugs — Cyclophosphamide is the alkylating drug most commonly used to treat metastatic breast cancer, usually in combination regimens, as described above. Side effects — Treatment with alkylating drugs carries a slight risk of bladder inflammation and blood in the urine, but this risk can be minimized by drinking plenty of fluids and urinating frequently during treatment. Cyclophosphamide is also associated with an approximately three-fold increased risk of leukemia at a later time, and a loss of fertility, particularly in women over the age of 30 at the time of treatment.
Antimetabolites — The antimetabolites methotrexate and 5-FU are generally used in combination regimens such as CMF (cyclophosphamide, methotrexate, and 5-FU). 5-FU may also be combined with the drug leucovorin. Both of these drugs may be used together in the triple combination NFL (mitoxantrone, 5-FU, and leucovorin).
An oral (tablet form) derivative of 5-FU with activity against breast cancer is available (Xeloda® [capecitabine]). When used alone for the treatment of patients with breast cancer that has progressed in spite of multiple prior therapies, about 20 percent of women have a response, including those whose breast cancers have responded poorly to intravenous 5-FU. Side effects — 5-FU and related drugs are less likely than many other chemotherapy drugs to cause hair loss or suppress bone marrow function. Furthermore, fewer than 10 percent of women experience nausea and vomiting when treated with these drugs. However, 5-FU and related drugs can cause other gastrointestinal symptoms, including diarrhea and inflammation of the mouth (mucositis). The dose of Xeloda may be reduced if a temporary side effect called hand-foot syndrome develops. This causes the skin of the palms and soles of the feet become red and sore, sometimes with peeling.
Gemcitabine — Gemcitabine (Gemzar®) has a low frequency of side effects such as nausea, vomiting, hair loss, and temporary suppression of bone marrow function. It is more often used,in combination with paclitaxel (see above), for treatment of metastatic breast cancer in patients whose disease has progressed while receiving anthracycline-containing regimens.
Vinca drugs — Vinorelbine (Navelbine®) is the most widely used vinca-type drug for advanced breast cancer. Weekly administration results in a response in over 50 percent of women. Side effects — All of these agents can cause damage to the nervous system, which may cause a feeling of numbness and tingling in the fingers and toes (called peripheral neuropathy). This typically develops after several courses of therapy, and is usually reversible when treatment is stopped. Vinorelbine is less likely than vincristine to cause peripheral neuropathy, and the likelihood of bone marrow suppression is low. Occasionally, vinca alkaloids can cause sudden, severe pain around the tumor that begins during or immediately after the drug is administered, and lasts several minutes to hours.
Summary — Among the many chemotherapy drugs available for treatment of metastatic breast cancer, the most active are the anthracyclines and taxanes. Taxanes are often used first in women with metastatic breast cancer whose cancers are unlikely to respond to hormone therapy, and for breast cancers that have recurred after other types of chemotherapy. An anthracycline combination may be used for women who have not previously received anthracycline or those who have had a recurrence more than 12 months since anthracyclines were used. Xeloda, Navelbine, and Gemzar are good second or third-line options, or they may be used as a first line treatment in combination with a taxane.
Due to the small survival difference and more favorable side effect profile, therapy with serial single agents is a reasonable alternative to combination regimens, especially in the second, third, or fourth-line treatment setting (show figure 1). On the other hand, for symptomatic patients or those with rapidly progressive vital organ metastases, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response.
HERCEPTIN — Herceptin (trastuzumab) is an antibody (a type of protein) that specifically targets HER2/neu, a protein present on the cells of some breast cancers. About 30 percent of breast cancers express very high levels of HER2/neu, and Herceptin appears to be effective only in this group of women. The level of HER2/neu within a tumor is determined using a special stain on a microscopic slide containing a sample of the tumor.
Herceptin inhibits the growth of breast cancer cells when given alone or in combination with other chemotherapy drugs. For women with metastatic breast cancer whose breast cancers have not responded to conventional cytotoxic chemotherapy drugs, Herceptin used alone has a response rate of 15 percent.
Herceptin plus other chemotherapy drugs — Adding Herceptin to treatment with other chemotherapy drugs may improve the effectiveness of treatment [5]. Herceptin plus anthracyclines — The use of Herceptin plus an anthracycline-containing drug has been found to cause serious side effects affecting the heart. Thus, despite their high level of activity, combinations of Herceptin and doxorubicin are avoided. Herceptin plus taxanes — The combination of Herceptin plus a taxane may be associated with less toxicity than Herceptin plus an anthracycline, and a better outcome when compared to paclitaxel alone. In one research study, women with breast cancers that produced high levels of the HER2/neu marker and that were resistant to doxorubicin were treated with either paclitaxel alone or paclitaxel plus Herceptin [6]. The women treated with combination therapy had a higher response rate (57 versus 25 percent), a longer time until the cancer progressed, and they also survived for four months longer. Herceptin plus other drugs — High response rates have been reported with combinations of Herceptin plus other cytotoxic drugs such as cisplatin, and vinorelbine, even in women who have used several prior therapies [7]. These combinations may be considered in women with HER2/neu-producing metastatic breast cancer who have failed Herceptin alone or in combination with a taxane.
Side effects — Herceptin occasionally causes a hypersensitivity or allergic reaction, which can be severe. Rarely, severe lung damage can occur. Heart damage develops in about 3 to 5 percent of women treated with Herceptin alone or with paclitaxel; the risk is higher in women who receive Herceptin with an anthracycline drug. Because of this, Herceptin is NOT given with an anthracycline-type drug. When given alone, Herceptin does not cause bone marrow suppression, nausea, vomiting, or hair loss.
Summary — Herceptin alone is a reasonable treatment option for women whose metastatic breast cancers make have high levels of HER2/neu, and that have become resistant to standard hormone therapy and chemotherapy drugs. The combination of Herceptin with paclitaxel is also a reasonable choice.
Herceptin resistance — Lapatinib is an oral medication that targets HER2 in a different way than Herceptin. It can be effective for women whose disease is resistant to Herceptin. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin. It is not yet approved as an initial treatment for women with HER2-positive advanced breast cancer.
AVASTIN (BEVACIZUMAB) — Avastin® (bevacizumab) is an antibody that targets a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the process by which a growing cancer develops its own blood supply, which is essential in order for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.
Early data suggest that selected patients with metastatic breast cancer may benefit from the use of bevacizumab. In one study, bevacizumab was combined with paclitaxel and compared to paclitaxel alone as initial chemotherapy for metastatic breast cancer [8]. Combined therapy was associated with a higher response rate (28 versus 14 percent), and a longer time to progression of the breast cancer; however, the study has not yet determined the impact on survival [8]. Potentially serious side effects with bevacizumab included high blood pressure, bleeding, and loss of protein in the urine.
At present, bevacizumab is not approved for treatment of metastatic breast cancer in the United States; it is only approved for patients with advanced colorectal cancer. Nevertheless, using bevacizumab plus paclitaxel could be considered for a woman who had not received chemotherapy for metastatic breast cancer, and who does not have clotting or bleeding problems, kidney problems, recent surgery, or spread of cancer to the brain (brain metastases). It is not yet known whether the modestly better outcomes from this approach justify the more serious side effect profile and greater expense.
CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of chemotherapy for women with metastatic breast cancer is unknown. Several studies have compared the effectiveness of continuous chemotherapy until it becomes ineffective versus intermittent chemotherapy (approximately six cycles or courses of chemotherapy followed by a discontinuation of chemotherapy until progression of the cancer). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor progression may be delayed a little while longer in women treated with continuous therapy.
Because of the periods of time where chemotherapy is not being given, intermittent chemotherapy may also be associated with a better quality of life. Intermittent chemotherapy may therefore be a reasonable option for women whose cancer-related symptoms are relieved with this therapy.
BONE MARROW TRANSPLANTATION — The improved outcomes with higher as compared to lower doses of chemotherapy drugs raise the possibility that outcomes can be further improved by administering very high doses of chemotherapy. Such doses not only kill more cancer cells, but also destroy young blood cells (stem cells) in the circulating blood and bone marrow. This requires that new stem cells be provided or transplanted into the patient in order to restore the production of blood cells. This entire procedure is referred to as high dose chemotherapy with stem cell transplantation (commonly called a bone marrow transplant). (See "Patient information: Overview of bone marrow transplantation").
Although some women with metastatic breast cancer and few sites of tumor involvement have been offered a bone marrow transplant in the past, this approach has fallen out of favor since studies suggest that it does not provide any benefit over the currently recommended standard dose treatment regimens that do not require stem cell support [1,9]. Because of this, and the substantially greater toxicity of high-dose chemotherapy, this approach should not be considered standard for any women with metastatic breast cancer.
SELECTING OPTIMAL THERAPY
Hormone receptor status — Because hormone therapy generally causes fewer side effects than chemotherapy or biologic therapy, it is usually chosen as initial treatment for women with hormone receptor-positive metastatic breast cancer.
Chemotherapy is initially recommended if the cancer is ER-negative, and in some circumstances for ER-positive tumors. Women with ER-positive breast cancer are most likely to be treated with chemotherapy initially if: The breast cancer is progressing rapidly Metastases are present in vital organs There are many cancer-related symptoms
Chemotherapy is also an appropriate option for treatment of ER-positive breast cancers when hormone therapy is no longer effective.
HER2/neu-negative — Options for initial chemotherapy depend on whether a woman's breast cancer makes the protein HER2/neu. Several options are available for initial treatment in women with HER2/neu-negative metastatic breast cancer: Combination therapy with an anthracycline-containing regimen such as AC (doxorubicin plus cyclophosphamide), FAC (5-FU plus doxorubicin and cyclophosphamide), or FEC (5-FU plus epirubicin and cyclophosphamide) Single agent treatment with an anthracycline or a taxane The combination of a taxane plus either capecitabine or gemcitabine The combination of paclitaxel plus bevacizumab
All of these options have a 30 to 60 percent likelihood of response and relief of cancer-related symptoms. However, questions remain as to whether any of these regimens have a significant survival benefit over another. If there is a survival benefit from combination therapy, it is probably modest (between two and five months); this has been seen with the combinations of paclitaxel plus either gemcitabine or bevacizumab (compared to paclitaxel alone), and docetaxel plus capecitabine (compared to docetaxel alone) [2,3,5].
The decision regarding which regimen to choose, and whether to choose single agent or combination chemotherapy is complex, and depends upon a number of different factors, including what treatments have been used and the length of time since the last treatment. For women considering paclitaxel plus bevacizumab, a history of bleeding problems, blood clots, kidney problems, recent surgery, or poorly controlled high blood pressure are important considerations.
HER2/neu-positive — For women whose breast cancers contain high levels of the HER2/neu protein, Herceptin alone or in combination with a taxane are reasonable choices for initial treatment. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin.
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
(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/healthtopics.html)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[1-3,5-9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Albain, KS, Nag, S, Calderillo-Ruiz, G, et al. Global phase III study of gemcitabine plus paclitaxel versus paclitaxel as frontline therapy for metastatic breast cancer: first report of overall survival (abstract). Proc Am Soc Clin Oncol 2004; 22:5a.
2. O'Shaughnessy, J, Miles, D, Vukelja, S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812.
3. Sledge, GW, Neuberg, D, Bernardo, P, et al. Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193). J Clin Oncol 2003; 21:588.
4. Bria, E, Giannarelli, D, Felici, A, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103:672.
5. Pegram, MD, Konecny, GE, O'Callaghan, C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739.
6. Slamon, DJ, Leyland-Jones, B, Shak, S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783.
7. Pegram, M, Lipton, A, Hayes, DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16:2659.
8. Miller, KD. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Data presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 16, 2005. (Available at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD (Accessed May 26, 2006).
9. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
Friday, October 12, 2007
Breast cancer guide to diagnosis and treatment
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.
UpToDate contains a number of patient information topic reviews that discuss breast cancer. The purpose of this overview is to provide a guide to the issues and questions that arise in women with newly diagnosed breast cancer. This topic can serve as a "road map" to the patient information topic reviews that are relevant to your particular situation.
This guide will focus only on the diagnosis and treatment of breast cancer. The reader is referred to other patient information materials for a discussion of the risk factors for breast cancer and methods to prevent breast cancer in women who are at high risk. (See "Patient information: Risk factors for breast cancer" and see "Patient information: Postmenopausal hormone therapy and breast cancer" and see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
IMPROVEMENTS IN CANCER CARE — While the number of new cases of breast cancer is rising over time, the death rate from breast cancer has declined about 20 percent over the past decade, in part because increased screening for breast cancer is catching the disease at an earlier stage when the chances of successful recovery are higher. (See "Patient information: Screening for breast cancer"). Early detection and treatment of breast cancer clearly improve survival because the breast tumor is removed before it has a chance to spread (metastasize).
The other factor that has improved outcomes in breast cancer is the early use of systemic (bodywide) anticancer treatment. The term "adjuvant systemic therapy" refers to additional anticancer treatment that is given after a cancer is removed surgically in order to eliminate any remaining tumor cells in the body (often termed micrometastases). Such therapy significantly decreases the chance that the cancer will return (or recur), and also improves the likelihood of surviving breast cancer. As a result, systemic adjuvant therapy has become an important component of treatment. The systemic treatments used for breast cancer include hormone therapy, chemotherapy, and antibody therapy.
DIAGNOSING BREAST CANCER
Mammogram — Breast cancer is often suspected because of an abnormal mammogram. An example of an abnormal finding is shown in radiograph 1 (show radiograph 1). In other cases, a woman (or her clinician) feels a lump or discovers a change in the breast. Changes may include dimpling of the skin, a change in the size or shape of one breast, inversion (inward turning) of the nipple when it previously pointed outward, or a discoloration of the skin of the breast.
A suspicious lump should not be ignored, even if the mammogram is negative. Up to 20 percent of new breast cancers are not visible on a mammogram.
Breast MRI — Magnetic resonance imaging (MRI) uses a strong magnet to create a detailed image of a part of the body. It does not use x-rays or radiation. Breast MRI may be recommended to aid in the diagnosis of breast cancer in selected situations. MRI is not recommended to detect breast cancer in all women because it is not as good as mammogram for certain breast conditions, such as ductal carcinoma in situ. The role of breast MRI in the diagnosis and management of breast cancer is evolving. Most experts restrict the use of breast MRI for diagnosis to the following situations: Breast cancer screening for young women (particularly those with dense breasts) who have an inherited susceptibility to breast cancer (eg, mutations in BRCA1 or BRCA2). Evaluation for breast cancer in a woman who is diagnosed with cancer of the lymph nodes (glands) under the arm. In this case, the breast MRI is done to determine if the cancer first developed in the breast. Evaluation of a woman with newly diagnosed breast cancer who has dense breasts. Evaluation of a woman with a small abnormality on mammogram who has a biopsy that indicates a large area of cancer. In this case, the MRI is often helpful to better define the size of the abnormal area (show radiograph 2), which can guide treatment (complete removal of the breast versus removal of the cancerous area). Evaluation of a woman with newly diagnosed breast cancer in one breast who has no evidence of breast cancer (based upon examination and mammography) in the opposite breast.
Breast biopsy — If breast cancer is suspected, the next step is to remove a small piece of the abnormal area (called a biopsy) to confirm the diagnosis. The biopsy technique depends upon whether a lump is present in the breast. If the physician feels a lump, a biopsy can often be performed in the office.
If the abnormality is only found on the mammogram and the breast feels normal, then the biopsy will need to be done using a test to guide where to perform the biopsy. A mammogram is often used for this purpose. The area of abnormality is visualized by the radiologist on the mammogram, and its location marked, often with a wire. A surgeon uses the wire to know which area to remove. This procedure is called a needle localization biopsy.
Types of breast cancer — Although there are several different types of breast cancer, they are treated similarly, with some exceptions.
In situ — The earliest breast cancers are called "in situ" cancers. If they arise in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), and are limited to the ducts themselves, the tumor is called ductal carcinoma in situ, abbreviated DCIS.
Other in situ cancers arise in the lobules of the breast (where breast milk is made) and are referred to as lobular carcinoma in situ (LCIS). In situ carcinomas, which are the earliest recognizable breast cancers, seldom spread beyond the breast tissue. Thus, evaluation for evidence of tumor spread beyond the breast is usually unnecessary and adjuvant systemic therapy is not recommended.
The optimal local treatment for in situ cancers is controversial. Conservative surgery alone may be an option for some women, while others have surgery followed by radiation therapy, or even a mastectomy.
Invasive — The majority of breast cancers are referred to as invasive breast cancers because they have invaded beyond the ducts or lobules of the breast. Several varieties of invasive breast cancers are identified (eg, ductal, lobular, medullary, tubular, metaplastic) In general they are treated similarly.
Hormone receptors — About 50 to 70 percent of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce hormone receptors, which can be estrogen receptors (ER), progesterone receptors (PR), or both.
If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as hormone-responsive. In contrast, women whose tumors do not contain any ER or PR do not benefit from adjuvant hormone therapy, and it is not recommended. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women")
HER2 — HER2 is a protein that is present in about one-third of breast cancers. The presence of HER2 can help to determine if adjuvant chemotherapy is needed. In particular, benefit from the drug trastuzumab (Herceptin) appears to be limited to women whose breast cancers express very high levels of this marker. The level of HER2 within a tumor can be determined by the pathologist. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer")
HAS THE BREAST CANCER SPREAD? — Once a diagnosis of breast cancer is established, the next important questions to be answered are the following: How extensive is the cancer involvement within the breast? Is there evidence that the tumor has spread outside of the breast?
The extent of cancer involvement within the breast is usually determined by the findings on the biopsy and the results of the mammogram (both breasts need to be studied because there is a small risk of having cancer in both breasts).
Although by definition, breast cancer starts within the breast, tiny microscopic cells or pieces of the cancer may break off from the breast tumor at any point and travel to other places through the bloodstream or the lymph channels; this process is called metastasis.
When these metastases lodge themselves in a lymph node (also called glands) or an organ, they grow, eventually producing a mass or lump that can sometimes be felt (eg, if it involves the skin or the lymph nodes in the armpit). In other cases, metastases may only be evident on an x-ray such as a CT scan. The use of studies such as CT scans to evaluate the extent of breast cancer spread is discussed below. (See "Staging and the staging workup" below).
The importance of the axillary lymph nodes — One of the first sites breast cancer spreads is the lymph nodes located in the armpit (axilla). These nodes can become enlarged and can be felt during a clinician's examination. However, the only way to determine if they contain cancer is for the surgeon to remove them so that they can be examined under the microscope.
The presence or absence of lymph node involvement by a breast cancer is one of the most important factors in determining the long-term outcome of the cancer (prognosis), and it often guides the selection of adjuvant systemic therapy. If the axillary lymph nodes are involved with cancer (positive nodes), there is a higher chance that the tumor has spread elsewhere, and all of these women should receive adjuvant systemic therapy. Even if these nodes are negative (no cancer cells detected), there is a small chance that the tumor has spread elsewhere in the body.
Because of this, adjuvant therapy is recommended for some women with node-negative breast cancer. A further discussion of factors that affect the choice of breast cancer treatment is presented elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Factors affecting treatment).
Sentinel node biopsy — Removal of the axillary lymph nodes can be done by removing all of the axillary lymph nodes (called axillary lymph node dissection, or ALND), or with a less invasive sentinel lymph node biopsy. The pros and cons of these two approaches to evaluating the possibility of spread of cancer to the axillary lymph nodes are discussed in detail elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", sections on How is breast cancer staged? and Management of axillary lymph nodes).
In general, the major benefit of sentinel lymph node procedure is that it can provide the necessary information while causing fewer long-term side effects (particularly arm swelling, also called lymphedema). (See "Patient information: Lymphedema after breast cancer surgery").
Staging and the staging workup — For all cancers, treatment and prognosis depend upon the "stage" of the cancer (how far it has spread). The stage of a breast cancer is based upon tumor size, involvement of the skin, chest wall, or local lymph nodes, and whether the cancer has spread to other organs (metastasis). Staging studies are done to determine if the cancer has spread, which may include: A complete physical examination, including a neurologic exam, to evaluate for signs of distant metastatic disease Blood tests, including a complete blood count and liver function tests Bone scan Chest X-ray or CT scan CT scan of the abdomen and pelvis CT scan or magnetic resonance imaging (MRI) of the brain A PET scan
Oncologists use a standard system, called the TNM staging system to describe the stage of individual cancers. "T" stands for the primary tumor, "N" reflects for the status of the regional lymph nodes, and "M" designates the presence of absence of metastases to other organs.
In general, the size and extent of the breast tumor, involvement of adjacent lymph nodes, and the presence or absence of spread to other organs are grouped together to form the stage grouping of a breast cancer, which ranges from stage I to IV. Table 1 describes these stages (show table 1). Treatment differs according to stage.
Stage I and II breast cancer — Women with either stage I or II breast cancers are referred to as having early stage localized breast cancer. Stage I breast cancer means that the tumor is less than 2 cm in size, and is node-negative.
Stage II tumors are those that are node-positive (but the axillary lymph nodes are small and either nonpalpable or movable on physical examination), or the tumor size is larger than 2 cm but not larger than 5 cm. A tumor that is larger than 5 cm must be node-negative to be considered early stage (show table 1).
Stage III breast cancers — Stage III tumors are referred to as locally advanced breast cancer. They consist of large breast cancers (greater than 5 cm across), those with extensive axillary nodal involvement, or nodal involvement of the soft tissues above or below the collarbone (termed the infraclavicular and supraclavicular nodes, show table 1).
A tumor is also designated stage III if the tumor extends to underlying muscles of the chest wall or the overlying skin. Stage III breast cancer also includes inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Stage IV breast cancer — Stage IV breast cancer includes tumors that have metastasized to areas outside the breast, including the brain, bones, skin, or other organs. The primary tumor may be any size, and there may be any number of affected lymph nodes. This is referred to as metastatic breast cancer (show table 1)
OVERVIEW OF TREATMENT — The treatment of breast cancer must be individualized and is based upon several factors. Optimal management in most cases requires collaboration between surgeons (breast cancer surgeons and reconstructive surgeons, who are typically plastic surgeons) and physicians who specialize in radiation and medical oncology. Each woman should carefully discuss the available treatment options with her doctors to determine which is the best choice for her.
Early stage localized breast cancer — Women with stage I and II breast cancer are treated similarly with minor exceptions. Two surgical options are available for treating localized breast cancer: mastectomy (removal of the breast) and breast conserving therapy. The latter consists of removal of the cancerous tissue (designated "lumpectomy", wide excision, quadrantectomy, or partial mastectomy, show figure 1).
Several studies have confirmed that unless the breast tissue removal is extensive, radiation to the breast should be given postoperatively. The combination of carefully performed excision and judiciously applied radiation frequently results in cosmetically satisfactory breast preservation without compromising overall survival.
In centers that specialize in breast cancer treatment, approximately 75 percent of women with early stage breast cancer are considered appropriate candidates for breast conserving therapy, while the remainder undergo mastectomy. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Breast reconstruction is an important option for women who undergo mastectomy, and may be considered at the time of the mastectomy or at a later date. Consultation with a plastic surgeon prior to the mastectomy is essential.
Adjuvant therapy — As noted above, adjuvant systemic therapy is recommended to the vast majority of women with stage II breast cancer, and to selected women with stage I disease. Adjuvant hormone therapy is recommended for all women with hormone receptor-positive breast cancer, while selected women also receive chemotherapy. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").
Adjuvant chemotherapy is recommended for women with hormone receptor-negative breast cancer. Adjuvant trastuzumab is generally reserved for women with HER2-positive breast cancer, regardless of hormone receptor status. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Locally advanced and inflammatory breast cancer — The term locally advanced breast cancer is used to describe a breast cancer that has progressed locally but has not yet spread beyond the breast and regional lymph nodes. inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Although the likelihood of curing locally advanced and inflammatory breast cancer is lower than it would be if the cancer were small and confined to the breast, cure is possible with aggressive treatment using a combination of chemotherapy, radiation therapy and surgery. In most cases, chemotherapy is given before surgery. (See "Patient information: Locally advanced and inflammatory breast cancer")
Metastatic breast cancer — Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, endocrine therapy, trastuzumab, or some combination of these options. Although these treatments only occasionally lead to long-term survival without disease recurrence (termed relapse-free survival), they can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life. Cure is possible, but it is very uncommon in women with metastatic breast cancer. (See "Patient information: General principles of treatment for metastatic breast cancer").
The choice of treatment for metastatic breast cancer depends upon many individual factors, including features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to various therapies, treatment-related side effects, and a woman's personal preferences. Each woman should discuss the available treatment options with her physician to determine which is the best choice for her. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
SUMMARY Early detection and treatment of breast cancer improve a woman's chance of survival. (See "Improvements in cancer care" above). Breast cancer can be diagnosed if a woman or her doctor/nurse notices a lump in the breast. Some women with cancer have changes in their breast's skin, such as dimpling or color changes. Mammograms (x-ray of the breast tissue) can also help to diagnose breast cancer (show radiograph 1). (See "Diagnosing breast cancer" above). The earliest breast cancers are called "in situ" cancers. If the cancer develops in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), it is called ductal carcinoma in situ (DCIS). Other in situ cancers develop in the lobules of the breast (where breast milk is made); this is called lobular carcinoma in situ (LCIS). (See "In situ" above). In situ cancers rarely spread beyond the breast. Whole body treatments (eg, chemotherapy) are usually not needed for in situ cancer. If the cancer spreads outside the ducts, it is called invasive ductal carcinoma. Cancer that spreads outside the lobules is called invasive lobular carcinoma. Treatment is similar for most types of invasive breast cancer. (See "Invasive" above). In a woman with breast cancer, tests will be done to determine the best type of treatment. Tests will also be done to see if the cancer has spread outside the breast. One of the most common places for breast cancer to spread first is the lymph nodes (glands). (See "Hormone receptors" above). Most women with breast cancer require surgery to remove the part of the breast that contains cancer; this is called breast conserving surgery (show figure 2). Some women need to have the entire breast removed; this is called a mastectomy. After the breast tumor is removed, there is a lower chance that the cancer will spread to other areas. (See "Overview of treatment" above). A number of whole body treatments may be given to some women with breast cancer, include hormone therapy, chemotherapy, and antibody therapy. Some of these treatments are taken as pills while others are given into a vein. Most women require treatment for several months to years. (See "Adjuvant therapy" above). Whole body treatments reduce the risk that the cancer will spread to areas outside the breast. Whole body treatments also improve a woman's chance of surviving the cancer. Women with more advanced types of breast cancer, or breast cancer that has spread, can also be treated. Although cure is less likely with advanced breast cancer, treatment can prolong life and improve comfort. (See "Locally advanced and inflammatory breast cancer" above).
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. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
UpToDate contains a number of patient information topic reviews that discuss breast cancer. The purpose of this overview is to provide a guide to the issues and questions that arise in women with newly diagnosed breast cancer. This topic can serve as a "road map" to the patient information topic reviews that are relevant to your particular situation.
This guide will focus only on the diagnosis and treatment of breast cancer. The reader is referred to other patient information materials for a discussion of the risk factors for breast cancer and methods to prevent breast cancer in women who are at high risk. (See "Patient information: Risk factors for breast cancer" and see "Patient information: Postmenopausal hormone therapy and breast cancer" and see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
IMPROVEMENTS IN CANCER CARE — While the number of new cases of breast cancer is rising over time, the death rate from breast cancer has declined about 20 percent over the past decade, in part because increased screening for breast cancer is catching the disease at an earlier stage when the chances of successful recovery are higher. (See "Patient information: Screening for breast cancer"). Early detection and treatment of breast cancer clearly improve survival because the breast tumor is removed before it has a chance to spread (metastasize).
The other factor that has improved outcomes in breast cancer is the early use of systemic (bodywide) anticancer treatment. The term "adjuvant systemic therapy" refers to additional anticancer treatment that is given after a cancer is removed surgically in order to eliminate any remaining tumor cells in the body (often termed micrometastases). Such therapy significantly decreases the chance that the cancer will return (or recur), and also improves the likelihood of surviving breast cancer. As a result, systemic adjuvant therapy has become an important component of treatment. The systemic treatments used for breast cancer include hormone therapy, chemotherapy, and antibody therapy.
DIAGNOSING BREAST CANCER
Mammogram — Breast cancer is often suspected because of an abnormal mammogram. An example of an abnormal finding is shown in radiograph 1 (show radiograph 1). In other cases, a woman (or her clinician) feels a lump or discovers a change in the breast. Changes may include dimpling of the skin, a change in the size or shape of one breast, inversion (inward turning) of the nipple when it previously pointed outward, or a discoloration of the skin of the breast.
A suspicious lump should not be ignored, even if the mammogram is negative. Up to 20 percent of new breast cancers are not visible on a mammogram.
Breast MRI — Magnetic resonance imaging (MRI) uses a strong magnet to create a detailed image of a part of the body. It does not use x-rays or radiation. Breast MRI may be recommended to aid in the diagnosis of breast cancer in selected situations. MRI is not recommended to detect breast cancer in all women because it is not as good as mammogram for certain breast conditions, such as ductal carcinoma in situ. The role of breast MRI in the diagnosis and management of breast cancer is evolving. Most experts restrict the use of breast MRI for diagnosis to the following situations: Breast cancer screening for young women (particularly those with dense breasts) who have an inherited susceptibility to breast cancer (eg, mutations in BRCA1 or BRCA2). Evaluation for breast cancer in a woman who is diagnosed with cancer of the lymph nodes (glands) under the arm. In this case, the breast MRI is done to determine if the cancer first developed in the breast. Evaluation of a woman with newly diagnosed breast cancer who has dense breasts. Evaluation of a woman with a small abnormality on mammogram who has a biopsy that indicates a large area of cancer. In this case, the MRI is often helpful to better define the size of the abnormal area (show radiograph 2), which can guide treatment (complete removal of the breast versus removal of the cancerous area). Evaluation of a woman with newly diagnosed breast cancer in one breast who has no evidence of breast cancer (based upon examination and mammography) in the opposite breast.
Breast biopsy — If breast cancer is suspected, the next step is to remove a small piece of the abnormal area (called a biopsy) to confirm the diagnosis. The biopsy technique depends upon whether a lump is present in the breast. If the physician feels a lump, a biopsy can often be performed in the office.
If the abnormality is only found on the mammogram and the breast feels normal, then the biopsy will need to be done using a test to guide where to perform the biopsy. A mammogram is often used for this purpose. The area of abnormality is visualized by the radiologist on the mammogram, and its location marked, often with a wire. A surgeon uses the wire to know which area to remove. This procedure is called a needle localization biopsy.
Types of breast cancer — Although there are several different types of breast cancer, they are treated similarly, with some exceptions.
In situ — The earliest breast cancers are called "in situ" cancers. If they arise in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), and are limited to the ducts themselves, the tumor is called ductal carcinoma in situ, abbreviated DCIS.
Other in situ cancers arise in the lobules of the breast (where breast milk is made) and are referred to as lobular carcinoma in situ (LCIS). In situ carcinomas, which are the earliest recognizable breast cancers, seldom spread beyond the breast tissue. Thus, evaluation for evidence of tumor spread beyond the breast is usually unnecessary and adjuvant systemic therapy is not recommended.
The optimal local treatment for in situ cancers is controversial. Conservative surgery alone may be an option for some women, while others have surgery followed by radiation therapy, or even a mastectomy.
Invasive — The majority of breast cancers are referred to as invasive breast cancers because they have invaded beyond the ducts or lobules of the breast. Several varieties of invasive breast cancers are identified (eg, ductal, lobular, medullary, tubular, metaplastic) In general they are treated similarly.
Hormone receptors — About 50 to 70 percent of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce hormone receptors, which can be estrogen receptors (ER), progesterone receptors (PR), or both.
If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as hormone-responsive. In contrast, women whose tumors do not contain any ER or PR do not benefit from adjuvant hormone therapy, and it is not recommended. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women")
HER2 — HER2 is a protein that is present in about one-third of breast cancers. The presence of HER2 can help to determine if adjuvant chemotherapy is needed. In particular, benefit from the drug trastuzumab (Herceptin) appears to be limited to women whose breast cancers express very high levels of this marker. The level of HER2 within a tumor can be determined by the pathologist. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer")
HAS THE BREAST CANCER SPREAD? — Once a diagnosis of breast cancer is established, the next important questions to be answered are the following: How extensive is the cancer involvement within the breast? Is there evidence that the tumor has spread outside of the breast?
The extent of cancer involvement within the breast is usually determined by the findings on the biopsy and the results of the mammogram (both breasts need to be studied because there is a small risk of having cancer in both breasts).
Although by definition, breast cancer starts within the breast, tiny microscopic cells or pieces of the cancer may break off from the breast tumor at any point and travel to other places through the bloodstream or the lymph channels; this process is called metastasis.
When these metastases lodge themselves in a lymph node (also called glands) or an organ, they grow, eventually producing a mass or lump that can sometimes be felt (eg, if it involves the skin or the lymph nodes in the armpit). In other cases, metastases may only be evident on an x-ray such as a CT scan. The use of studies such as CT scans to evaluate the extent of breast cancer spread is discussed below. (See "Staging and the staging workup" below).
The importance of the axillary lymph nodes — One of the first sites breast cancer spreads is the lymph nodes located in the armpit (axilla). These nodes can become enlarged and can be felt during a clinician's examination. However, the only way to determine if they contain cancer is for the surgeon to remove them so that they can be examined under the microscope.
The presence or absence of lymph node involvement by a breast cancer is one of the most important factors in determining the long-term outcome of the cancer (prognosis), and it often guides the selection of adjuvant systemic therapy. If the axillary lymph nodes are involved with cancer (positive nodes), there is a higher chance that the tumor has spread elsewhere, and all of these women should receive adjuvant systemic therapy. Even if these nodes are negative (no cancer cells detected), there is a small chance that the tumor has spread elsewhere in the body.
Because of this, adjuvant therapy is recommended for some women with node-negative breast cancer. A further discussion of factors that affect the choice of breast cancer treatment is presented elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Factors affecting treatment).
Sentinel node biopsy — Removal of the axillary lymph nodes can be done by removing all of the axillary lymph nodes (called axillary lymph node dissection, or ALND), or with a less invasive sentinel lymph node biopsy. The pros and cons of these two approaches to evaluating the possibility of spread of cancer to the axillary lymph nodes are discussed in detail elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", sections on How is breast cancer staged? and Management of axillary lymph nodes).
In general, the major benefit of sentinel lymph node procedure is that it can provide the necessary information while causing fewer long-term side effects (particularly arm swelling, also called lymphedema). (See "Patient information: Lymphedema after breast cancer surgery").
Staging and the staging workup — For all cancers, treatment and prognosis depend upon the "stage" of the cancer (how far it has spread). The stage of a breast cancer is based upon tumor size, involvement of the skin, chest wall, or local lymph nodes, and whether the cancer has spread to other organs (metastasis). Staging studies are done to determine if the cancer has spread, which may include: A complete physical examination, including a neurologic exam, to evaluate for signs of distant metastatic disease Blood tests, including a complete blood count and liver function tests Bone scan Chest X-ray or CT scan CT scan of the abdomen and pelvis CT scan or magnetic resonance imaging (MRI) of the brain A PET scan
Oncologists use a standard system, called the TNM staging system to describe the stage of individual cancers. "T" stands for the primary tumor, "N" reflects for the status of the regional lymph nodes, and "M" designates the presence of absence of metastases to other organs.
In general, the size and extent of the breast tumor, involvement of adjacent lymph nodes, and the presence or absence of spread to other organs are grouped together to form the stage grouping of a breast cancer, which ranges from stage I to IV. Table 1 describes these stages (show table 1). Treatment differs according to stage.
Stage I and II breast cancer — Women with either stage I or II breast cancers are referred to as having early stage localized breast cancer. Stage I breast cancer means that the tumor is less than 2 cm in size, and is node-negative.
Stage II tumors are those that are node-positive (but the axillary lymph nodes are small and either nonpalpable or movable on physical examination), or the tumor size is larger than 2 cm but not larger than 5 cm. A tumor that is larger than 5 cm must be node-negative to be considered early stage (show table 1).
Stage III breast cancers — Stage III tumors are referred to as locally advanced breast cancer. They consist of large breast cancers (greater than 5 cm across), those with extensive axillary nodal involvement, or nodal involvement of the soft tissues above or below the collarbone (termed the infraclavicular and supraclavicular nodes, show table 1).
A tumor is also designated stage III if the tumor extends to underlying muscles of the chest wall or the overlying skin. Stage III breast cancer also includes inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Stage IV breast cancer — Stage IV breast cancer includes tumors that have metastasized to areas outside the breast, including the brain, bones, skin, or other organs. The primary tumor may be any size, and there may be any number of affected lymph nodes. This is referred to as metastatic breast cancer (show table 1)
OVERVIEW OF TREATMENT — The treatment of breast cancer must be individualized and is based upon several factors. Optimal management in most cases requires collaboration between surgeons (breast cancer surgeons and reconstructive surgeons, who are typically plastic surgeons) and physicians who specialize in radiation and medical oncology. Each woman should carefully discuss the available treatment options with her doctors to determine which is the best choice for her.
Early stage localized breast cancer — Women with stage I and II breast cancer are treated similarly with minor exceptions. Two surgical options are available for treating localized breast cancer: mastectomy (removal of the breast) and breast conserving therapy. The latter consists of removal of the cancerous tissue (designated "lumpectomy", wide excision, quadrantectomy, or partial mastectomy, show figure 1).
Several studies have confirmed that unless the breast tissue removal is extensive, radiation to the breast should be given postoperatively. The combination of carefully performed excision and judiciously applied radiation frequently results in cosmetically satisfactory breast preservation without compromising overall survival.
In centers that specialize in breast cancer treatment, approximately 75 percent of women with early stage breast cancer are considered appropriate candidates for breast conserving therapy, while the remainder undergo mastectomy. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Breast reconstruction is an important option for women who undergo mastectomy, and may be considered at the time of the mastectomy or at a later date. Consultation with a plastic surgeon prior to the mastectomy is essential.
Adjuvant therapy — As noted above, adjuvant systemic therapy is recommended to the vast majority of women with stage II breast cancer, and to selected women with stage I disease. Adjuvant hormone therapy is recommended for all women with hormone receptor-positive breast cancer, while selected women also receive chemotherapy. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").
Adjuvant chemotherapy is recommended for women with hormone receptor-negative breast cancer. Adjuvant trastuzumab is generally reserved for women with HER2-positive breast cancer, regardless of hormone receptor status. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Locally advanced and inflammatory breast cancer — The term locally advanced breast cancer is used to describe a breast cancer that has progressed locally but has not yet spread beyond the breast and regional lymph nodes. inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Although the likelihood of curing locally advanced and inflammatory breast cancer is lower than it would be if the cancer were small and confined to the breast, cure is possible with aggressive treatment using a combination of chemotherapy, radiation therapy and surgery. In most cases, chemotherapy is given before surgery. (See "Patient information: Locally advanced and inflammatory breast cancer")
Metastatic breast cancer — Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, endocrine therapy, trastuzumab, or some combination of these options. Although these treatments only occasionally lead to long-term survival without disease recurrence (termed relapse-free survival), they can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life. Cure is possible, but it is very uncommon in women with metastatic breast cancer. (See "Patient information: General principles of treatment for metastatic breast cancer").
The choice of treatment for metastatic breast cancer depends upon many individual factors, including features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to various therapies, treatment-related side effects, and a woman's personal preferences. Each woman should discuss the available treatment options with her physician to determine which is the best choice for her. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
SUMMARY Early detection and treatment of breast cancer improve a woman's chance of survival. (See "Improvements in cancer care" above). Breast cancer can be diagnosed if a woman or her doctor/nurse notices a lump in the breast. Some women with cancer have changes in their breast's skin, such as dimpling or color changes. Mammograms (x-ray of the breast tissue) can also help to diagnose breast cancer (show radiograph 1). (See "Diagnosing breast cancer" above). The earliest breast cancers are called "in situ" cancers. If the cancer develops in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), it is called ductal carcinoma in situ (DCIS). Other in situ cancers develop in the lobules of the breast (where breast milk is made); this is called lobular carcinoma in situ (LCIS). (See "In situ" above). In situ cancers rarely spread beyond the breast. Whole body treatments (eg, chemotherapy) are usually not needed for in situ cancer. If the cancer spreads outside the ducts, it is called invasive ductal carcinoma. Cancer that spreads outside the lobules is called invasive lobular carcinoma. Treatment is similar for most types of invasive breast cancer. (See "Invasive" above). In a woman with breast cancer, tests will be done to determine the best type of treatment. Tests will also be done to see if the cancer has spread outside the breast. One of the most common places for breast cancer to spread first is the lymph nodes (glands). (See "Hormone receptors" above). Most women with breast cancer require surgery to remove the part of the breast that contains cancer; this is called breast conserving surgery (show figure 2). Some women need to have the entire breast removed; this is called a mastectomy. After the breast tumor is removed, there is a lower chance that the cancer will spread to other areas. (See "Overview of treatment" above). A number of whole body treatments may be given to some women with breast cancer, include hormone therapy, chemotherapy, and antibody therapy. Some of these treatments are taken as pills while others are given into a vein. Most women require treatment for several months to years. (See "Adjuvant therapy" above). Whole body treatments reduce the risk that the cancer will spread to areas outside the breast. Whole body treatments also improve a woman's chance of surviving the cancer. Women with more advanced types of breast cancer, or breast cancer that has spread, can also be treated. Although cure is less likely with advanced breast cancer, treatment can prolong life and improve comfort. (See "Locally advanced and inflammatory breast cancer" above).
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. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Breast cancer guide to diagnosis and treatment
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.
UpToDate contains a number of patient information topic reviews that discuss breast cancer. The purpose of this overview is to provide a guide to the issues and questions that arise in women with newly diagnosed breast cancer. This topic can serve as a "road map" to the patient information topic reviews that are relevant to your particular situation.
This guide will focus only on the diagnosis and treatment of breast cancer. The reader is referred to other patient information materials for a discussion of the risk factors for breast cancer and methods to prevent breast cancer in women who are at high risk. (See "Patient information: Risk factors for breast cancer" and see "Patient information: Postmenopausal hormone therapy and breast cancer" and see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
IMPROVEMENTS IN CANCER CARE — While the number of new cases of breast cancer is rising over time, the death rate from breast cancer has declined about 20 percent over the past decade, in part because increased screening for breast cancer is catching the disease at an earlier stage when the chances of successful recovery are higher. (See "Patient information: Screening for breast cancer"). Early detection and treatment of breast cancer clearly improve survival because the breast tumor is removed before it has a chance to spread (metastasize).
The other factor that has improved outcomes in breast cancer is the early use of systemic (bodywide) anticancer treatment. The term "adjuvant systemic therapy" refers to additional anticancer treatment that is given after a cancer is removed surgically in order to eliminate any remaining tumor cells in the body (often termed micrometastases). Such therapy significantly decreases the chance that the cancer will return (or recur), and also improves the likelihood of surviving breast cancer. As a result, systemic adjuvant therapy has become an important component of treatment. The systemic treatments used for breast cancer include hormone therapy, chemotherapy, and antibody therapy.
DIAGNOSING BREAST CANCER
Mammogram — Breast cancer is often suspected because of an abnormal mammogram. An example of an abnormal finding is shown in radiograph 1 (show radiograph 1). In other cases, a woman (or her clinician) feels a lump or discovers a change in the breast. Changes may include dimpling of the skin, a change in the size or shape of one breast, inversion (inward turning) of the nipple when it previously pointed outward, or a discoloration of the skin of the breast.
A suspicious lump should not be ignored, even if the mammogram is negative. Up to 20 percent of new breast cancers are not visible on a mammogram.
Breast MRI — Magnetic resonance imaging (MRI) uses a strong magnet to create a detailed image of a part of the body. It does not use x-rays or radiation. Breast MRI may be recommended to aid in the diagnosis of breast cancer in selected situations. MRI is not recommended to detect breast cancer in all women because it is not as good as mammogram for certain breast conditions, such as ductal carcinoma in situ. The role of breast MRI in the diagnosis and management of breast cancer is evolving. Most experts restrict the use of breast MRI for diagnosis to the following situations: Breast cancer screening for young women (particularly those with dense breasts) who have an inherited susceptibility to breast cancer (eg, mutations in BRCA1 or BRCA2). Evaluation for breast cancer in a woman who is diagnosed with cancer of the lymph nodes (glands) under the arm. In this case, the breast MRI is done to determine if the cancer first developed in the breast. Evaluation of a woman with newly diagnosed breast cancer who has dense breasts. Evaluation of a woman with a small abnormality on mammogram who has a biopsy that indicates a large area of cancer. In this case, the MRI is often helpful to better define the size of the abnormal area (show radiograph 2), which can guide treatment (complete removal of the breast versus removal of the cancerous area). Evaluation of a woman with newly diagnosed breast cancer in one breast who has no evidence of breast cancer (based upon examination and mammography) in the opposite breast.
Breast biopsy — If breast cancer is suspected, the next step is to remove a small piece of the abnormal area (called a biopsy) to confirm the diagnosis. The biopsy technique depends upon whether a lump is present in the breast. If the physician feels a lump, a biopsy can often be performed in the office.
If the abnormality is only found on the mammogram and the breast feels normal, then the biopsy will need to be done using a test to guide where to perform the biopsy. A mammogram is often used for this purpose. The area of abnormality is visualized by the radiologist on the mammogram, and its location marked, often with a wire. A surgeon uses the wire to know which area to remove. This procedure is called a needle localization biopsy.
Types of breast cancer — Although there are several different types of breast cancer, they are treated similarly, with some exceptions.
In situ — The earliest breast cancers are called "in situ" cancers. If they arise in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), and are limited to the ducts themselves, the tumor is called ductal carcinoma in situ, abbreviated DCIS.
Other in situ cancers arise in the lobules of the breast (where breast milk is made) and are referred to as lobular carcinoma in situ (LCIS). In situ carcinomas, which are the earliest recognizable breast cancers, seldom spread beyond the breast tissue. Thus, evaluation for evidence of tumor spread beyond the breast is usually unnecessary and adjuvant systemic therapy is not recommended.
The optimal local treatment for in situ cancers is controversial. Conservative surgery alone may be an option for some women, while others have surgery followed by radiation therapy, or even a mastectomy.
Invasive — The majority of breast cancers are referred to as invasive breast cancers because they have invaded beyond the ducts or lobules of the breast. Several varieties of invasive breast cancers are identified (eg, ductal, lobular, medullary, tubular, metaplastic) In general they are treated similarly.
Hormone receptors — About 50 to 70 percent of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce hormone receptors, which can be estrogen receptors (ER), progesterone receptors (PR), or both.
If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as hormone-responsive. In contrast, women whose tumors do not contain any ER or PR do not benefit from adjuvant hormone therapy, and it is not recommended. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women")
HER2 — HER2 is a protein that is present in about one-third of breast cancers. The presence of HER2 can help to determine if adjuvant chemotherapy is needed. In particular, benefit from the drug trastuzumab (Herceptin) appears to be limited to women whose breast cancers express very high levels of this marker. The level of HER2 within a tumor can be determined by the pathologist. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer")
HAS THE BREAST CANCER SPREAD? — Once a diagnosis of breast cancer is established, the next important questions to be answered are the following: How extensive is the cancer involvement within the breast? Is there evidence that the tumor has spread outside of the breast?
The extent of cancer involvement within the breast is usually determined by the findings on the biopsy and the results of the mammogram (both breasts need to be studied because there is a small risk of having cancer in both breasts).
Although by definition, breast cancer starts within the breast, tiny microscopic cells or pieces of the cancer may break off from the breast tumor at any point and travel to other places through the bloodstream or the lymph channels; this process is called metastasis.
When these metastases lodge themselves in a lymph node (also called glands) or an organ, they grow, eventually producing a mass or lump that can sometimes be felt (eg, if it involves the skin or the lymph nodes in the armpit). In other cases, metastases may only be evident on an x-ray such as a CT scan. The use of studies such as CT scans to evaluate the extent of breast cancer spread is discussed below. (See "Staging and the staging workup" below).
The importance of the axillary lymph nodes — One of the first sites breast cancer spreads is the lymph nodes located in the armpit (axilla). These nodes can become enlarged and can be felt during a clinician's examination. However, the only way to determine if they contain cancer is for the surgeon to remove them so that they can be examined under the microscope.
The presence or absence of lymph node involvement by a breast cancer is one of the most important factors in determining the long-term outcome of the cancer (prognosis), and it often guides the selection of adjuvant systemic therapy. If the axillary lymph nodes are involved with cancer (positive nodes), there is a higher chance that the tumor has spread elsewhere, and all of these women should receive adjuvant systemic therapy. Even if these nodes are negative (no cancer cells detected), there is a small chance that the tumor has spread elsewhere in the body.
Because of this, adjuvant therapy is recommended for some women with node-negative breast cancer. A further discussion of factors that affect the choice of breast cancer treatment is presented elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Factors affecting treatment).
Sentinel node biopsy — Removal of the axillary lymph nodes can be done by removing all of the axillary lymph nodes (called axillary lymph node dissection, or ALND), or with a less invasive sentinel lymph node biopsy. The pros and cons of these two approaches to evaluating the possibility of spread of cancer to the axillary lymph nodes are discussed in detail elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", sections on How is breast cancer staged? and Management of axillary lymph nodes).
In general, the major benefit of sentinel lymph node procedure is that it can provide the necessary information while causing fewer long-term side effects (particularly arm swelling, also called lymphedema). (See "Patient information: Lymphedema after breast cancer surgery").
Staging and the staging workup — For all cancers, treatment and prognosis depend upon the "stage" of the cancer (how far it has spread). The stage of a breast cancer is based upon tumor size, involvement of the skin, chest wall, or local lymph nodes, and whether the cancer has spread to other organs (metastasis). Staging studies are done to determine if the cancer has spread, which may include: A complete physical examination, including a neurologic exam, to evaluate for signs of distant metastatic disease Blood tests, including a complete blood count and liver function tests Bone scan Chest X-ray or CT scan CT scan of the abdomen and pelvis CT scan or magnetic resonance imaging (MRI) of the brain A PET scan
Oncologists use a standard system, called the TNM staging system to describe the stage of individual cancers. "T" stands for the primary tumor, "N" reflects for the status of the regional lymph nodes, and "M" designates the presence of absence of metastases to other organs.
In general, the size and extent of the breast tumor, involvement of adjacent lymph nodes, and the presence or absence of spread to other organs are grouped together to form the stage grouping of a breast cancer, which ranges from stage I to IV. Table 1 describes these stages (show table 1). Treatment differs according to stage.
Stage I and II breast cancer — Women with either stage I or II breast cancers are referred to as having early stage localized breast cancer. Stage I breast cancer means that the tumor is less than 2 cm in size, and is node-negative.
Stage II tumors are those that are node-positive (but the axillary lymph nodes are small and either nonpalpable or movable on physical examination), or the tumor size is larger than 2 cm but not larger than 5 cm. A tumor that is larger than 5 cm must be node-negative to be considered early stage (show table 1).
Stage III breast cancers — Stage III tumors are referred to as locally advanced breast cancer. They consist of large breast cancers (greater than 5 cm across), those with extensive axillary nodal involvement, or nodal involvement of the soft tissues above or below the collarbone (termed the infraclavicular and supraclavicular nodes, show table 1).
A tumor is also designated stage III if the tumor extends to underlying muscles of the chest wall or the overlying skin. Stage III breast cancer also includes inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Stage IV breast cancer — Stage IV breast cancer includes tumors that have metastasized to areas outside the breast, including the brain, bones, skin, or other organs. The primary tumor may be any size, and there may be any number of affected lymph nodes. This is referred to as metastatic breast cancer (show table 1)
OVERVIEW OF TREATMENT — The treatment of breast cancer must be individualized and is based upon several factors. Optimal management in most cases requires collaboration between surgeons (breast cancer surgeons and reconstructive surgeons, who are typically plastic surgeons) and physicians who specialize in radiation and medical oncology. Each woman should carefully discuss the available treatment options with her doctors to determine which is the best choice for her.
Early stage localized breast cancer — Women with stage I and II breast cancer are treated similarly with minor exceptions. Two surgical options are available for treating localized breast cancer: mastectomy (removal of the breast) and breast conserving therapy. The latter consists of removal of the cancerous tissue (designated "lumpectomy", wide excision, quadrantectomy, or partial mastectomy, show figure 1).
Several studies have confirmed that unless the breast tissue removal is extensive, radiation to the breast should be given postoperatively. The combination of carefully performed excision and judiciously applied radiation frequently results in cosmetically satisfactory breast preservation without compromising overall survival.
In centers that specialize in breast cancer treatment, approximately 75 percent of women with early stage breast cancer are considered appropriate candidates for breast conserving therapy, while the remainder undergo mastectomy. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Breast reconstruction is an important option for women who undergo mastectomy, and may be considered at the time of the mastectomy or at a later date. Consultation with a plastic surgeon prior to the mastectomy is essential.
Adjuvant therapy — As noted above, adjuvant systemic therapy is recommended to the vast majority of women with stage II breast cancer, and to selected women with stage I disease. Adjuvant hormone therapy is recommended for all women with hormone receptor-positive breast cancer, while selected women also receive chemotherapy. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").
Adjuvant chemotherapy is recommended for women with hormone receptor-negative breast cancer. Adjuvant trastuzumab is generally reserved for women with HER2-positive breast cancer, regardless of hormone receptor status. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Locally advanced and inflammatory breast cancer — The term locally advanced breast cancer is used to describe a breast cancer that has progressed locally but has not yet spread beyond the breast and regional lymph nodes. inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Although the likelihood of curing locally advanced and inflammatory breast cancer is lower than it would be if the cancer were small and confined to the breast, cure is possible with aggressive treatment using a combination of chemotherapy, radiation therapy and surgery. In most cases, chemotherapy is given before surgery. (See "Patient information: Locally advanced and inflammatory breast cancer")
Metastatic breast cancer — Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, endocrine therapy, trastuzumab, or some combination of these options. Although these treatments only occasionally lead to long-term survival without disease recurrence (termed relapse-free survival), they can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life. Cure is possible, but it is very uncommon in women with metastatic breast cancer. (See "Patient information: General principles of treatment for metastatic breast cancer").
The choice of treatment for metastatic breast cancer depends upon many individual factors, including features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to various therapies, treatment-related side effects, and a woman's personal preferences. Each woman should discuss the available treatment options with her physician to determine which is the best choice for her. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
SUMMARY Early detection and treatment of breast cancer improve a woman's chance of survival. (See "Improvements in cancer care" above). Breast cancer can be diagnosed if a woman or her doctor/nurse notices a lump in the breast. Some women with cancer have changes in their breast's skin, such as dimpling or color changes. Mammograms (x-ray of the breast tissue) can also help to diagnose breast cancer (show radiograph 1). (See "Diagnosing breast cancer" above). The earliest breast cancers are called "in situ" cancers. If the cancer develops in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), it is called ductal carcinoma in situ (DCIS). Other in situ cancers develop in the lobules of the breast (where breast milk is made); this is called lobular carcinoma in situ (LCIS). (See "In situ" above). In situ cancers rarely spread beyond the breast. Whole body treatments (eg, chemotherapy) are usually not needed for in situ cancer. If the cancer spreads outside the ducts, it is called invasive ductal carcinoma. Cancer that spreads outside the lobules is called invasive lobular carcinoma. Treatment is similar for most types of invasive breast cancer. (See "Invasive" above). In a woman with breast cancer, tests will be done to determine the best type of treatment. Tests will also be done to see if the cancer has spread outside the breast. One of the most common places for breast cancer to spread first is the lymph nodes (glands). (See "Hormone receptors" above). Most women with breast cancer require surgery to remove the part of the breast that contains cancer; this is called breast conserving surgery (show figure 2). Some women need to have the entire breast removed; this is called a mastectomy. After the breast tumor is removed, there is a lower chance that the cancer will spread to other areas. (See "Overview of treatment" above). A number of whole body treatments may be given to some women with breast cancer, include hormone therapy, chemotherapy, and antibody therapy. Some of these treatments are taken as pills while others are given into a vein. Most women require treatment for several months to years. (See "Adjuvant therapy" above). Whole body treatments reduce the risk that the cancer will spread to areas outside the breast. Whole body treatments also improve a woman's chance of surviving the cancer. Women with more advanced types of breast cancer, or breast cancer that has spread, can also be treated. Although cure is less likely with advanced breast cancer, treatment can prolong life and improve comfort. (See "Locally advanced and inflammatory breast cancer" above).
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. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
UpToDate contains a number of patient information topic reviews that discuss breast cancer. The purpose of this overview is to provide a guide to the issues and questions that arise in women with newly diagnosed breast cancer. This topic can serve as a "road map" to the patient information topic reviews that are relevant to your particular situation.
This guide will focus only on the diagnosis and treatment of breast cancer. The reader is referred to other patient information materials for a discussion of the risk factors for breast cancer and methods to prevent breast cancer in women who are at high risk. (See "Patient information: Risk factors for breast cancer" and see "Patient information: Postmenopausal hormone therapy and breast cancer" and see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
IMPROVEMENTS IN CANCER CARE — While the number of new cases of breast cancer is rising over time, the death rate from breast cancer has declined about 20 percent over the past decade, in part because increased screening for breast cancer is catching the disease at an earlier stage when the chances of successful recovery are higher. (See "Patient information: Screening for breast cancer"). Early detection and treatment of breast cancer clearly improve survival because the breast tumor is removed before it has a chance to spread (metastasize).
The other factor that has improved outcomes in breast cancer is the early use of systemic (bodywide) anticancer treatment. The term "adjuvant systemic therapy" refers to additional anticancer treatment that is given after a cancer is removed surgically in order to eliminate any remaining tumor cells in the body (often termed micrometastases). Such therapy significantly decreases the chance that the cancer will return (or recur), and also improves the likelihood of surviving breast cancer. As a result, systemic adjuvant therapy has become an important component of treatment. The systemic treatments used for breast cancer include hormone therapy, chemotherapy, and antibody therapy.
DIAGNOSING BREAST CANCER
Mammogram — Breast cancer is often suspected because of an abnormal mammogram. An example of an abnormal finding is shown in radiograph 1 (show radiograph 1). In other cases, a woman (or her clinician) feels a lump or discovers a change in the breast. Changes may include dimpling of the skin, a change in the size or shape of one breast, inversion (inward turning) of the nipple when it previously pointed outward, or a discoloration of the skin of the breast.
A suspicious lump should not be ignored, even if the mammogram is negative. Up to 20 percent of new breast cancers are not visible on a mammogram.
Breast MRI — Magnetic resonance imaging (MRI) uses a strong magnet to create a detailed image of a part of the body. It does not use x-rays or radiation. Breast MRI may be recommended to aid in the diagnosis of breast cancer in selected situations. MRI is not recommended to detect breast cancer in all women because it is not as good as mammogram for certain breast conditions, such as ductal carcinoma in situ. The role of breast MRI in the diagnosis and management of breast cancer is evolving. Most experts restrict the use of breast MRI for diagnosis to the following situations: Breast cancer screening for young women (particularly those with dense breasts) who have an inherited susceptibility to breast cancer (eg, mutations in BRCA1 or BRCA2). Evaluation for breast cancer in a woman who is diagnosed with cancer of the lymph nodes (glands) under the arm. In this case, the breast MRI is done to determine if the cancer first developed in the breast. Evaluation of a woman with newly diagnosed breast cancer who has dense breasts. Evaluation of a woman with a small abnormality on mammogram who has a biopsy that indicates a large area of cancer. In this case, the MRI is often helpful to better define the size of the abnormal area (show radiograph 2), which can guide treatment (complete removal of the breast versus removal of the cancerous area). Evaluation of a woman with newly diagnosed breast cancer in one breast who has no evidence of breast cancer (based upon examination and mammography) in the opposite breast.
Breast biopsy — If breast cancer is suspected, the next step is to remove a small piece of the abnormal area (called a biopsy) to confirm the diagnosis. The biopsy technique depends upon whether a lump is present in the breast. If the physician feels a lump, a biopsy can often be performed in the office.
If the abnormality is only found on the mammogram and the breast feels normal, then the biopsy will need to be done using a test to guide where to perform the biopsy. A mammogram is often used for this purpose. The area of abnormality is visualized by the radiologist on the mammogram, and its location marked, often with a wire. A surgeon uses the wire to know which area to remove. This procedure is called a needle localization biopsy.
Types of breast cancer — Although there are several different types of breast cancer, they are treated similarly, with some exceptions.
In situ — The earliest breast cancers are called "in situ" cancers. If they arise in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), and are limited to the ducts themselves, the tumor is called ductal carcinoma in situ, abbreviated DCIS.
Other in situ cancers arise in the lobules of the breast (where breast milk is made) and are referred to as lobular carcinoma in situ (LCIS). In situ carcinomas, which are the earliest recognizable breast cancers, seldom spread beyond the breast tissue. Thus, evaluation for evidence of tumor spread beyond the breast is usually unnecessary and adjuvant systemic therapy is not recommended.
The optimal local treatment for in situ cancers is controversial. Conservative surgery alone may be an option for some women, while others have surgery followed by radiation therapy, or even a mastectomy.
Invasive — The majority of breast cancers are referred to as invasive breast cancers because they have invaded beyond the ducts or lobules of the breast. Several varieties of invasive breast cancers are identified (eg, ductal, lobular, medullary, tubular, metaplastic) In general they are treated similarly.
Hormone receptors — About 50 to 70 percent of breast cancers require the female hormone estrogen to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce hormone receptors, which can be estrogen receptors (ER), progesterone receptors (PR), or both.
If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as hormone-responsive. In contrast, women whose tumors do not contain any ER or PR do not benefit from adjuvant hormone therapy, and it is not recommended. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women")
HER2 — HER2 is a protein that is present in about one-third of breast cancers. The presence of HER2 can help to determine if adjuvant chemotherapy is needed. In particular, benefit from the drug trastuzumab (Herceptin) appears to be limited to women whose breast cancers express very high levels of this marker. The level of HER2 within a tumor can be determined by the pathologist. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer")
HAS THE BREAST CANCER SPREAD? — Once a diagnosis of breast cancer is established, the next important questions to be answered are the following: How extensive is the cancer involvement within the breast? Is there evidence that the tumor has spread outside of the breast?
The extent of cancer involvement within the breast is usually determined by the findings on the biopsy and the results of the mammogram (both breasts need to be studied because there is a small risk of having cancer in both breasts).
Although by definition, breast cancer starts within the breast, tiny microscopic cells or pieces of the cancer may break off from the breast tumor at any point and travel to other places through the bloodstream or the lymph channels; this process is called metastasis.
When these metastases lodge themselves in a lymph node (also called glands) or an organ, they grow, eventually producing a mass or lump that can sometimes be felt (eg, if it involves the skin or the lymph nodes in the armpit). In other cases, metastases may only be evident on an x-ray such as a CT scan. The use of studies such as CT scans to evaluate the extent of breast cancer spread is discussed below. (See "Staging and the staging workup" below).
The importance of the axillary lymph nodes — One of the first sites breast cancer spreads is the lymph nodes located in the armpit (axilla). These nodes can become enlarged and can be felt during a clinician's examination. However, the only way to determine if they contain cancer is for the surgeon to remove them so that they can be examined under the microscope.
The presence or absence of lymph node involvement by a breast cancer is one of the most important factors in determining the long-term outcome of the cancer (prognosis), and it often guides the selection of adjuvant systemic therapy. If the axillary lymph nodes are involved with cancer (positive nodes), there is a higher chance that the tumor has spread elsewhere, and all of these women should receive adjuvant systemic therapy. Even if these nodes are negative (no cancer cells detected), there is a small chance that the tumor has spread elsewhere in the body.
Because of this, adjuvant therapy is recommended for some women with node-negative breast cancer. A further discussion of factors that affect the choice of breast cancer treatment is presented elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Factors affecting treatment).
Sentinel node biopsy — Removal of the axillary lymph nodes can be done by removing all of the axillary lymph nodes (called axillary lymph node dissection, or ALND), or with a less invasive sentinel lymph node biopsy. The pros and cons of these two approaches to evaluating the possibility of spread of cancer to the axillary lymph nodes are discussed in detail elsewhere. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", sections on How is breast cancer staged? and Management of axillary lymph nodes).
In general, the major benefit of sentinel lymph node procedure is that it can provide the necessary information while causing fewer long-term side effects (particularly arm swelling, also called lymphedema). (See "Patient information: Lymphedema after breast cancer surgery").
Staging and the staging workup — For all cancers, treatment and prognosis depend upon the "stage" of the cancer (how far it has spread). The stage of a breast cancer is based upon tumor size, involvement of the skin, chest wall, or local lymph nodes, and whether the cancer has spread to other organs (metastasis). Staging studies are done to determine if the cancer has spread, which may include: A complete physical examination, including a neurologic exam, to evaluate for signs of distant metastatic disease Blood tests, including a complete blood count and liver function tests Bone scan Chest X-ray or CT scan CT scan of the abdomen and pelvis CT scan or magnetic resonance imaging (MRI) of the brain A PET scan
Oncologists use a standard system, called the TNM staging system to describe the stage of individual cancers. "T" stands for the primary tumor, "N" reflects for the status of the regional lymph nodes, and "M" designates the presence of absence of metastases to other organs.
In general, the size and extent of the breast tumor, involvement of adjacent lymph nodes, and the presence or absence of spread to other organs are grouped together to form the stage grouping of a breast cancer, which ranges from stage I to IV. Table 1 describes these stages (show table 1). Treatment differs according to stage.
Stage I and II breast cancer — Women with either stage I or II breast cancers are referred to as having early stage localized breast cancer. Stage I breast cancer means that the tumor is less than 2 cm in size, and is node-negative.
Stage II tumors are those that are node-positive (but the axillary lymph nodes are small and either nonpalpable or movable on physical examination), or the tumor size is larger than 2 cm but not larger than 5 cm. A tumor that is larger than 5 cm must be node-negative to be considered early stage (show table 1).
Stage III breast cancers — Stage III tumors are referred to as locally advanced breast cancer. They consist of large breast cancers (greater than 5 cm across), those with extensive axillary nodal involvement, or nodal involvement of the soft tissues above or below the collarbone (termed the infraclavicular and supraclavicular nodes, show table 1).
A tumor is also designated stage III if the tumor extends to underlying muscles of the chest wall or the overlying skin. Stage III breast cancer also includes inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Stage IV breast cancer — Stage IV breast cancer includes tumors that have metastasized to areas outside the breast, including the brain, bones, skin, or other organs. The primary tumor may be any size, and there may be any number of affected lymph nodes. This is referred to as metastatic breast cancer (show table 1)
OVERVIEW OF TREATMENT — The treatment of breast cancer must be individualized and is based upon several factors. Optimal management in most cases requires collaboration between surgeons (breast cancer surgeons and reconstructive surgeons, who are typically plastic surgeons) and physicians who specialize in radiation and medical oncology. Each woman should carefully discuss the available treatment options with her doctors to determine which is the best choice for her.
Early stage localized breast cancer — Women with stage I and II breast cancer are treated similarly with minor exceptions. Two surgical options are available for treating localized breast cancer: mastectomy (removal of the breast) and breast conserving therapy. The latter consists of removal of the cancerous tissue (designated "lumpectomy", wide excision, quadrantectomy, or partial mastectomy, show figure 1).
Several studies have confirmed that unless the breast tissue removal is extensive, radiation to the breast should be given postoperatively. The combination of carefully performed excision and judiciously applied radiation frequently results in cosmetically satisfactory breast preservation without compromising overall survival.
In centers that specialize in breast cancer treatment, approximately 75 percent of women with early stage breast cancer are considered appropriate candidates for breast conserving therapy, while the remainder undergo mastectomy. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Breast reconstruction is an important option for women who undergo mastectomy, and may be considered at the time of the mastectomy or at a later date. Consultation with a plastic surgeon prior to the mastectomy is essential.
Adjuvant therapy — As noted above, adjuvant systemic therapy is recommended to the vast majority of women with stage II breast cancer, and to selected women with stage I disease. Adjuvant hormone therapy is recommended for all women with hormone receptor-positive breast cancer, while selected women also receive chemotherapy. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").
Adjuvant chemotherapy is recommended for women with hormone receptor-negative breast cancer. Adjuvant trastuzumab is generally reserved for women with HER2-positive breast cancer, regardless of hormone receptor status. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Locally advanced and inflammatory breast cancer — The term locally advanced breast cancer is used to describe a breast cancer that has progressed locally but has not yet spread beyond the breast and regional lymph nodes. inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).
Although the likelihood of curing locally advanced and inflammatory breast cancer is lower than it would be if the cancer were small and confined to the breast, cure is possible with aggressive treatment using a combination of chemotherapy, radiation therapy and surgery. In most cases, chemotherapy is given before surgery. (See "Patient information: Locally advanced and inflammatory breast cancer")
Metastatic breast cancer — Metastatic breast cancer can be treated with surgery, radiation therapy, chemotherapy, endocrine therapy, trastuzumab, or some combination of these options. Although these treatments only occasionally lead to long-term survival without disease recurrence (termed relapse-free survival), they can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life. Cure is possible, but it is very uncommon in women with metastatic breast cancer. (See "Patient information: General principles of treatment for metastatic breast cancer").
The choice of treatment for metastatic breast cancer depends upon many individual factors, including features of the woman's breast cancer, the extent and location of metastases, the expected response of the cancer to various therapies, treatment-related side effects, and a woman's personal preferences. Each woman should discuss the available treatment options with her physician to determine which is the best choice for her. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
SUMMARY Early detection and treatment of breast cancer improve a woman's chance of survival. (See "Improvements in cancer care" above). Breast cancer can be diagnosed if a woman or her doctor/nurse notices a lump in the breast. Some women with cancer have changes in their breast's skin, such as dimpling or color changes. Mammograms (x-ray of the breast tissue) can also help to diagnose breast cancer (show radiograph 1). (See "Diagnosing breast cancer" above). The earliest breast cancers are called "in situ" cancers. If the cancer develops in the ducts of the breast (the tubes that carry milk to the nipple when a woman is breastfeeding), it is called ductal carcinoma in situ (DCIS). Other in situ cancers develop in the lobules of the breast (where breast milk is made); this is called lobular carcinoma in situ (LCIS). (See "In situ" above). In situ cancers rarely spread beyond the breast. Whole body treatments (eg, chemotherapy) are usually not needed for in situ cancer. If the cancer spreads outside the ducts, it is called invasive ductal carcinoma. Cancer that spreads outside the lobules is called invasive lobular carcinoma. Treatment is similar for most types of invasive breast cancer. (See "Invasive" above). In a woman with breast cancer, tests will be done to determine the best type of treatment. Tests will also be done to see if the cancer has spread outside the breast. One of the most common places for breast cancer to spread first is the lymph nodes (glands). (See "Hormone receptors" above). Most women with breast cancer require surgery to remove the part of the breast that contains cancer; this is called breast conserving surgery (show figure 2). Some women need to have the entire breast removed; this is called a mastectomy. After the breast tumor is removed, there is a lower chance that the cancer will spread to other areas. (See "Overview of treatment" above). A number of whole body treatments may be given to some women with breast cancer, include hormone therapy, chemotherapy, and antibody therapy. Some of these treatments are taken as pills while others are given into a vein. Most women require treatment for several months to years. (See "Adjuvant therapy" above). Whole body treatments reduce the risk that the cancer will spread to areas outside the breast. Whole body treatments also improve a woman's chance of surviving the cancer. Women with more advanced types of breast cancer, or breast cancer that has spread, can also be treated. Although cure is less likely with advanced breast cancer, treatment can prolong life and improve comfort. (See "Locally advanced and inflammatory breast cancer" above).
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. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women
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 primary cause of death in women ages 45 to 55. Each year, 211,000 American women are diagnosed with breast cancer, and 40,000 die from this disease. Early detection and treatment can often lead to a cure. Cure is most likely in women whose breast cancers are confined to the breast, while a substantial number of women with spread to the locoregional lymph nodes (glands) can also be cured with appropriate therapy.
Breast cancer is a very complex topic. An introduction to breast cancer and an overview of available treatments is available elsewhere. (See "Patient information: Breast cancer guide to diagnosis and treatment").
The choices and recommendations for adjuvant therapy are slightly different for postmenopausal and premenopausal women who have hormone-responsive tumors. This topic review will focus on adjuvant therapy for premenopausal women with hormone-responsive breast cancer. Adjuvant treatment for postmenopausal women with hormone-responsive breast cancer is discussed separately. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").
Adjuvant treatment for women with hormone-nonresponsive breast cancers and a discussion about the side effects and indications for chemotherapy and trastuzumab (Herceptin®) is also presented elsewhere. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
DEFINING HORMONE-RESPONSIVE BREAST CANCER — About 50 to 70 percent of breast cancers require the female hormone estrogen (estradiol) to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce molecules called hormone receptors, which are essential in order for the cell to use estrogen for growth. These hormone receptors can be estrogen receptors (ER), progesterone receptors (PR), or both.
If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen, thus depriving the cancer cells of the material that stimulates their growth. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as "hormone-responsive". In contrast, women whose tumors do not contain ER or PR do not benefit from adjuvant hormone therapy (ie, they are hormone-nonresponsive), and it is not recommended.
ADJUVANT SYSTEMIC THERAPY — Adjuvant systemic therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. It is given to eliminate any remaining tumor cells in the body (often termed micrometastases). Because such therapy decreases the chance that the cancer will return (or recur), it also improves the likelihood of surviving the cancer.
Advances in adjuvant therapy have decreased the risk of dying of breast cancer by 20 to 30 percent, and substantially increased the chance of curing early breast cancer. As a result, adjuvant therapy is a very important component of modern breast cancer treatment. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
There are three different types of systemic (bodywide) adjuvant therapy that are useful in women with breast cancer: hormone therapy, chemotherapy, and targeted therapy using the monoclonal antibody trastuzumab (Herceptin®). The choice of hormone therapy, chemotherapy, Herceptin, or a combination of these treatments is mainly dependent upon whether a woman's breast cancer is hormone-responsive, and whether it makes a protein called HER2.
In general: When adjuvant systemic therapy is indicated, hormone therapy is used for women with ER/PR-positive breast cancer, while chemotherapy is recommended for women whose breast cancers are ER/PR-negative. Chemotherapy may be recommended in addition to hormone therapy for women with ER/PR-positive breast cancer, particularly if they have node-positive disease, a large tumor size, or other features that suggest a higher risk for a cancer recurrence. The protein tumor marker HER2 indicates which women might benefit from treatment with Herceptin. In addition, preliminary studies suggest that HER2 may help to identify women who are most likely to benefit from specific types of chemotherapy. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
AVAILABLE TREATMENT OPTIONS — The goal of adjuvant hormone therapy is to prevent breast cancer cells from receiving stimulation from estrogen. There are several ways in which this can be accomplished. Choices for hormone therapy in postmenopausal women with early breast cancer include the drug tamoxifen (which blocks the hormone receptors on breast cancer cells, thus preventing the body's estrogen from interacting with the receptors) and a class of drugs called aromatase inhibitors (AIs).
In contrast, premenopausal (menstruating) women are not routinely offered AIs. Because a premenopausal woman's ovaries are still functioning and making hormones, AIs will cause the ovaries to produce more male rather than female hormones, which is usually not desirable. Instead, the available options for hormone therapy in premenopausal women include the drug tamoxifen and disruption of the ovaries' ability to make estrogen (termed ovarian function suppression) (see "Ovarian function suppression" below).
Tamoxifen — Tamoxifen (Nolvadex®) is a member of a drug class called selective estrogen receptor modulators, or SERMs. SERMs appear chemically similar to estrogen, but are in fact very different. Tamoxifen and other SERMs prevent estrogen from binding to the ER (and thereby preventing it from stimulating growth of the cells). Tamoxifen also interacts directly with the ER, disrupting the normal function of breast cancer cells and the cells of other organs as well. Thus, tamoxifen is associated with effects on bones, the heart, blood clotting, and the uterus. Some of these effects are beneficial, while others are detrimental.
Effects on breast cancer and other organs — The interaction of SERMs with the ER can affect the cells of different organs in ways that mimic the effects of estrogen (referred to as estrogenic effects), or block the effects of estrogen (referred to as antiestrogenic effects). In the same person, SERMs can be antiestrogenic in some tissues and estrogenic in others (show figure 1): Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, in women at high risk for developing breast cancer, taking tamoxifen can prevent new breast cancers. Tamoxifen also has antiestrogenic activity on certain parts of the brain. This can lead to detrimental effects, because it is thought to be the cause of many of the menopausal symptoms (eg, hot flashes, sweating, insomnia) that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in the bones of postmenopausal women, preventing progression of osteoporosis. Tamoxifen is also estrogenic in the liver, and increases the liver's production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during tamoxifen use, particularly in women who are otherwise at high risk for these events (ie, smokers, those with a past history of blood clots). Higher levels of clotting proteins also increase the risk of blood clots in the major veins of the leg (deep vein thrombosis) and migration of such a blood clot to the lungs (pulmonary embolus). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). Although most abnormal uterine growths are benign (eg, thickening of the lining of the uterus, or polyps), the risk of cancer of the uterus is increased by two- to threefold in women taking tamoxifen.
Benefits — Tamoxifen is effective adjuvant treatment for women of all ages who have hormone responsive breast cancer, whether they have involved lymph nodes (node-positive) or not (node-negative) [1]. The amount of benefit can best be illustrated in results from the Early Breast Cancer Trialists Collaborative Group (EBCTCG), an international group that evaluates the worth of adjuvant therapy for early breast cancer.
Studies have suggested that five years of tamoxifen (compared to no adjuvant treatment) reduces the risk of a breast cancer recurrence by about 40 percent, and the risk of death by about 30 percent [1]. This is a 12 percent reduction in the chance of a breast cancer recurrence within 15 years after treatment, and a 9 percent reduction in the risk of a breast cancer-related death [1].
In addition to reducing the chance of a breast cancer recurrence and death from breast cancer, tamoxifen also decreases the chance that a woman will develop a breast cancer in the opposite breast (contralateral breast cancer) by about one-half.
Duration of therapy — The standard duration of adjuvant tamoxifen is five years. Taking tamoxifen for more than five years does not add further benefit, and the risk of side effects such as uterine cancers increases with longer treatment.
Side effects — Tamoxifen therapy may increase the risk of the following, all of which are more common in women over the age of 50: Cancer of the uterus (endometrial cancers and sarcomas) Blood clots within deep veins, usually in the legs (deep vein thrombosis), which can travel to the lungs (pulmonary embolism) (See "Patient information: Venous thrombosis"). Stroke
Although concerning, this information must be placed in appropriate context for women who are considering tamoxifen for early breast cancer. For most women, the benefits of tamoxifen in preventing a recurrence of breast cancer far outweigh the risks of uterine cancer, blood clots, or other long-term effects. However, the risks may be higher for women with risk factors for blood clots (eg, prior history of blood clots in the leg or lung, history of smoking), and for those who take tamoxifen for longer than five years.
Tamoxifen therapy may also cause other more minor but still bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.
Ovarian function suppression — Ovarian function suppression, which disrupts the ability of the ovaries to make estrogen, can be accomplished in several ways: Surgical removal of the ovaries (called oophorectomy) or radiation treatment of the ovaries, both of which stop the production of hormones permanently The production of estrogen by the ovaries can be temporarily blocked with drugs called gonadotropin releasing hormone (GnRH) agonists. The most commonly used drug in this class is goserelin (Zoladex®), which is given as a monthly injection
In addition, chemotherapy also provides some hormonal effects; many women who receive it become menopausal (ie, their ovaries no longer function), particularly if they are over the age of 40 at the time of treatment. Some physicians believe this is one of the reasons chemotherapy seems to be more beneficial in younger (premenopausal) women. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Suppression of ovarian function appears to be as effective as tamoxifen in premenopausal women with early breast cancer. However, in the United States, it is used less often than tamoxifen.
Unlike tamoxifen, ovarian function suppression is not associated with a higher risk of blood clots, stroke, or uterine cancers. However, all forms of ovarian function suppression cause a rapid onset of menopause symptoms (hot flashes, night sweats, mood swings, vaginal dryness), which can be severe. However, women who take GnRH analogs such as goserelin generally resume menstruating when drug treatment is discontinued, causing menopausal symptoms to disappear.
Some trials suggest that combining tamoxifen and ovarian function suppression provides better outcomes than can be achieved by using either treatment alone. However, the best form of adjuvant hormone therapy in premenopausal women is currently unknown. Several important international clinical trials are underway that will help to address the issue of which hormone therapy is best in young women (show table 1). Eligible patients are encouraged to enroll in these trials (www.cancer.gov/clinicaltrials).
Hormone therapy versus chemotherapy versus both — Whether hormone therapy (tamoxifen, ovarian function suppression, or both) is as good as adjuvant chemotherapy in premenopausal women is another controversial issue. Most doctors agree that hormone therapy alone is adequate systemic adjuvant therapy for premenopausal women with node-negative, hormone-responsive breast cancer, as long as the tumor size is small (less than 1 to 2 centimeters) and has no other high-risk features [2,3].
Whether hormone therapy alone is as good as adjuvant chemotherapy for premenopausal women with higher risk ER-positive breast cancers (ie, those with involved lymph nodes, tumor size larger than 2 centimeters, or unfavorable pathologic features) is more controversial, since most of the trials studying this issue have not used the best available chemotherapy regimens. As a result, at least in North America, premenopausal women with node-positive (or higher-risk node-negative) breast cancers are more likely to be offered chemotherapy plus hormone therapy rather than hormone therapy alone.
However, the benefit of chemotherapy for women with ER-positive breast cancer has been called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [4]. When these investigators reviewed the results of newer adjuvant chemotherapy regimens that have been developed over the last 20 years, women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors. As a result, the recommendations for chemotherapy in women with ER-positive breast cancer are difficult to define at present.
It is particularly difficult to know whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with small ER-positive, node-negative breast cancers.
Recommendations of expert groups — The uncertainty of benefit for adding chemotherapy to hormone therapy for women with hormone receptor-positive breast cancer is reflected in the differing recommendations of two major consensus groups, the National Comprehensive Cancer Network (NCCN [2]) and the International Consensus Group [3]. NCCN guidelines suggest adjuvant chemotherapy for patients with tumor size >1 cm or node-positive breast cancer, regardless of hormone receptor status The International Consensus Group guidelines recommend hormone therapy alone for ER-positive node-negative tumors 2 cm as long as they have favorable features, and for some node-positive tumors with fewer than three involved lymph nodes that do not have high risk features (such as HER2).
For higher-risk disease, or in cases where the hormone responsiveness of the tumor is uncertain (for example, if the amount of hormone receptors on the tumor is very small), the addition of chemotherapy is suggested.
Oncotype DX assay — Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive, node-negative breast cancer who will benefit the most from adding chemotherapy to hormone therapy. This test, which is performed by pathologists on a specimen of the breast tumor, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [5]. If the recurrence score indicates that the patient is in a low-risk category, hormone therapy alone may be sufficient, while for patients whose recurrence score puts them in a high-risk category, chemotherapy followed by hormone therapy may provide a better outcome. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in this group.
Whether the information gained from the Oncotype DX assay should be used for clinical decision making regarding the need for adjuvant chemotherapy at this time is controversial. In the opinion of the author, use of this test to select women for adjuvant chemotherapy is still experimental, although the information gained may be used in conjunction with other data when estimating a woman's level of risk of having a breast cancer recurrence.
A web-based assessment program (Adjuvant! Online, www.adjuvantonline.com) can assist in estimating the relative risks and benefits of chemotherapy and hormone therapy in individual women based upon their prognostic profile. Particularly for women who are considering undergoing hormone therapy alone, calculation of the absolute expected survival benefit of adding chemotherapy to hormone therapy using a program such as Adjuvant! Online is recommended by many oncologists [6]. The results are useful in providing complete information regarding the potential benefits she may be giving up if she decides to avoid chemotherapy due to its potential risks. A version of Adjuvant! Online is available that incorporates information derived from the Oncotype DX assay.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 2 (show table 2).
SUMMARY AND RECOMMENDATIONS — The many options for the adjuvant therapy of breast cancer can be very confusing. General guidelines help clarify which therapies are likely to be most appropriate for specific groups of women. However, because individual factors strongly influence the choice of therapy, each woman should discuss the options for adjuvant therapy with her doctor to determine which therapy is best for her.
Adjuvant treatment should be selected based upon the estimated risk of a breast cancer recurrence, and an estimate of the benefits to be achieved using hormone therapy, chemotherapy, or a combination of both approaches. The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. The best adjuvant treatment strategy for premenopausal women with hormone responsive early breast cancer is unknown. We encourage eligible women to enroll in one of the international clinical trials studying this issue (show table 1) [7]. For women who are either not eligible to participate in these trials or who choose not to enroll, international guidelines for breast cancer treatment suggest adjuvant hormone therapy alone for those with ER-positive, node-negative tumors 2 cm as long as they have favorable features. Hormone therapy alone is also recommended for some node-positive tumors with fewer than three involved lymph nodes that do not have high risk features (such as HER2 production).
On the other hand, in the United States, most clinicians follow guidelines from the National Comprehensive Cancer Network, which recommend that hormone therapy alone is appropriate only for women with node-negative tumors, 1 cm or less in size [2].
Particularly for women who are considering treatment with hormone therapy alone, calculation of the absolute expected survival benefit of adding chemotherapy to hormone therapy using a program such as Adjuvant! Online is recommended by many oncologists [6]. The results should be used to fully inform each patient regarding the potential benefits she might be foregoing to avoid the risks of chemotherapy. The optimal hormone therapy (tamoxifen or ovarian function suppression) is controversial. For women who are not eligible or who choose not to participate in a clinical trial, we suggest five years of tamoxifen.
An alternative approach is to use ovarian function suppression; if goserelin is chosen rather than surgical removal of the ovaries, the optimal duration is not known. A combination of tamoxifen and ovarian function suppression is not currently recommended, although this recommendation is also controversial. Gene expression analysis on an individual tumor (ie, the Oncotype DX assay) may be useful to select those women with ER-positive, node-negative breast cancers whose risk of recurrence is low enough to avoid adjuvant chemotherapy. However, due to the scant amount of data available to support the value of this approach, we suggest not basing treatment decisions on the results of the Oncotype DX assay until further data become available. However, many physicians disagree and routinely use this test to assist in the decision-making process.
Two clinical trials are ongoing (the North American TAILORx and European MINDACT trials) to determine the benefit of using gene expression analysis to select the adjuvant treatment strategy; eligible women are encouraged to enroll [8,9]. For higher-risk (ie, node-positive, tumor size >2 cm, adverse pathologic features) early stage breast cancers, or if endocrine responsiveness is uncertain, we recommend hormone therapy in addition to chemotherapy. If combined therapy is chosen, tamoxifen therapy should not be started until after chemotherapy is completed because of concerns that giving both at the same time could decrease the effectiveness of the chemotherapy. Furthermore, there is an increased risk of a blood clot in the legs or lungs when chemotherapy and tamoxifen are given together.
Although the timing of ovarian function suppression is less clearly defined, we suggest waiting until after the completion of chemotherapy to start it as well. A web-based assessment program (Adjuvant! Online) is available (www.adjuvantonline.com) that can assist in estimating the relative risks and benefits of chemotherapy (as well as hormone therapy) in individual women based upon their prognostic profile. A version is available that incorporates information derived from the Oncotype DX assay.
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. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Adjuvant! Online
(www.adjuvantonline.com/)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.
2. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
3. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
4. Berry, DA, Cirrincione, C, Henderson, IC, et al. Estrogen receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006; 295:1658.
5. Paik, S, Shak, S, Tang, G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:2817.
6. Adjuvant! Online program available online at www.adjuvantonline.com (accessed September 6, 2006).
7. Enrollment information for the TEXT, SOFT, and PERCHE trials summarized at www.youngsurvival.org/research/current-studies/clinical-trial-listing/ (Accessed September 6,2006).
8. Information on the TAILORx trial available online at www.cancer.gov/clinicaltrials/ECOG-PACCT-1. (Accessed Spetember 6,2006).
9. Information on the MINDACT trial available online at www.eortc.be/services/unit/mindact/default.asp (accessed September 6,2006).
Breast cancer is a very complex topic. An introduction to breast cancer and an overview of available treatments is available elsewhere. (See "Patient information: Breast cancer guide to diagnosis and treatment").
The choices and recommendations for adjuvant therapy are slightly different for postmenopausal and premenopausal women who have hormone-responsive tumors. This topic review will focus on adjuvant therapy for premenopausal women with hormone-responsive breast cancer. Adjuvant treatment for postmenopausal women with hormone-responsive breast cancer is discussed separately. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").
Adjuvant treatment for women with hormone-nonresponsive breast cancers and a discussion about the side effects and indications for chemotherapy and trastuzumab (Herceptin®) is also presented elsewhere. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
DEFINING HORMONE-RESPONSIVE BREAST CANCER — About 50 to 70 percent of breast cancers require the female hormone estrogen (estradiol) to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce molecules called hormone receptors, which are essential in order for the cell to use estrogen for growth. These hormone receptors can be estrogen receptors (ER), progesterone receptors (PR), or both.
If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen, thus depriving the cancer cells of the material that stimulates their growth. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as "hormone-responsive". In contrast, women whose tumors do not contain ER or PR do not benefit from adjuvant hormone therapy (ie, they are hormone-nonresponsive), and it is not recommended.
ADJUVANT SYSTEMIC THERAPY — Adjuvant systemic therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. It is given to eliminate any remaining tumor cells in the body (often termed micrometastases). Because such therapy decreases the chance that the cancer will return (or recur), it also improves the likelihood of surviving the cancer.
Advances in adjuvant therapy have decreased the risk of dying of breast cancer by 20 to 30 percent, and substantially increased the chance of curing early breast cancer. As a result, adjuvant therapy is a very important component of modern breast cancer treatment. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
There are three different types of systemic (bodywide) adjuvant therapy that are useful in women with breast cancer: hormone therapy, chemotherapy, and targeted therapy using the monoclonal antibody trastuzumab (Herceptin®). The choice of hormone therapy, chemotherapy, Herceptin, or a combination of these treatments is mainly dependent upon whether a woman's breast cancer is hormone-responsive, and whether it makes a protein called HER2.
In general: When adjuvant systemic therapy is indicated, hormone therapy is used for women with ER/PR-positive breast cancer, while chemotherapy is recommended for women whose breast cancers are ER/PR-negative. Chemotherapy may be recommended in addition to hormone therapy for women with ER/PR-positive breast cancer, particularly if they have node-positive disease, a large tumor size, or other features that suggest a higher risk for a cancer recurrence. The protein tumor marker HER2 indicates which women might benefit from treatment with Herceptin. In addition, preliminary studies suggest that HER2 may help to identify women who are most likely to benefit from specific types of chemotherapy. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
AVAILABLE TREATMENT OPTIONS — The goal of adjuvant hormone therapy is to prevent breast cancer cells from receiving stimulation from estrogen. There are several ways in which this can be accomplished. Choices for hormone therapy in postmenopausal women with early breast cancer include the drug tamoxifen (which blocks the hormone receptors on breast cancer cells, thus preventing the body's estrogen from interacting with the receptors) and a class of drugs called aromatase inhibitors (AIs).
In contrast, premenopausal (menstruating) women are not routinely offered AIs. Because a premenopausal woman's ovaries are still functioning and making hormones, AIs will cause the ovaries to produce more male rather than female hormones, which is usually not desirable. Instead, the available options for hormone therapy in premenopausal women include the drug tamoxifen and disruption of the ovaries' ability to make estrogen (termed ovarian function suppression) (see "Ovarian function suppression" below).
Tamoxifen — Tamoxifen (Nolvadex®) is a member of a drug class called selective estrogen receptor modulators, or SERMs. SERMs appear chemically similar to estrogen, but are in fact very different. Tamoxifen and other SERMs prevent estrogen from binding to the ER (and thereby preventing it from stimulating growth of the cells). Tamoxifen also interacts directly with the ER, disrupting the normal function of breast cancer cells and the cells of other organs as well. Thus, tamoxifen is associated with effects on bones, the heart, blood clotting, and the uterus. Some of these effects are beneficial, while others are detrimental.
Effects on breast cancer and other organs — The interaction of SERMs with the ER can affect the cells of different organs in ways that mimic the effects of estrogen (referred to as estrogenic effects), or block the effects of estrogen (referred to as antiestrogenic effects). In the same person, SERMs can be antiestrogenic in some tissues and estrogenic in others (show figure 1): Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, in women at high risk for developing breast cancer, taking tamoxifen can prevent new breast cancers. Tamoxifen also has antiestrogenic activity on certain parts of the brain. This can lead to detrimental effects, because it is thought to be the cause of many of the menopausal symptoms (eg, hot flashes, sweating, insomnia) that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in the bones of postmenopausal women, preventing progression of osteoporosis. Tamoxifen is also estrogenic in the liver, and increases the liver's production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during tamoxifen use, particularly in women who are otherwise at high risk for these events (ie, smokers, those with a past history of blood clots). Higher levels of clotting proteins also increase the risk of blood clots in the major veins of the leg (deep vein thrombosis) and migration of such a blood clot to the lungs (pulmonary embolus). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). Although most abnormal uterine growths are benign (eg, thickening of the lining of the uterus, or polyps), the risk of cancer of the uterus is increased by two- to threefold in women taking tamoxifen.
Benefits — Tamoxifen is effective adjuvant treatment for women of all ages who have hormone responsive breast cancer, whether they have involved lymph nodes (node-positive) or not (node-negative) [1]. The amount of benefit can best be illustrated in results from the Early Breast Cancer Trialists Collaborative Group (EBCTCG), an international group that evaluates the worth of adjuvant therapy for early breast cancer.
Studies have suggested that five years of tamoxifen (compared to no adjuvant treatment) reduces the risk of a breast cancer recurrence by about 40 percent, and the risk of death by about 30 percent [1]. This is a 12 percent reduction in the chance of a breast cancer recurrence within 15 years after treatment, and a 9 percent reduction in the risk of a breast cancer-related death [1].
In addition to reducing the chance of a breast cancer recurrence and death from breast cancer, tamoxifen also decreases the chance that a woman will develop a breast cancer in the opposite breast (contralateral breast cancer) by about one-half.
Duration of therapy — The standard duration of adjuvant tamoxifen is five years. Taking tamoxifen for more than five years does not add further benefit, and the risk of side effects such as uterine cancers increases with longer treatment.
Side effects — Tamoxifen therapy may increase the risk of the following, all of which are more common in women over the age of 50: Cancer of the uterus (endometrial cancers and sarcomas) Blood clots within deep veins, usually in the legs (deep vein thrombosis), which can travel to the lungs (pulmonary embolism) (See "Patient information: Venous thrombosis"). Stroke
Although concerning, this information must be placed in appropriate context for women who are considering tamoxifen for early breast cancer. For most women, the benefits of tamoxifen in preventing a recurrence of breast cancer far outweigh the risks of uterine cancer, blood clots, or other long-term effects. However, the risks may be higher for women with risk factors for blood clots (eg, prior history of blood clots in the leg or lung, history of smoking), and for those who take tamoxifen for longer than five years.
Tamoxifen therapy may also cause other more minor but still bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.
Ovarian function suppression — Ovarian function suppression, which disrupts the ability of the ovaries to make estrogen, can be accomplished in several ways: Surgical removal of the ovaries (called oophorectomy) or radiation treatment of the ovaries, both of which stop the production of hormones permanently The production of estrogen by the ovaries can be temporarily blocked with drugs called gonadotropin releasing hormone (GnRH) agonists. The most commonly used drug in this class is goserelin (Zoladex®), which is given as a monthly injection
In addition, chemotherapy also provides some hormonal effects; many women who receive it become menopausal (ie, their ovaries no longer function), particularly if they are over the age of 40 at the time of treatment. Some physicians believe this is one of the reasons chemotherapy seems to be more beneficial in younger (premenopausal) women. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").
Suppression of ovarian function appears to be as effective as tamoxifen in premenopausal women with early breast cancer. However, in the United States, it is used less often than tamoxifen.
Unlike tamoxifen, ovarian function suppression is not associated with a higher risk of blood clots, stroke, or uterine cancers. However, all forms of ovarian function suppression cause a rapid onset of menopause symptoms (hot flashes, night sweats, mood swings, vaginal dryness), which can be severe. However, women who take GnRH analogs such as goserelin generally resume menstruating when drug treatment is discontinued, causing menopausal symptoms to disappear.
Some trials suggest that combining tamoxifen and ovarian function suppression provides better outcomes than can be achieved by using either treatment alone. However, the best form of adjuvant hormone therapy in premenopausal women is currently unknown. Several important international clinical trials are underway that will help to address the issue of which hormone therapy is best in young women (show table 1). Eligible patients are encouraged to enroll in these trials (www.cancer.gov/clinicaltrials).
Hormone therapy versus chemotherapy versus both — Whether hormone therapy (tamoxifen, ovarian function suppression, or both) is as good as adjuvant chemotherapy in premenopausal women is another controversial issue. Most doctors agree that hormone therapy alone is adequate systemic adjuvant therapy for premenopausal women with node-negative, hormone-responsive breast cancer, as long as the tumor size is small (less than 1 to 2 centimeters) and has no other high-risk features [2,3].
Whether hormone therapy alone is as good as adjuvant chemotherapy for premenopausal women with higher risk ER-positive breast cancers (ie, those with involved lymph nodes, tumor size larger than 2 centimeters, or unfavorable pathologic features) is more controversial, since most of the trials studying this issue have not used the best available chemotherapy regimens. As a result, at least in North America, premenopausal women with node-positive (or higher-risk node-negative) breast cancers are more likely to be offered chemotherapy plus hormone therapy rather than hormone therapy alone.
However, the benefit of chemotherapy for women with ER-positive breast cancer has been called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [4]. When these investigators reviewed the results of newer adjuvant chemotherapy regimens that have been developed over the last 20 years, women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors. As a result, the recommendations for chemotherapy in women with ER-positive breast cancer are difficult to define at present.
It is particularly difficult to know whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with small ER-positive, node-negative breast cancers.
Recommendations of expert groups — The uncertainty of benefit for adding chemotherapy to hormone therapy for women with hormone receptor-positive breast cancer is reflected in the differing recommendations of two major consensus groups, the National Comprehensive Cancer Network (NCCN [2]) and the International Consensus Group [3]. NCCN guidelines suggest adjuvant chemotherapy for patients with tumor size >1 cm or node-positive breast cancer, regardless of hormone receptor status The International Consensus Group guidelines recommend hormone therapy alone for ER-positive node-negative tumors 2 cm as long as they have favorable features, and for some node-positive tumors with fewer than three involved lymph nodes that do not have high risk features (such as HER2).
For higher-risk disease, or in cases where the hormone responsiveness of the tumor is uncertain (for example, if the amount of hormone receptors on the tumor is very small), the addition of chemotherapy is suggested.
Oncotype DX assay — Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive, node-negative breast cancer who will benefit the most from adding chemotherapy to hormone therapy. This test, which is performed by pathologists on a specimen of the breast tumor, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [5]. If the recurrence score indicates that the patient is in a low-risk category, hormone therapy alone may be sufficient, while for patients whose recurrence score puts them in a high-risk category, chemotherapy followed by hormone therapy may provide a better outcome. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in this group.
Whether the information gained from the Oncotype DX assay should be used for clinical decision making regarding the need for adjuvant chemotherapy at this time is controversial. In the opinion of the author, use of this test to select women for adjuvant chemotherapy is still experimental, although the information gained may be used in conjunction with other data when estimating a woman's level of risk of having a breast cancer recurrence.
A web-based assessment program (Adjuvant! Online, www.adjuvantonline.com) can assist in estimating the relative risks and benefits of chemotherapy and hormone therapy in individual women based upon their prognostic profile. Particularly for women who are considering undergoing hormone therapy alone, calculation of the absolute expected survival benefit of adding chemotherapy to hormone therapy using a program such as Adjuvant! Online is recommended by many oncologists [6]. The results are useful in providing complete information regarding the potential benefits she may be giving up if she decides to avoid chemotherapy due to its potential risks. A version of Adjuvant! Online is available that incorporates information derived from the Oncotype DX assay.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 2 (show table 2).
SUMMARY AND RECOMMENDATIONS — The many options for the adjuvant therapy of breast cancer can be very confusing. General guidelines help clarify which therapies are likely to be most appropriate for specific groups of women. However, because individual factors strongly influence the choice of therapy, each woman should discuss the options for adjuvant therapy with her doctor to determine which therapy is best for her.
Adjuvant treatment should be selected based upon the estimated risk of a breast cancer recurrence, and an estimate of the benefits to be achieved using hormone therapy, chemotherapy, or a combination of both approaches. The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. The best adjuvant treatment strategy for premenopausal women with hormone responsive early breast cancer is unknown. We encourage eligible women to enroll in one of the international clinical trials studying this issue (show table 1) [7]. For women who are either not eligible to participate in these trials or who choose not to enroll, international guidelines for breast cancer treatment suggest adjuvant hormone therapy alone for those with ER-positive, node-negative tumors 2 cm as long as they have favorable features. Hormone therapy alone is also recommended for some node-positive tumors with fewer than three involved lymph nodes that do not have high risk features (such as HER2 production).
On the other hand, in the United States, most clinicians follow guidelines from the National Comprehensive Cancer Network, which recommend that hormone therapy alone is appropriate only for women with node-negative tumors, 1 cm or less in size [2].
Particularly for women who are considering treatment with hormone therapy alone, calculation of the absolute expected survival benefit of adding chemotherapy to hormone therapy using a program such as Adjuvant! Online is recommended by many oncologists [6]. The results should be used to fully inform each patient regarding the potential benefits she might be foregoing to avoid the risks of chemotherapy. The optimal hormone therapy (tamoxifen or ovarian function suppression) is controversial. For women who are not eligible or who choose not to participate in a clinical trial, we suggest five years of tamoxifen.
An alternative approach is to use ovarian function suppression; if goserelin is chosen rather than surgical removal of the ovaries, the optimal duration is not known. A combination of tamoxifen and ovarian function suppression is not currently recommended, although this recommendation is also controversial. Gene expression analysis on an individual tumor (ie, the Oncotype DX assay) may be useful to select those women with ER-positive, node-negative breast cancers whose risk of recurrence is low enough to avoid adjuvant chemotherapy. However, due to the scant amount of data available to support the value of this approach, we suggest not basing treatment decisions on the results of the Oncotype DX assay until further data become available. However, many physicians disagree and routinely use this test to assist in the decision-making process.
Two clinical trials are ongoing (the North American TAILORx and European MINDACT trials) to determine the benefit of using gene expression analysis to select the adjuvant treatment strategy; eligible women are encouraged to enroll [8,9]. For higher-risk (ie, node-positive, tumor size >2 cm, adverse pathologic features) early stage breast cancers, or if endocrine responsiveness is uncertain, we recommend hormone therapy in addition to chemotherapy. If combined therapy is chosen, tamoxifen therapy should not be started until after chemotherapy is completed because of concerns that giving both at the same time could decrease the effectiveness of the chemotherapy. Furthermore, there is an increased risk of a blood clot in the legs or lungs when chemotherapy and tamoxifen are given together.
Although the timing of ovarian function suppression is less clearly defined, we suggest waiting until after the completion of chemotherapy to start it as well. A web-based assessment program (Adjuvant! Online) is available (www.adjuvantonline.com) that can assist in estimating the relative risks and benefits of chemotherapy (as well as hormone therapy) in individual women based upon their prognostic profile. A version is available that incorporates information derived from the Oncotype DX assay.
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. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus)
Adjuvant! Online
(www.adjuvantonline.com/)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.
2. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
3. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
4. Berry, DA, Cirrincione, C, Henderson, IC, et al. Estrogen receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006; 295:1658.
5. Paik, S, Shak, S, Tang, G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:2817.
6. Adjuvant! Online program available online at www.adjuvantonline.com (accessed September 6, 2006).
7. Enrollment information for the TEXT, SOFT, and PERCHE trials summarized at www.youngsurvival.org/research/current-studies/clinical-trial-listing/ (Accessed September 6,2006).
8. Information on the TAILORx trial available online at www.cancer.gov/clinicaltrials/ECOG-PACCT-1. (Accessed Spetember 6,2006).
9. Information on the MINDACT trial available online at www.eortc.be/services/unit/mindact/default.asp (accessed September 6,2006).
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