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).
Friday, October 12, 2007
Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal 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 postmenopausal women with hormone-responsive breast cancer. Adjuvant treatment for premenopausal women with hormone-responsive breast cancer is discussed in a separate monograph. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Adjuvant treatment for women with hormone-nonresponsive breast cancers, as well as a discussion about the side effects and indications for chemotherapy and trastuzumab 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. These 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 (PgR), 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 any ER or PgR 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 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 HER1. 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 also 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 HORMONE THERAPY 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, and a woman's menopausal status often determines the type of adjuvant hormone therapy that is recommended. Choices for hormone therapy in postmenopausal women with early breast cancer are 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).
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 which 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 the first two years of 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 women get from taking tamoxifen can best be illustrated by results from a group of breast cancer experts who track the results of clinical studies performed worldwide, called the Early Breast Cancer Trialists Collaborative Group (EBCTCG).
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.
There is added benefit to switching over to an aromatase inhibitor for women who complete five years of tamoxifen. This topic is discussed below. (See "Aromatase inhibitors in addition to tamoxifen" below).
Side effects — Tamoxifen therapy may increase the risk of the following, particularly in women over age 50 years: Cancer of the uterus (endometrial cancer and sarcoma) 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 cause other minor but bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.
Aromatase inhibitors — Aromatase inhibitors (AIs) are drugs that block estrogen from being made in postmenopausal women. They are not effective, and may in fact be dangerous, in premenopausal women.
As adjuvant hormone therapy, AIs such as anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) appear to be at least as effective as tamoxifen in women with early breast cancer. Some of the side effects are similar to those of tamoxifen, while others are different.
Aromatase inhibitors as a substitute for tamoxifen — The similar effectiveness of anastrozole as compared to tamoxifen for adjuvant hormone therapy was suggested by an important large trial called the ATAC trial in which 9366 postmenopausal women with ER-positive breast cancer received anastrozole (1 mg daily), tamoxifen (20 mg daily) or the combination of both drugs for five years [2]. Anastrozole decreased the risk of a breast cancer recurrence beyond that achieved by tamoxifen (the absolute risk was decreased by about 2 percent at four years), and it also significantly decreased the risk of a contralateral breast cancer. There was no advantage to combined therapy. Compared to tamoxifen, anastrozole was associated with fewer blood clots in the legs, uterine cancers, and episodes of vaginal bleeding, but more bone fractures and pain in the muscles and joints.
Similar results have been noted in clinical studies in which a different aromatase inhibitor (letrozole, or Femara®) has been compared directly to tamoxifen.
Aromatase inhibitors in addition to tamoxifen — Other studies suggest that the sequential use of both tamoxifen and AIs may be better than five years of tamoxifen alone: A benefit for continuing treatment with letrozole after five years of tamoxifen was reported in a trial conducted in North America in which 5187 postmenopausal women with early breast cancer received either letrozole (2.5 mg daily for five years) or placebo (a sugar pill) after a standard five-year course of tamoxifen [3]. The study was stopped early when it became evident that women taking letrozole had a significantly lower risk of a breast cancer recurrence. Letrozole was associated with more hot flashes, and muscle and joint aches than were seen in the placebo group. In another study, women who switched over to the AI exemestane (to complete five years of adjuvant hormone treatment) after receiving tamoxifen for two to three years had a better outcome compared to those who took full five years of tamoxifen [4]. A similar result has been shown with anastrozole.
Based upon these results, an expert panel convened by the American Society of Clinical Oncology (ASCO) in 2006 recommended that an aromatase inhibitor be included as a component of adjuvant hormone therapy in all postmenopausal women with hormone-responsive breast cancer [5]. They did not specify whether it was preferable to just give five years of an AI, or start with tamoxifen and then switch over to an AI after either two to three or five years. In addition, it is not known whether there is any benefit to giving tamoxifen after five years of an AI.
Added benefit of chemotherapy — A major area of controversy in breast cancer treatment at present is whether there is benefit to giving chemotherapy in addition to hormone therapy for women with ER-positive breast cancer. Some clinical studies have shown benefit for chemotherapy in this setting, while others have not. In the EBCTCG analysis discussed above, there was a benefit to adding chemotherapy to tamoxifen compared to tamoxifen alone for women with ER-positive breast cancer; however, the magnitude of benefit was significantly smaller for older women age 50 to 69 as compared to those younger than 50 [1].
The benefit of chemotherapy for women with ER-positive breast cancer was further called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [6]. These investigators showed that the benefits from substantial improvements in adjuvant chemotherapy over the last 20 years were not distributed uniformly across all subsets of women with breast cancer. Women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors.
In particular, a major unanswered question is whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with ER-positive, node-negative breast cancers. Adjuvant hormone therapy alone may be sufficient for most women as long as the tumor is small (less than one to two centimeter), and other tumor features are favorable.
Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive node-negative tumors who stand to benefit the most from chemotherapy. This test, which is performed by pathologists on a breast tumor specimen, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [7]. 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.
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 base a decision regarding 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. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in these women.
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.
RECOMMENDATIONS — 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 [8]) and the International Consensus Group [9]. 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.
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 compromise 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.
The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. We suggest hormone therapy alone for women with node-negative tumors 2 cm as long as they have favorable pathologic features, and as a possible alternative for some node-positive tumors with fewer than three involved lymph nodes and no HER2 overexpression or other unfavorable histopathologic features. For higher-risk early stage breast cancers (ie, node-positive, tumor size >2 cm, adverse pathologic features), or if endocrine responsiveness is uncertain, we recommend the addition of chemotherapy. Some clinicians use gene expression analysis (ie, the Oncotype DX assay) to select women with ER-positive, node-negative breast cancer whose risk of recurrence is low enough to avoid adjuvant chemotherapy. We suggest not basing treatment decisions on the recurrence score from the Oncotype DX assay until further data become available, 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) 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. As recommended by ASCO, an aromatase inhibitor-type drug should be included as a component of adjuvant hormone therapy in postmenopausal women who have hormone-responsive breast cancers. It is unknown whether it is better to start with an aromatase inhibitor first, or if it is better to start with tamoxifen. Anastrozole alone for five years is a reasonable option for postmenopausal women, particularly those for whom tamoxifen is not an option (either because it is contraindicated or because of concern for side effects). If tamoxifen is chosen as the initial adjuvant hormone therapy, patients should be switched to an AI after two to three, or five years of tamoxifen. The optimal duration of the AI in this setting is unknown; we recommend five years. Whether there is benefit to tamoxifen after five years of an AI is also unknown. When combined chemotherapy and hormone therapy is used, hormone therapy should not be started until after chemotherapy is completed.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 1 (show table 1).
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)
[1-5,7-10]
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. Baum, M, Buzdar, A, Cuzick, J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98:1802.
3. Goss, PE, Ingle, JN, Martino, S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793.
4. Coombes, RC, Kilburn, LS, Snowdon, CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369:559.
5. Winer, EP, Hudis, C, Burstein, HJ, et al. American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619.
6. 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.
7. 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.
8. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
9. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
10. Enrollment information available at www.cancer.gov/clinicaltrials (Accessed 5/26/05).
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 postmenopausal women with hormone-responsive breast cancer. Adjuvant treatment for premenopausal women with hormone-responsive breast cancer is discussed in a separate monograph. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Adjuvant treatment for women with hormone-nonresponsive breast cancers, as well as a discussion about the side effects and indications for chemotherapy and trastuzumab 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. These 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 (PgR), 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 any ER or PgR 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 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 HER1. 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 also 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 HORMONE THERAPY 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, and a woman's menopausal status often determines the type of adjuvant hormone therapy that is recommended. Choices for hormone therapy in postmenopausal women with early breast cancer are 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).
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 which 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 the first two years of 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 women get from taking tamoxifen can best be illustrated by results from a group of breast cancer experts who track the results of clinical studies performed worldwide, called the Early Breast Cancer Trialists Collaborative Group (EBCTCG).
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.
There is added benefit to switching over to an aromatase inhibitor for women who complete five years of tamoxifen. This topic is discussed below. (See "Aromatase inhibitors in addition to tamoxifen" below).
Side effects — Tamoxifen therapy may increase the risk of the following, particularly in women over age 50 years: Cancer of the uterus (endometrial cancer and sarcoma) 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 cause other minor but bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.
Aromatase inhibitors — Aromatase inhibitors (AIs) are drugs that block estrogen from being made in postmenopausal women. They are not effective, and may in fact be dangerous, in premenopausal women.
As adjuvant hormone therapy, AIs such as anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) appear to be at least as effective as tamoxifen in women with early breast cancer. Some of the side effects are similar to those of tamoxifen, while others are different.
Aromatase inhibitors as a substitute for tamoxifen — The similar effectiveness of anastrozole as compared to tamoxifen for adjuvant hormone therapy was suggested by an important large trial called the ATAC trial in which 9366 postmenopausal women with ER-positive breast cancer received anastrozole (1 mg daily), tamoxifen (20 mg daily) or the combination of both drugs for five years [2]. Anastrozole decreased the risk of a breast cancer recurrence beyond that achieved by tamoxifen (the absolute risk was decreased by about 2 percent at four years), and it also significantly decreased the risk of a contralateral breast cancer. There was no advantage to combined therapy. Compared to tamoxifen, anastrozole was associated with fewer blood clots in the legs, uterine cancers, and episodes of vaginal bleeding, but more bone fractures and pain in the muscles and joints.
Similar results have been noted in clinical studies in which a different aromatase inhibitor (letrozole, or Femara®) has been compared directly to tamoxifen.
Aromatase inhibitors in addition to tamoxifen — Other studies suggest that the sequential use of both tamoxifen and AIs may be better than five years of tamoxifen alone: A benefit for continuing treatment with letrozole after five years of tamoxifen was reported in a trial conducted in North America in which 5187 postmenopausal women with early breast cancer received either letrozole (2.5 mg daily for five years) or placebo (a sugar pill) after a standard five-year course of tamoxifen [3]. The study was stopped early when it became evident that women taking letrozole had a significantly lower risk of a breast cancer recurrence. Letrozole was associated with more hot flashes, and muscle and joint aches than were seen in the placebo group. In another study, women who switched over to the AI exemestane (to complete five years of adjuvant hormone treatment) after receiving tamoxifen for two to three years had a better outcome compared to those who took full five years of tamoxifen [4]. A similar result has been shown with anastrozole.
Based upon these results, an expert panel convened by the American Society of Clinical Oncology (ASCO) in 2006 recommended that an aromatase inhibitor be included as a component of adjuvant hormone therapy in all postmenopausal women with hormone-responsive breast cancer [5]. They did not specify whether it was preferable to just give five years of an AI, or start with tamoxifen and then switch over to an AI after either two to three or five years. In addition, it is not known whether there is any benefit to giving tamoxifen after five years of an AI.
Added benefit of chemotherapy — A major area of controversy in breast cancer treatment at present is whether there is benefit to giving chemotherapy in addition to hormone therapy for women with ER-positive breast cancer. Some clinical studies have shown benefit for chemotherapy in this setting, while others have not. In the EBCTCG analysis discussed above, there was a benefit to adding chemotherapy to tamoxifen compared to tamoxifen alone for women with ER-positive breast cancer; however, the magnitude of benefit was significantly smaller for older women age 50 to 69 as compared to those younger than 50 [1].
The benefit of chemotherapy for women with ER-positive breast cancer was further called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [6]. These investigators showed that the benefits from substantial improvements in adjuvant chemotherapy over the last 20 years were not distributed uniformly across all subsets of women with breast cancer. Women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors.
In particular, a major unanswered question is whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with ER-positive, node-negative breast cancers. Adjuvant hormone therapy alone may be sufficient for most women as long as the tumor is small (less than one to two centimeter), and other tumor features are favorable.
Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive node-negative tumors who stand to benefit the most from chemotherapy. This test, which is performed by pathologists on a breast tumor specimen, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [7]. 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.
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 base a decision regarding 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. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in these women.
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.
RECOMMENDATIONS — 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 [8]) and the International Consensus Group [9]. 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.
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 compromise 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.
The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. We suggest hormone therapy alone for women with node-negative tumors 2 cm as long as they have favorable pathologic features, and as a possible alternative for some node-positive tumors with fewer than three involved lymph nodes and no HER2 overexpression or other unfavorable histopathologic features. For higher-risk early stage breast cancers (ie, node-positive, tumor size >2 cm, adverse pathologic features), or if endocrine responsiveness is uncertain, we recommend the addition of chemotherapy. Some clinicians use gene expression analysis (ie, the Oncotype DX assay) to select women with ER-positive, node-negative breast cancer whose risk of recurrence is low enough to avoid adjuvant chemotherapy. We suggest not basing treatment decisions on the recurrence score from the Oncotype DX assay until further data become available, 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) 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. As recommended by ASCO, an aromatase inhibitor-type drug should be included as a component of adjuvant hormone therapy in postmenopausal women who have hormone-responsive breast cancers. It is unknown whether it is better to start with an aromatase inhibitor first, or if it is better to start with tamoxifen. Anastrozole alone for five years is a reasonable option for postmenopausal women, particularly those for whom tamoxifen is not an option (either because it is contraindicated or because of concern for side effects). If tamoxifen is chosen as the initial adjuvant hormone therapy, patients should be switched to an AI after two to three, or five years of tamoxifen. The optimal duration of the AI in this setting is unknown; we recommend five years. Whether there is benefit to tamoxifen after five years of an AI is also unknown. When combined chemotherapy and hormone therapy is used, hormone therapy should not be started until after chemotherapy is completed.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 1 (show table 1).
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)
[1-5,7-10]
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. Baum, M, Buzdar, A, Cuzick, J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98:1802.
3. Goss, PE, Ingle, JN, Martino, S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793.
4. Coombes, RC, Kilburn, LS, Snowdon, CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369:559.
5. Winer, EP, Hudis, C, Burstein, HJ, et al. American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619.
6. 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.
7. 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.
8. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
9. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
10. Enrollment information available at www.cancer.gov/clinicaltrials (Accessed 5/26/05).
Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal 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 postmenopausal women with hormone-responsive breast cancer. Adjuvant treatment for premenopausal women with hormone-responsive breast cancer is discussed in a separate monograph. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Adjuvant treatment for women with hormone-nonresponsive breast cancers, as well as a discussion about the side effects and indications for chemotherapy and trastuzumab 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. These 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 (PgR), 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 any ER or PgR 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 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 HER1. 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 also 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 HORMONE THERAPY 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, and a woman's menopausal status often determines the type of adjuvant hormone therapy that is recommended. Choices for hormone therapy in postmenopausal women with early breast cancer are 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).
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 which 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 the first two years of 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 women get from taking tamoxifen can best be illustrated by results from a group of breast cancer experts who track the results of clinical studies performed worldwide, called the Early Breast Cancer Trialists Collaborative Group (EBCTCG).
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.
There is added benefit to switching over to an aromatase inhibitor for women who complete five years of tamoxifen. This topic is discussed below. (See "Aromatase inhibitors in addition to tamoxifen" below).
Side effects — Tamoxifen therapy may increase the risk of the following, particularly in women over age 50 years: Cancer of the uterus (endometrial cancer and sarcoma) 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 cause other minor but bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.
Aromatase inhibitors — Aromatase inhibitors (AIs) are drugs that block estrogen from being made in postmenopausal women. They are not effective, and may in fact be dangerous, in premenopausal women.
As adjuvant hormone therapy, AIs such as anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) appear to be at least as effective as tamoxifen in women with early breast cancer. Some of the side effects are similar to those of tamoxifen, while others are different.
Aromatase inhibitors as a substitute for tamoxifen — The similar effectiveness of anastrozole as compared to tamoxifen for adjuvant hormone therapy was suggested by an important large trial called the ATAC trial in which 9366 postmenopausal women with ER-positive breast cancer received anastrozole (1 mg daily), tamoxifen (20 mg daily) or the combination of both drugs for five years [2]. Anastrozole decreased the risk of a breast cancer recurrence beyond that achieved by tamoxifen (the absolute risk was decreased by about 2 percent at four years), and it also significantly decreased the risk of a contralateral breast cancer. There was no advantage to combined therapy. Compared to tamoxifen, anastrozole was associated with fewer blood clots in the legs, uterine cancers, and episodes of vaginal bleeding, but more bone fractures and pain in the muscles and joints.
Similar results have been noted in clinical studies in which a different aromatase inhibitor (letrozole, or Femara®) has been compared directly to tamoxifen.
Aromatase inhibitors in addition to tamoxifen — Other studies suggest that the sequential use of both tamoxifen and AIs may be better than five years of tamoxifen alone: A benefit for continuing treatment with letrozole after five years of tamoxifen was reported in a trial conducted in North America in which 5187 postmenopausal women with early breast cancer received either letrozole (2.5 mg daily for five years) or placebo (a sugar pill) after a standard five-year course of tamoxifen [3]. The study was stopped early when it became evident that women taking letrozole had a significantly lower risk of a breast cancer recurrence. Letrozole was associated with more hot flashes, and muscle and joint aches than were seen in the placebo group. In another study, women who switched over to the AI exemestane (to complete five years of adjuvant hormone treatment) after receiving tamoxifen for two to three years had a better outcome compared to those who took full five years of tamoxifen [4]. A similar result has been shown with anastrozole.
Based upon these results, an expert panel convened by the American Society of Clinical Oncology (ASCO) in 2006 recommended that an aromatase inhibitor be included as a component of adjuvant hormone therapy in all postmenopausal women with hormone-responsive breast cancer [5]. They did not specify whether it was preferable to just give five years of an AI, or start with tamoxifen and then switch over to an AI after either two to three or five years. In addition, it is not known whether there is any benefit to giving tamoxifen after five years of an AI.
Added benefit of chemotherapy — A major area of controversy in breast cancer treatment at present is whether there is benefit to giving chemotherapy in addition to hormone therapy for women with ER-positive breast cancer. Some clinical studies have shown benefit for chemotherapy in this setting, while others have not. In the EBCTCG analysis discussed above, there was a benefit to adding chemotherapy to tamoxifen compared to tamoxifen alone for women with ER-positive breast cancer; however, the magnitude of benefit was significantly smaller for older women age 50 to 69 as compared to those younger than 50 [1].
The benefit of chemotherapy for women with ER-positive breast cancer was further called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [6]. These investigators showed that the benefits from substantial improvements in adjuvant chemotherapy over the last 20 years were not distributed uniformly across all subsets of women with breast cancer. Women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors.
In particular, a major unanswered question is whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with ER-positive, node-negative breast cancers. Adjuvant hormone therapy alone may be sufficient for most women as long as the tumor is small (less than one to two centimeter), and other tumor features are favorable.
Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive node-negative tumors who stand to benefit the most from chemotherapy. This test, which is performed by pathologists on a breast tumor specimen, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [7]. 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.
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 base a decision regarding 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. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in these women.
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.
RECOMMENDATIONS — 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 [8]) and the International Consensus Group [9]. 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.
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 compromise 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.
The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. We suggest hormone therapy alone for women with node-negative tumors 2 cm as long as they have favorable pathologic features, and as a possible alternative for some node-positive tumors with fewer than three involved lymph nodes and no HER2 overexpression or other unfavorable histopathologic features. For higher-risk early stage breast cancers (ie, node-positive, tumor size >2 cm, adverse pathologic features), or if endocrine responsiveness is uncertain, we recommend the addition of chemotherapy. Some clinicians use gene expression analysis (ie, the Oncotype DX assay) to select women with ER-positive, node-negative breast cancer whose risk of recurrence is low enough to avoid adjuvant chemotherapy. We suggest not basing treatment decisions on the recurrence score from the Oncotype DX assay until further data become available, 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) 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. As recommended by ASCO, an aromatase inhibitor-type drug should be included as a component of adjuvant hormone therapy in postmenopausal women who have hormone-responsive breast cancers. It is unknown whether it is better to start with an aromatase inhibitor first, or if it is better to start with tamoxifen. Anastrozole alone for five years is a reasonable option for postmenopausal women, particularly those for whom tamoxifen is not an option (either because it is contraindicated or because of concern for side effects). If tamoxifen is chosen as the initial adjuvant hormone therapy, patients should be switched to an AI after two to three, or five years of tamoxifen. The optimal duration of the AI in this setting is unknown; we recommend five years. Whether there is benefit to tamoxifen after five years of an AI is also unknown. When combined chemotherapy and hormone therapy is used, hormone therapy should not be started until after chemotherapy is completed.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 1 (show table 1).
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)
[1-5,7-10]
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. Baum, M, Buzdar, A, Cuzick, J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98:1802.
3. Goss, PE, Ingle, JN, Martino, S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793.
4. Coombes, RC, Kilburn, LS, Snowdon, CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369:559.
5. Winer, EP, Hudis, C, Burstein, HJ, et al. American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619.
6. 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.
7. 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.
8. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
9. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
10. Enrollment information available at www.cancer.gov/clinicaltrials (Accessed 5/26/05).
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 postmenopausal women with hormone-responsive breast cancer. Adjuvant treatment for premenopausal women with hormone-responsive breast cancer is discussed in a separate monograph. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Adjuvant treatment for women with hormone-nonresponsive breast cancers, as well as a discussion about the side effects and indications for chemotherapy and trastuzumab 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. These 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 (PgR), 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 any ER or PgR 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 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 HER1. 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 also 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 HORMONE THERAPY 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, and a woman's menopausal status often determines the type of adjuvant hormone therapy that is recommended. Choices for hormone therapy in postmenopausal women with early breast cancer are 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).
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 which 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 the first two years of 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 women get from taking tamoxifen can best be illustrated by results from a group of breast cancer experts who track the results of clinical studies performed worldwide, called the Early Breast Cancer Trialists Collaborative Group (EBCTCG).
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.
There is added benefit to switching over to an aromatase inhibitor for women who complete five years of tamoxifen. This topic is discussed below. (See "Aromatase inhibitors in addition to tamoxifen" below).
Side effects — Tamoxifen therapy may increase the risk of the following, particularly in women over age 50 years: Cancer of the uterus (endometrial cancer and sarcoma) 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 cause other minor but bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.
Aromatase inhibitors — Aromatase inhibitors (AIs) are drugs that block estrogen from being made in postmenopausal women. They are not effective, and may in fact be dangerous, in premenopausal women.
As adjuvant hormone therapy, AIs such as anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) appear to be at least as effective as tamoxifen in women with early breast cancer. Some of the side effects are similar to those of tamoxifen, while others are different.
Aromatase inhibitors as a substitute for tamoxifen — The similar effectiveness of anastrozole as compared to tamoxifen for adjuvant hormone therapy was suggested by an important large trial called the ATAC trial in which 9366 postmenopausal women with ER-positive breast cancer received anastrozole (1 mg daily), tamoxifen (20 mg daily) or the combination of both drugs for five years [2]. Anastrozole decreased the risk of a breast cancer recurrence beyond that achieved by tamoxifen (the absolute risk was decreased by about 2 percent at four years), and it also significantly decreased the risk of a contralateral breast cancer. There was no advantage to combined therapy. Compared to tamoxifen, anastrozole was associated with fewer blood clots in the legs, uterine cancers, and episodes of vaginal bleeding, but more bone fractures and pain in the muscles and joints.
Similar results have been noted in clinical studies in which a different aromatase inhibitor (letrozole, or Femara®) has been compared directly to tamoxifen.
Aromatase inhibitors in addition to tamoxifen — Other studies suggest that the sequential use of both tamoxifen and AIs may be better than five years of tamoxifen alone: A benefit for continuing treatment with letrozole after five years of tamoxifen was reported in a trial conducted in North America in which 5187 postmenopausal women with early breast cancer received either letrozole (2.5 mg daily for five years) or placebo (a sugar pill) after a standard five-year course of tamoxifen [3]. The study was stopped early when it became evident that women taking letrozole had a significantly lower risk of a breast cancer recurrence. Letrozole was associated with more hot flashes, and muscle and joint aches than were seen in the placebo group. In another study, women who switched over to the AI exemestane (to complete five years of adjuvant hormone treatment) after receiving tamoxifen for two to three years had a better outcome compared to those who took full five years of tamoxifen [4]. A similar result has been shown with anastrozole.
Based upon these results, an expert panel convened by the American Society of Clinical Oncology (ASCO) in 2006 recommended that an aromatase inhibitor be included as a component of adjuvant hormone therapy in all postmenopausal women with hormone-responsive breast cancer [5]. They did not specify whether it was preferable to just give five years of an AI, or start with tamoxifen and then switch over to an AI after either two to three or five years. In addition, it is not known whether there is any benefit to giving tamoxifen after five years of an AI.
Added benefit of chemotherapy — A major area of controversy in breast cancer treatment at present is whether there is benefit to giving chemotherapy in addition to hormone therapy for women with ER-positive breast cancer. Some clinical studies have shown benefit for chemotherapy in this setting, while others have not. In the EBCTCG analysis discussed above, there was a benefit to adding chemotherapy to tamoxifen compared to tamoxifen alone for women with ER-positive breast cancer; however, the magnitude of benefit was significantly smaller for older women age 50 to 69 as compared to those younger than 50 [1].
The benefit of chemotherapy for women with ER-positive breast cancer was further called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [6]. These investigators showed that the benefits from substantial improvements in adjuvant chemotherapy over the last 20 years were not distributed uniformly across all subsets of women with breast cancer. Women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors.
In particular, a major unanswered question is whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with ER-positive, node-negative breast cancers. Adjuvant hormone therapy alone may be sufficient for most women as long as the tumor is small (less than one to two centimeter), and other tumor features are favorable.
Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive node-negative tumors who stand to benefit the most from chemotherapy. This test, which is performed by pathologists on a breast tumor specimen, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [7]. 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.
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 base a decision regarding 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. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in these women.
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.
RECOMMENDATIONS — 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 [8]) and the International Consensus Group [9]. 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.
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 compromise 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.
The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. We suggest hormone therapy alone for women with node-negative tumors 2 cm as long as they have favorable pathologic features, and as a possible alternative for some node-positive tumors with fewer than three involved lymph nodes and no HER2 overexpression or other unfavorable histopathologic features. For higher-risk early stage breast cancers (ie, node-positive, tumor size >2 cm, adverse pathologic features), or if endocrine responsiveness is uncertain, we recommend the addition of chemotherapy. Some clinicians use gene expression analysis (ie, the Oncotype DX assay) to select women with ER-positive, node-negative breast cancer whose risk of recurrence is low enough to avoid adjuvant chemotherapy. We suggest not basing treatment decisions on the recurrence score from the Oncotype DX assay until further data become available, 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) 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. As recommended by ASCO, an aromatase inhibitor-type drug should be included as a component of adjuvant hormone therapy in postmenopausal women who have hormone-responsive breast cancers. It is unknown whether it is better to start with an aromatase inhibitor first, or if it is better to start with tamoxifen. Anastrozole alone for five years is a reasonable option for postmenopausal women, particularly those for whom tamoxifen is not an option (either because it is contraindicated or because of concern for side effects). If tamoxifen is chosen as the initial adjuvant hormone therapy, patients should be switched to an AI after two to three, or five years of tamoxifen. The optimal duration of the AI in this setting is unknown; we recommend five years. Whether there is benefit to tamoxifen after five years of an AI is also unknown. When combined chemotherapy and hormone therapy is used, hormone therapy should not be started until after chemotherapy is completed.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 1 (show table 1).
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)
[1-5,7-10]
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. Baum, M, Buzdar, A, Cuzick, J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003; 98:1802.
3. Goss, PE, Ingle, JN, Martino, S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793.
4. Coombes, RC, Kilburn, LS, Snowdon, CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369:559.
5. Winer, EP, Hudis, C, Burstein, HJ, et al. American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619.
6. 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.
7. 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.
8. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
9. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
10. Enrollment information available at www.cancer.gov/clinicaltrials (Accessed 5/26/05).
Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer
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 cancers are confined to the breast, while a substantial number of women with spread to the local lymph nodes 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"). This topic review will focus on the use of adjuvant chemotherapy and trastuzumab (Herceptin®) after surgery in women with early stage breast cancer.
SURGICAL TREATMENT — Surgery for localized breast cancer consists of either a mastectomy (removal of the entire breast) or breast-conserving surgery (often called lumpectomy because it removes only the cancerous tissue, preserving the unaffected part of the breast) (show figure 1). If breast-conserving surgery is chosen, radiation treatment to the remainder of the breast is needed. Together, breast-conserving surgery and radiation are referred to as breast-conserving treatment. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Lymph nodes — Even if a breast cancer is removed completely, there is still a risk that cancer cells have broken away from the tumor and spread to other parts of the body. The most common site of spread is the lymph nodes (glands) located in the armpit (also called the axilla). These nodes are usually removed by the surgeon and examined under the microscope for evidence of cancer spread. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Management of axillary lymph nodes).
If cancer cells are found in the lymph nodes (node-positive breast cancer), there is a higher chance that the cancer has spread elsewhere. Even if no cancer cells are detected (node-negative breast cancer), there is still a chance that the tumor could have spread elsewhere in the body; however the chance of spread is 50 percent lower if the nodes are uninvolved.
DEFINING ADJUVANT THERAPY — The term "adjuvant therapy" refers to any additional anticancer treatment that is given after a cancer is surgically removed. The purpose is to eliminate any remaining tumor cells in the body (often termed micrometastases). Advances in adjuvant therapy have improved the chance of curing localized breast cancer and decreased the risk of dying of breast cancer by 20 to 30 percent. Thus, adjuvant therapy is a very important component of modern breast cancer treatment.
Choice of therapy — There are three different types of systemic (bodywide) adjuvant therapy that are useful in women with breast cancer: hormone therapy, chemotherapy, and trastuzumab (Herceptin®). The choice of which treatment to use is mainly dependent upon whether a woman's breast cancer is hormone-responsive and whether it makes a protein called HER2.
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 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. (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").
Hormone-responsive breast cancers appear to benefit less from chemotherapy than do those that are hormone nonresponsive. Nevertheless, chemotherapy may still be recommended, in addition to hormone therapy, for some ER-positive tumors, particularly if there is node-positive disease, a large tumor size, or other features that suggest a higher risk for a cancer recurrence. (See "Indications for chemotherapy" below).
HER2 expression — Breast cancers that make high levels of the protein tumor marker HER2 (ie, those that overexpress HER2) have a poorer prognosis (outcome) as compared to those that either do not make this protein or make lower levels. On the other hand, overexpression of HER2 also identifies those women who may benefit from the targeted drug Herceptin, and those who do better with chemotherapy regimens that contain a drug of the anthracycline class (see below).
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues.
Modern adjuvant chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. Most drugs are given intravenously (IV) rather than by mouth. They are not usually taken daily, but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen is a one hour IV infusion of two different chemotherapy medications given once every three weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three months, four cycles of chemotherapy would be administered.
Types of chemotherapy — There are many different types of adjuvant chemotherapy regimens. They differ with regard to the specific chemotherapy drugs that are given, the number of treatment days within the cycle, and the duration of each cycle.
There are two broad categories of chemotherapy regimens for the adjuvant treatment of breast cancer. These regimens vary based on the drugs they contain, how they are given, and also in the side effects they cause. CMF-type chemotherapy Anthracycline-based chemotherapy (using either doxorubicin [Adriamycin®] or epirubicin [Ellence®]), which may be combined with a taxane (paclitaxel [Taxol®] or docetaxel [Taxotere®])
Anthracycline-based regimens can cause hair loss, vomiting, and mouth soreness (mucositis) and have a long-term risk of heart muscle damage. In contrast, CMF is more likely to cause nausea (especially the oral version, see below), and premature menopause. (See "Side effects of chemotherapy" below).
CMF chemotherapy — The CMF chemotherapy regimen includes a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (abbreviated 5-FU). This combination can be administered entirely IV (called IV CMF), or with oral cyclophosphamide plus IV methotrexate and 5-FU (termed oral or classic CMF). Most doctors consider oral CMF to be more effective than the all-IV version.
Anthracycline-based chemotherapy — There are several different regimens of anthracycline-based chemotherapy: AC chemotherapy — doxorubicin and cyclophosphamide CAF or FAC chemotherapy — cyclophosphamide, doxorubicin, and 5-FU CEF or FEC chemotherapy — cyclophosphamide, epirubicin, and 5-FU
CMF versus anthracycline-based chemotherapy — Several studies have compared the benefits of CMF versus anthracycline-based adjuvant chemotherapy in women with early breast cancer. In general, anthracycline-containing chemotherapy regimens seem to provide modestly better outcomes over CMF chemotherapy, particularly for women with HER2 overexpression, and are preferred in most cases. If an anthracycline-type drug cannot be used (eg, if a woman has underlying heart disease, or if she received prior anthracycline-based therapy for a previous breast cancer), oral CMF or another type of chemotherapy that does not contain an anthracycline may be used.
Taxane-containing chemotherapy — Taxanes (paclitaxel or docetaxel) are usually combined with an anthracycline-based chemotherapy regimen. One active non-anthracycline-containing taxane regimen is TC (docetaxel plus cyclophosphamide).
Taxanes are some of the most effective drugs for women with advanced breast cancer. An increasing amount of data supports their use in women with earlier-stage breast cancer. Taxanes are now routinely included as a component of the adjuvant chemotherapy regimen for women with node-positive breast cancer, and for some high-risk node-negative breast cancers. A popular type of anthracycline- and taxane-containing adjuvant chemotherapy called dose-dense therapy is discussed below. (See "Dose-dense therapy" below).
INDICATIONS FOR CHEMOTHERAPY — Combination chemotherapy is the adjuvant treatment of choice for women with hormone-nonresponsive (ie, ER-negative) breast cancer. It is also appropriate for some women with hormone-responsive breast cancer, in conjunction with hormone therapy, although there is some disagreement as to which of these patients needs chemotherapy. This is due, at least in part, to the more favorable prognosis of these tumors and the more marginal benefits of chemotherapy in this group [1].
Recommendations from expert groups — This disagreement is reflected in the differing recommendations of expert groups.
NCCN guidelines — In the United States, many doctors follow the recommendations of the National Comprehensive Cancer Network (NCCN). [2]. Chemotherapy is recommended for women whose breast cancers are node-positive or 1 centimeter in size, regardless of hormone-responsiveness.
International Consensus Panel — Practice outside the United States is more often guided by recommendations from the International Consensus Panel on the Primary Therapy of Early Breast Cancer [3]. Unlike the NCCN recommendations, these guidelines consider HER2 expression and other pathologic features in addition to node status and tumor size. Their recommendations are presented in Table 1 (show table 1). Recommendations are based upon the estimated risk of cancer recurrence, outlined in the Table (show table 2). For hormone-nonresponsive breast cancer, adjuvant chemotherapy is recommended for those with either intermediate-risk or high-risk disease (show table 2). For hormone-responsive, node-negative breast cancers 2 centimeters in size, and for some node-positive tumors with few (less than four) involved lymph nodes, adjuvant hormone therapy alone is considered sufficient as long as a woman has low-risk disease (defined as tumors that are low-grade [grade 1], no evidence that the cancer has invaded blood or lymph vessels, and no evidence of HER2 overexpression).
The addition of adjuvant chemotherapy to hormone therapy is suggested for women with hormone-responsive, higher-risk disease.
Tools to help in making treatment decisions — Not all women benefit from or need adjuvant chemotherapy. Two tools are available to estimate the likelihood of a breast cancer recurrence and the relative risks and benefits of adjuvant therapy in individual women.
Adjuvant! Online — The Adjuvant! Online program (www.adjuvantonline.com) uses data from a large number of breast cancer patients and a proprietary formula to estimate an individual woman's prognosis and the benefit of adjuvant systemic therapy (hormone therapy, chemotherapy, and Herceptin).
Oncotype DX assay — Some experts feel that the Oncotype DX assay™ may be useful in deciding which women with node-negative hormone-responsive breast cancer require chemotherapy. This test uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence. If the recurrence score indicates that the patient is in a low-risk category, hormone therapy alone (tamoxifen) may be sufficient, while patients in a higher-risk category may have a better outcome with chemotherapy followed by tamoxifen.
Breast cancer experts disagree about whether the results of the Oncotype DX assay should be used for making decisions about the need for adjuvant chemotherapy. An important clinical trial (The TAILORx trial) is underway to determine the validity of the Oncotype DX results; eligible women are encouraged to enroll [4]. In the meantime, the author of this monograph suggests adding chemotherapy to hormone therapy for women with an intermediate or high recurrence score (18), and hormone therapy alone for women with hormone-responsive, node-negative breast cancer and a low recurrence score (<18).
TIMING, DURATION, SCHEDULING, AND DOSE CONSIDERATIONS — Adjuvant chemotherapy is usually started within four to six weeks after surgery for breast cancer. The optimal duration of CMF or anthracycline-based chemotherapy (with or without a taxane) is between 3 and 6 months. Chemotherapy for more than 6 months is not associated with any benefits, and therapy for less than three months is inferior to treatment for a longer duration. These treatment durations are for chemotherapy only, and do not include Herceptin, which is discussed below.
Scheduling chemotherapy and hormone therapy — In general, hormone therapy should not be started until after chemotherapy is completed. There are concerns that giving both at the same time could decrease the effectiveness of the chemotherapy.
Scheduling chemotherapy and postoperative radiation — Most women who undergo breast-conserving treatment will need radiation to their breast after the tumor is removed surgically. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Because of the risk of side effects, chemotherapy is usually not given at the same time as radiation. Instead, the entire course of chemotherapy is usually administered after surgery, before the start of radiation. Studies show that delaying the radiation until after chemotherapy is finished does not have a detrimental effect on outcome.
The importance of dose — The "dose intensity" of adjuvant chemotherapy refers to the drug doses that are administered in a given amount of time, such as the dose per week. Reducing the chemotherapy dose may decrease some of the beneficial effects of adjuvant therapy. Because of this, every effort should be made to avoid unnecessary dose reductions or delays. Some patients will need injections of proteins called growth factors during therapy to stimulate the bone marrow to produce blood cells (for example Neupogen® or Neulasta®).
Dose-dense therapy — Dose-dense therapy is a method of giving anthracycline and taxane-containing chemotherapy that increases the intensity of therapy by shortening the interval between cycles of therapy from 21 to 14 days. In one trial, dose-dense treatment with doxorubicin, cyclophosphamide, and paclitaxel every 14 days was associated with a significantly greater chance of being alive and free of a breast cancer recurrence at five years as compared to the same regimen given every 21 days [5]. This approach has become popular, at least in the United States, for the treatment of patients with node-positive breast cancer, as long as they do not require Herceptin (see below). Growth factor support is necessary during treatment, which can increase the cost of therapy and produce additional side effects (such as bone pain).
SIDE EFFECTS OF CHEMOTHERAPY — Chemotherapy can be associated with both short-term and long-term side effects. The type and severity of these side effects depends upon the particular regimen used.
Short-term side effects — Side effects that occur while chemotherapy is given are usually temporary and reversible. These include nausea, vomiting, mouth soreness, temporary lowering of the blood counts, and hair loss.
Hair loss — Temporary hair loss (alopecia) occurs in nearly all women who receive chemotherapy containing an anthracycline like doxorubicin or paclitaxel. Many women receiving CMF therapy do not lose as much of their hair.
Lowered blood counts — A moderate reduction in the white blood cell count often occurs 10 to 14 days after each cycle of therapy. However, the likelihood of a serious complication (eg, fever or life-threatening infection) related to a low blood count is small, 2 percent or less. As noted above, some patients will need injections of proteins called growth factors such as Neupogen® or Neulasta® during therapy to stimulate the bone marrow to produce white blood cells
Other blood components, such as red blood cells and platelets, can also decrease during therapy. If needed, injections of a protein growth factor called erythropoietin (Procrit®, Aranesp®) can stimulate the bone marrow to produce red blood cells, and diminish the need for blood transfusions during treatment. Platelets are rarely low enough during treatment to require platelet transfusions.
Nausea, vomiting, mouth soreness, and diarrhea — The majority of women receiving adjuvant chemotherapy will have some nausea or vomiting, although symptoms are severe in less than 5 percent. Most women can be treated with anti-nausea medications at the time of chemotherapy. Nausea is more common with CMF; vomiting is more common with anthracycline-based regimens. Severe mouth soreness (mucositis) is also more common with anthracycline-based regimens than CMF. In contrast, diarrhea is uncommon with AC, but more likely when 5-FU is added to AC (eg, with the CAF or FAC regimens).
Neurologic toxicity — Paclitaxel (and less commonly docetaxel) can be associated with numbness and tingling of the fingers and toes. In general, symptoms tend to improve with time (over weeks to months); if severe, recovery may not be complete.
In addition, temporary pain and soreness of the muscles and joints can occur within 72 hours of treatment. Muscle and joint aches may be diminished by pretreatment with gabapentin (Neurontin®), which decreases nerve pain.
Weight gain — The majority of women treated with adjuvant chemotherapy gain weight during treatment, on average 5 to 20 pounds with CMF, and less with AC. Since obesity has been associated with poorer outcomes in women with breast cancer, a diet and exercise program are important components of adjuvant therapy.
Fatigue — Moderate to severe fatigue is a common complaint during adjuvant chemotherapy. Factors that cause fatigue include low red blood count, hot flashes that lead to sleep disturbance, and depression. Symptoms usually resolve after treatment is completed.
Impaired memory and concentration — Many women have mildly impaired memory and a decreased ability to concentrate while receiving chemotherapy. Typically, these symptoms resolve with time.
Hot flashes — Hot flashes may occur during adjuvant treatment either because of premature menopause caused by the chemotherapy (see below), or because of the use of tamoxifen. Sweating and sleep disturbance may also occur. Several non-estrogenic treatments (eg, the antidepressant venlafaxine [Effexor®]) may provide relief.
Long-term side effects
Premature menopause — Menopause (ovarian failure) may develop prematurely when women are given adjuvant chemotherapy; the risk is greater with CMF or CEF regimens as compared with AC regimens with or without a taxane. In one study, only 18 percent of women between ages 20 and 45 were still menstruating 36 months after CMF chemotherapy was completed, while approximately 50 percent of women were still menstruating 12 months after completing AC chemotherapy (with or without a taxane).
Age at the time of treatment is a significant factor; women who receive CMF after the age of 40 are more likely to develop premature menopause. Chemotherapy may be more effective in premenopausal women who become menopausal. Women who become menopausal prematurely need to address concerns about the risk of bone loss with their healthcare provider.
Effects on the heart — The anthracycline drugs have been associated with damage to the heart muscle in some women. Heart failure occurs in up to 1 percent of women who receive standard adjuvant doses of doxorubicin (300 mg/m2 or less). Factors that increase this risk include high lifetime doses of doxorubicin, older age, a history of prior heart problems, and radiation therapy directed at the chest wall.
The risk of damage to the heart muscle appears to be higher with regimens that combine anthracyclines with Herceptin (see below).
Leukemia — There is a small risk of leukemia related to the use of alkylating agents (eg, cyclophosphamide) or anthracycline-based chemotherapy. The risk depends upon the dose, duration, type of chemotherapy given, and possibly whether hematopoietic growth factors were used during adjuvant therapy.
TRASTUZUMAB (HERCEPTIN) — Herceptin is a novel type of drug that specifically targets the protein HER2, present on the cells of some breast cancers. About 18 to 20 percent of breast cancers express very high levels of this marker, and Herceptin appears to be effective only in this group of women.
Herceptin was previously used only for the treatment of women with advanced breast cancer. However, several studies now demonstrate a significant benefit for adding adjuvant Herceptin to anthracycline- and taxane-containing chemotherapy in women with early stage, node-positive, HER2-overexpressing breast cancer. The use of Herceptin reduced the risk of breast cancer recurrence by about 50 percent, and the risk of death by about 33 percent [6,7].
Administration — Herceptin is given by IV injection over 30 to 90 minutes once per week, usually for one year. It is generally given after anthracycline administration has been completed.
Risks — Women who receive Herceptin in addition to chemotherapy have a small but serious increase in the risk of developing weakening of the heart muscle. In the early studies, approximately two to three percent of patients (2 to 3 of every 100 treated women) developed heart failure requiring treatment with medication, despite careful monitoring for early signs of heart problems. Furthermore, the long-term risk may be underestimated since initial reports only included short-term follow-up.
Heart failure is a serious, sometimes irreversible, and potentially life-threatening disease. However, the small risk of heart failure must be balanced against the increased risk of dying from breast caner for women with node-positive, HER2 overexpressing breast cancers. Ongoing studies are trying to determine whether combinations of Herceptin with non-anthracycline-containing chemotherapy regimens are as effective as regimens that contain an anthracycline, with less toxic effects on the heart.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 3 (show table 3).
SUMMARY AND RECOMMENDATIONS — There are many options for the adjuvant therapy of breast cancer, and deciding which is best can be confusing. General guidelines help clarify which therapies are most appropriate for large groups of women. 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 based upon her estimated risk of developing a breast cancer recurrence. The web-based program, Adjuvant! Online (www.adjuvantonline.com), can be used to estimate the risk of recurrence, long-term prognosis, and the expected benefit from different adjuvant therapy strategies. (See "Tools to help in making treatment decisions" above).
The following summarizes our general approach to adjuvant therapy:
HER2-negative breast cancer
ER-negative — In general, chemotherapy is recommended for all women with hormone nonresponsive, lymph node-positive breast cancer, and for women with hormone nonresponsive, lymph node-negative breast cancer who have a tumor size greater than 1 centimeter. Whether chemotherapy should be given to women with smaller, ER-negative tumors is controversial; the author suggests chemotherapy to all such women with tumors size >0.6 centimeters.
ER-positive — The recommendations for chemotherapy in women with ER-positive breast cancer are difficult to define at present. Many clinicians in the United States follow guidelines from the NCCN which suggest the addition of chemotherapy to hormone therapy for all patients with node-positive breast cancer or tumor size 1 centimeter [8].
On the other hand, the International Consensus Group suggests that hormone therapy alone is sufficient for patients with tumor size up to 2 cm, favorable pathologic features, and up to three positive nodes as long as their tumor does not overexpress HER2 [3]. In general, we agree with the International Consensus Group approach, but we discuss the pros and cons of chemotherapy individually with these women, taking personal preference into account as well. Although others disagree, we use the results of the Oncotype DX assay to stratify women with ER-positive, node-negative breast cancer into prognostic groups in order to tailor adjuvant therapy. We suggest chemotherapy for women with an intermediate or high recurrence score. We suggest not administering adjuvant chemotherapy to women with ER-positive, node-negative breast cancer and a low recurrence score (<18). Women with hormone-responsive breast cancer who receive both chemotherapy and hormone therapy should be given hormone therapy after chemotherapy has been completed, and not at the same time. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women"). Anthracycline-containing regimens offer a modest but significant benefit over other regimens (ie, CMF-type regimens), and they are preferred (see "CMF versus anthracycline-based chemotherapy" above and see "Tools to help in making treatment decisions" above). A drug of the taxane class (paclitaxel or docetaxel) should be added to anthracycline-containing adjuvant chemotherapy for women with node-positive breast cancer (see "Taxane-containing chemotherapy" above).
HER2-positive — Women whose tumors make high levels of HER2 derive additional benefits from use of Herceptin for one year. Herceptin should not be started until after the anthracycline portion of chemotherapy treatment is completed. However, combined treatment is associated with a small but real increase in the risk of heart muscle weakness (see "Trastuzumab (Herceptin)" 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)
Adjuvant! Online
(www.adjuvantonline.com)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[3,6,7,9-11]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. 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.
2. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls/_english/_breast/contents.asp. (accessed May 19, 2006).
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. Enrollment information for the TAILORx trial available at www.ctsu.org/data/protocols/ECOG/PACCT-1/pfs.pdf (accessed on May 8, 2006).
5. Citron, ML, Berry, DA, Cirrincione, C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21:1431.
6. Romond, EH, Perez, EA, Bryant, J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673.
7. Piccart-Gebhart, MJ, Procter, M, Leyland-Jones, B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659.
8. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org.
9. Shapiro, CL, Recht, A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344:1997.
10. Bines, J, Oleske, DM, Cobleigh, MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14:1718.
11. 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.
Early detection and treatment can often lead to a cure. Cure is most likely in women whose cancers are confined to the breast, while a substantial number of women with spread to the local lymph nodes 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"). This topic review will focus on the use of adjuvant chemotherapy and trastuzumab (Herceptin®) after surgery in women with early stage breast cancer.
SURGICAL TREATMENT — Surgery for localized breast cancer consists of either a mastectomy (removal of the entire breast) or breast-conserving surgery (often called lumpectomy because it removes only the cancerous tissue, preserving the unaffected part of the breast) (show figure 1). If breast-conserving surgery is chosen, radiation treatment to the remainder of the breast is needed. Together, breast-conserving surgery and radiation are referred to as breast-conserving treatment. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Lymph nodes — Even if a breast cancer is removed completely, there is still a risk that cancer cells have broken away from the tumor and spread to other parts of the body. The most common site of spread is the lymph nodes (glands) located in the armpit (also called the axilla). These nodes are usually removed by the surgeon and examined under the microscope for evidence of cancer spread. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy", section on Management of axillary lymph nodes).
If cancer cells are found in the lymph nodes (node-positive breast cancer), there is a higher chance that the cancer has spread elsewhere. Even if no cancer cells are detected (node-negative breast cancer), there is still a chance that the tumor could have spread elsewhere in the body; however the chance of spread is 50 percent lower if the nodes are uninvolved.
DEFINING ADJUVANT THERAPY — The term "adjuvant therapy" refers to any additional anticancer treatment that is given after a cancer is surgically removed. The purpose is to eliminate any remaining tumor cells in the body (often termed micrometastases). Advances in adjuvant therapy have improved the chance of curing localized breast cancer and decreased the risk of dying of breast cancer by 20 to 30 percent. Thus, adjuvant therapy is a very important component of modern breast cancer treatment.
Choice of therapy — There are three different types of systemic (bodywide) adjuvant therapy that are useful in women with breast cancer: hormone therapy, chemotherapy, and trastuzumab (Herceptin®). The choice of which treatment to use is mainly dependent upon whether a woman's breast cancer is hormone-responsive and whether it makes a protein called HER2.
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 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. (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").
Hormone-responsive breast cancers appear to benefit less from chemotherapy than do those that are hormone nonresponsive. Nevertheless, chemotherapy may still be recommended, in addition to hormone therapy, for some ER-positive tumors, particularly if there is node-positive disease, a large tumor size, or other features that suggest a higher risk for a cancer recurrence. (See "Indications for chemotherapy" below).
HER2 expression — Breast cancers that make high levels of the protein tumor marker HER2 (ie, those that overexpress HER2) have a poorer prognosis (outcome) as compared to those that either do not make this protein or make lower levels. On the other hand, overexpression of HER2 also identifies those women who may benefit from the targeted drug Herceptin, and those who do better with chemotherapy regimens that contain a drug of the anthracycline class (see below).
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues.
Modern adjuvant chemotherapy typically involves a combination of two or more drugs; these combinations are referred to as regimens. Most drugs are given intravenously (IV) rather than by mouth. They are not usually taken daily, but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen is a one hour IV infusion of two different chemotherapy medications given once every three weeks. This three week period is one cycle of therapy. If this regimen were repeated for a total of three months, four cycles of chemotherapy would be administered.
Types of chemotherapy — There are many different types of adjuvant chemotherapy regimens. They differ with regard to the specific chemotherapy drugs that are given, the number of treatment days within the cycle, and the duration of each cycle.
There are two broad categories of chemotherapy regimens for the adjuvant treatment of breast cancer. These regimens vary based on the drugs they contain, how they are given, and also in the side effects they cause. CMF-type chemotherapy Anthracycline-based chemotherapy (using either doxorubicin [Adriamycin®] or epirubicin [Ellence®]), which may be combined with a taxane (paclitaxel [Taxol®] or docetaxel [Taxotere®])
Anthracycline-based regimens can cause hair loss, vomiting, and mouth soreness (mucositis) and have a long-term risk of heart muscle damage. In contrast, CMF is more likely to cause nausea (especially the oral version, see below), and premature menopause. (See "Side effects of chemotherapy" below).
CMF chemotherapy — The CMF chemotherapy regimen includes a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (abbreviated 5-FU). This combination can be administered entirely IV (called IV CMF), or with oral cyclophosphamide plus IV methotrexate and 5-FU (termed oral or classic CMF). Most doctors consider oral CMF to be more effective than the all-IV version.
Anthracycline-based chemotherapy — There are several different regimens of anthracycline-based chemotherapy: AC chemotherapy — doxorubicin and cyclophosphamide CAF or FAC chemotherapy — cyclophosphamide, doxorubicin, and 5-FU CEF or FEC chemotherapy — cyclophosphamide, epirubicin, and 5-FU
CMF versus anthracycline-based chemotherapy — Several studies have compared the benefits of CMF versus anthracycline-based adjuvant chemotherapy in women with early breast cancer. In general, anthracycline-containing chemotherapy regimens seem to provide modestly better outcomes over CMF chemotherapy, particularly for women with HER2 overexpression, and are preferred in most cases. If an anthracycline-type drug cannot be used (eg, if a woman has underlying heart disease, or if she received prior anthracycline-based therapy for a previous breast cancer), oral CMF or another type of chemotherapy that does not contain an anthracycline may be used.
Taxane-containing chemotherapy — Taxanes (paclitaxel or docetaxel) are usually combined with an anthracycline-based chemotherapy regimen. One active non-anthracycline-containing taxane regimen is TC (docetaxel plus cyclophosphamide).
Taxanes are some of the most effective drugs for women with advanced breast cancer. An increasing amount of data supports their use in women with earlier-stage breast cancer. Taxanes are now routinely included as a component of the adjuvant chemotherapy regimen for women with node-positive breast cancer, and for some high-risk node-negative breast cancers. A popular type of anthracycline- and taxane-containing adjuvant chemotherapy called dose-dense therapy is discussed below. (See "Dose-dense therapy" below).
INDICATIONS FOR CHEMOTHERAPY — Combination chemotherapy is the adjuvant treatment of choice for women with hormone-nonresponsive (ie, ER-negative) breast cancer. It is also appropriate for some women with hormone-responsive breast cancer, in conjunction with hormone therapy, although there is some disagreement as to which of these patients needs chemotherapy. This is due, at least in part, to the more favorable prognosis of these tumors and the more marginal benefits of chemotherapy in this group [1].
Recommendations from expert groups — This disagreement is reflected in the differing recommendations of expert groups.
NCCN guidelines — In the United States, many doctors follow the recommendations of the National Comprehensive Cancer Network (NCCN). [2]. Chemotherapy is recommended for women whose breast cancers are node-positive or 1 centimeter in size, regardless of hormone-responsiveness.
International Consensus Panel — Practice outside the United States is more often guided by recommendations from the International Consensus Panel on the Primary Therapy of Early Breast Cancer [3]. Unlike the NCCN recommendations, these guidelines consider HER2 expression and other pathologic features in addition to node status and tumor size. Their recommendations are presented in Table 1 (show table 1). Recommendations are based upon the estimated risk of cancer recurrence, outlined in the Table (show table 2). For hormone-nonresponsive breast cancer, adjuvant chemotherapy is recommended for those with either intermediate-risk or high-risk disease (show table 2). For hormone-responsive, node-negative breast cancers 2 centimeters in size, and for some node-positive tumors with few (less than four) involved lymph nodes, adjuvant hormone therapy alone is considered sufficient as long as a woman has low-risk disease (defined as tumors that are low-grade [grade 1], no evidence that the cancer has invaded blood or lymph vessels, and no evidence of HER2 overexpression).
The addition of adjuvant chemotherapy to hormone therapy is suggested for women with hormone-responsive, higher-risk disease.
Tools to help in making treatment decisions — Not all women benefit from or need adjuvant chemotherapy. Two tools are available to estimate the likelihood of a breast cancer recurrence and the relative risks and benefits of adjuvant therapy in individual women.
Adjuvant! Online — The Adjuvant! Online program (www.adjuvantonline.com) uses data from a large number of breast cancer patients and a proprietary formula to estimate an individual woman's prognosis and the benefit of adjuvant systemic therapy (hormone therapy, chemotherapy, and Herceptin).
Oncotype DX assay — Some experts feel that the Oncotype DX assay™ may be useful in deciding which women with node-negative hormone-responsive breast cancer require chemotherapy. This test uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence. If the recurrence score indicates that the patient is in a low-risk category, hormone therapy alone (tamoxifen) may be sufficient, while patients in a higher-risk category may have a better outcome with chemotherapy followed by tamoxifen.
Breast cancer experts disagree about whether the results of the Oncotype DX assay should be used for making decisions about the need for adjuvant chemotherapy. An important clinical trial (The TAILORx trial) is underway to determine the validity of the Oncotype DX results; eligible women are encouraged to enroll [4]. In the meantime, the author of this monograph suggests adding chemotherapy to hormone therapy for women with an intermediate or high recurrence score (18), and hormone therapy alone for women with hormone-responsive, node-negative breast cancer and a low recurrence score (<18).
TIMING, DURATION, SCHEDULING, AND DOSE CONSIDERATIONS — Adjuvant chemotherapy is usually started within four to six weeks after surgery for breast cancer. The optimal duration of CMF or anthracycline-based chemotherapy (with or without a taxane) is between 3 and 6 months. Chemotherapy for more than 6 months is not associated with any benefits, and therapy for less than three months is inferior to treatment for a longer duration. These treatment durations are for chemotherapy only, and do not include Herceptin, which is discussed below.
Scheduling chemotherapy and hormone therapy — In general, hormone therapy should not be started until after chemotherapy is completed. There are concerns that giving both at the same time could decrease the effectiveness of the chemotherapy.
Scheduling chemotherapy and postoperative radiation — Most women who undergo breast-conserving treatment will need radiation to their breast after the tumor is removed surgically. (See "Patient information: Localized breast cancer evaluation, mastectomy, and breast conserving therapy").
Because of the risk of side effects, chemotherapy is usually not given at the same time as radiation. Instead, the entire course of chemotherapy is usually administered after surgery, before the start of radiation. Studies show that delaying the radiation until after chemotherapy is finished does not have a detrimental effect on outcome.
The importance of dose — The "dose intensity" of adjuvant chemotherapy refers to the drug doses that are administered in a given amount of time, such as the dose per week. Reducing the chemotherapy dose may decrease some of the beneficial effects of adjuvant therapy. Because of this, every effort should be made to avoid unnecessary dose reductions or delays. Some patients will need injections of proteins called growth factors during therapy to stimulate the bone marrow to produce blood cells (for example Neupogen® or Neulasta®).
Dose-dense therapy — Dose-dense therapy is a method of giving anthracycline and taxane-containing chemotherapy that increases the intensity of therapy by shortening the interval between cycles of therapy from 21 to 14 days. In one trial, dose-dense treatment with doxorubicin, cyclophosphamide, and paclitaxel every 14 days was associated with a significantly greater chance of being alive and free of a breast cancer recurrence at five years as compared to the same regimen given every 21 days [5]. This approach has become popular, at least in the United States, for the treatment of patients with node-positive breast cancer, as long as they do not require Herceptin (see below). Growth factor support is necessary during treatment, which can increase the cost of therapy and produce additional side effects (such as bone pain).
SIDE EFFECTS OF CHEMOTHERAPY — Chemotherapy can be associated with both short-term and long-term side effects. The type and severity of these side effects depends upon the particular regimen used.
Short-term side effects — Side effects that occur while chemotherapy is given are usually temporary and reversible. These include nausea, vomiting, mouth soreness, temporary lowering of the blood counts, and hair loss.
Hair loss — Temporary hair loss (alopecia) occurs in nearly all women who receive chemotherapy containing an anthracycline like doxorubicin or paclitaxel. Many women receiving CMF therapy do not lose as much of their hair.
Lowered blood counts — A moderate reduction in the white blood cell count often occurs 10 to 14 days after each cycle of therapy. However, the likelihood of a serious complication (eg, fever or life-threatening infection) related to a low blood count is small, 2 percent or less. As noted above, some patients will need injections of proteins called growth factors such as Neupogen® or Neulasta® during therapy to stimulate the bone marrow to produce white blood cells
Other blood components, such as red blood cells and platelets, can also decrease during therapy. If needed, injections of a protein growth factor called erythropoietin (Procrit®, Aranesp®) can stimulate the bone marrow to produce red blood cells, and diminish the need for blood transfusions during treatment. Platelets are rarely low enough during treatment to require platelet transfusions.
Nausea, vomiting, mouth soreness, and diarrhea — The majority of women receiving adjuvant chemotherapy will have some nausea or vomiting, although symptoms are severe in less than 5 percent. Most women can be treated with anti-nausea medications at the time of chemotherapy. Nausea is more common with CMF; vomiting is more common with anthracycline-based regimens. Severe mouth soreness (mucositis) is also more common with anthracycline-based regimens than CMF. In contrast, diarrhea is uncommon with AC, but more likely when 5-FU is added to AC (eg, with the CAF or FAC regimens).
Neurologic toxicity — Paclitaxel (and less commonly docetaxel) can be associated with numbness and tingling of the fingers and toes. In general, symptoms tend to improve with time (over weeks to months); if severe, recovery may not be complete.
In addition, temporary pain and soreness of the muscles and joints can occur within 72 hours of treatment. Muscle and joint aches may be diminished by pretreatment with gabapentin (Neurontin®), which decreases nerve pain.
Weight gain — The majority of women treated with adjuvant chemotherapy gain weight during treatment, on average 5 to 20 pounds with CMF, and less with AC. Since obesity has been associated with poorer outcomes in women with breast cancer, a diet and exercise program are important components of adjuvant therapy.
Fatigue — Moderate to severe fatigue is a common complaint during adjuvant chemotherapy. Factors that cause fatigue include low red blood count, hot flashes that lead to sleep disturbance, and depression. Symptoms usually resolve after treatment is completed.
Impaired memory and concentration — Many women have mildly impaired memory and a decreased ability to concentrate while receiving chemotherapy. Typically, these symptoms resolve with time.
Hot flashes — Hot flashes may occur during adjuvant treatment either because of premature menopause caused by the chemotherapy (see below), or because of the use of tamoxifen. Sweating and sleep disturbance may also occur. Several non-estrogenic treatments (eg, the antidepressant venlafaxine [Effexor®]) may provide relief.
Long-term side effects
Premature menopause — Menopause (ovarian failure) may develop prematurely when women are given adjuvant chemotherapy; the risk is greater with CMF or CEF regimens as compared with AC regimens with or without a taxane. In one study, only 18 percent of women between ages 20 and 45 were still menstruating 36 months after CMF chemotherapy was completed, while approximately 50 percent of women were still menstruating 12 months after completing AC chemotherapy (with or without a taxane).
Age at the time of treatment is a significant factor; women who receive CMF after the age of 40 are more likely to develop premature menopause. Chemotherapy may be more effective in premenopausal women who become menopausal. Women who become menopausal prematurely need to address concerns about the risk of bone loss with their healthcare provider.
Effects on the heart — The anthracycline drugs have been associated with damage to the heart muscle in some women. Heart failure occurs in up to 1 percent of women who receive standard adjuvant doses of doxorubicin (300 mg/m2 or less). Factors that increase this risk include high lifetime doses of doxorubicin, older age, a history of prior heart problems, and radiation therapy directed at the chest wall.
The risk of damage to the heart muscle appears to be higher with regimens that combine anthracyclines with Herceptin (see below).
Leukemia — There is a small risk of leukemia related to the use of alkylating agents (eg, cyclophosphamide) or anthracycline-based chemotherapy. The risk depends upon the dose, duration, type of chemotherapy given, and possibly whether hematopoietic growth factors were used during adjuvant therapy.
TRASTUZUMAB (HERCEPTIN) — Herceptin is a novel type of drug that specifically targets the protein HER2, present on the cells of some breast cancers. About 18 to 20 percent of breast cancers express very high levels of this marker, and Herceptin appears to be effective only in this group of women.
Herceptin was previously used only for the treatment of women with advanced breast cancer. However, several studies now demonstrate a significant benefit for adding adjuvant Herceptin to anthracycline- and taxane-containing chemotherapy in women with early stage, node-positive, HER2-overexpressing breast cancer. The use of Herceptin reduced the risk of breast cancer recurrence by about 50 percent, and the risk of death by about 33 percent [6,7].
Administration — Herceptin is given by IV injection over 30 to 90 minutes once per week, usually for one year. It is generally given after anthracycline administration has been completed.
Risks — Women who receive Herceptin in addition to chemotherapy have a small but serious increase in the risk of developing weakening of the heart muscle. In the early studies, approximately two to three percent of patients (2 to 3 of every 100 treated women) developed heart failure requiring treatment with medication, despite careful monitoring for early signs of heart problems. Furthermore, the long-term risk may be underestimated since initial reports only included short-term follow-up.
Heart failure is a serious, sometimes irreversible, and potentially life-threatening disease. However, the small risk of heart failure must be balanced against the increased risk of dying from breast caner for women with node-positive, HER2 overexpressing breast cancers. Ongoing studies are trying to determine whether combinations of Herceptin with non-anthracycline-containing chemotherapy regimens are as effective as regimens that contain an anthracycline, with less toxic effects on the heart.
SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 3 (show table 3).
SUMMARY AND RECOMMENDATIONS — There are many options for the adjuvant therapy of breast cancer, and deciding which is best can be confusing. General guidelines help clarify which therapies are most appropriate for large groups of women. 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 based upon her estimated risk of developing a breast cancer recurrence. The web-based program, Adjuvant! Online (www.adjuvantonline.com), can be used to estimate the risk of recurrence, long-term prognosis, and the expected benefit from different adjuvant therapy strategies. (See "Tools to help in making treatment decisions" above).
The following summarizes our general approach to adjuvant therapy:
HER2-negative breast cancer
ER-negative — In general, chemotherapy is recommended for all women with hormone nonresponsive, lymph node-positive breast cancer, and for women with hormone nonresponsive, lymph node-negative breast cancer who have a tumor size greater than 1 centimeter. Whether chemotherapy should be given to women with smaller, ER-negative tumors is controversial; the author suggests chemotherapy to all such women with tumors size >0.6 centimeters.
ER-positive — The recommendations for chemotherapy in women with ER-positive breast cancer are difficult to define at present. Many clinicians in the United States follow guidelines from the NCCN which suggest the addition of chemotherapy to hormone therapy for all patients with node-positive breast cancer or tumor size 1 centimeter [8].
On the other hand, the International Consensus Group suggests that hormone therapy alone is sufficient for patients with tumor size up to 2 cm, favorable pathologic features, and up to three positive nodes as long as their tumor does not overexpress HER2 [3]. In general, we agree with the International Consensus Group approach, but we discuss the pros and cons of chemotherapy individually with these women, taking personal preference into account as well. Although others disagree, we use the results of the Oncotype DX assay to stratify women with ER-positive, node-negative breast cancer into prognostic groups in order to tailor adjuvant therapy. We suggest chemotherapy for women with an intermediate or high recurrence score. We suggest not administering adjuvant chemotherapy to women with ER-positive, node-negative breast cancer and a low recurrence score (<18). Women with hormone-responsive breast cancer who receive both chemotherapy and hormone therapy should be given hormone therapy after chemotherapy has been completed, and not at the same time. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women"). Anthracycline-containing regimens offer a modest but significant benefit over other regimens (ie, CMF-type regimens), and they are preferred (see "CMF versus anthracycline-based chemotherapy" above and see "Tools to help in making treatment decisions" above). A drug of the taxane class (paclitaxel or docetaxel) should be added to anthracycline-containing adjuvant chemotherapy for women with node-positive breast cancer (see "Taxane-containing chemotherapy" above).
HER2-positive — Women whose tumors make high levels of HER2 derive additional benefits from use of Herceptin for one year. Herceptin should not be started until after the anthracycline portion of chemotherapy treatment is completed. However, combined treatment is associated with a small but real increase in the risk of heart muscle weakness (see "Trastuzumab (Herceptin)" 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)
Adjuvant! Online
(www.adjuvantonline.com)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[3,6,7,9-11]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. 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.
2. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org/patients/patient_gls/_english/_breast/contents.asp. (accessed May 19, 2006).
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. Enrollment information for the TAILORx trial available at www.ctsu.org/data/protocols/ECOG/PACCT-1/pfs.pdf (accessed on May 8, 2006).
5. Citron, ML, Berry, DA, Cirrincione, C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21:1431.
6. Romond, EH, Perez, EA, Bryant, J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673.
7. Piccart-Gebhart, MJ, Procter, M, Leyland-Jones, B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659.
8. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org.
9. Shapiro, CL, Recht, A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344:1997.
10. Bines, J, Oleske, DM, Cobleigh, MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14:1718.
11. 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.
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