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)


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