Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women

INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the primary cause of death in women ages 45 to 55. Each year, 211,000 American women are diagnosed with breast cancer, and 40,000 die from this disease. Early detection and treatment can often lead to a cure. Cure is most likely in women whose breast cancers are confined to the breast, while a substantial number of women with spread to the locoregional lymph nodes (glands) can also be cured with appropriate therapy.

Breast cancer is a very complex topic. An introduction to breast cancer and an overview of available treatments is available elsewhere. (See "Patient information: Breast cancer guide to diagnosis and treatment").

The choices and recommendations for adjuvant therapy are slightly different for postmenopausal and premenopausal women who have hormone-responsive tumors. This topic review will focus on adjuvant therapy for premenopausal women with hormone-responsive breast cancer. Adjuvant treatment for postmenopausal women with hormone-responsive breast cancer is discussed separately. (See "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women").

Adjuvant treatment for women with hormone-nonresponsive breast cancers and a discussion about the side effects and indications for chemotherapy and trastuzumab (Herceptin®) is also presented elsewhere. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").

DEFINING HORMONE-RESPONSIVE BREAST CANCER — About 50 to 70 percent of breast cancers require the female hormone estrogen (estradiol) to grow, while other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce molecules called hormone receptors, which are essential in order for the cell to use estrogen for growth. These hormone receptors can be estrogen receptors (ER), progesterone receptors (PR), or both.

If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen, thus depriving the cancer cells of the material that stimulates their growth. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as "hormone-responsive". In contrast, women whose tumors do not contain ER or PR do not benefit from adjuvant hormone therapy (ie, they are hormone-nonresponsive), and it is not recommended.

ADJUVANT SYSTEMIC THERAPY — Adjuvant systemic therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. It is given to eliminate any remaining tumor cells in the body (often termed micrometastases). Because such therapy decreases the chance that the cancer will return (or recur), it also improves the likelihood of surviving the cancer.

Advances in adjuvant therapy have decreased the risk of dying of breast cancer by 20 to 30 percent, and substantially increased the chance of curing early breast cancer. As a result, adjuvant therapy is a very important component of modern breast cancer treatment. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").

There are three different types of systemic (bodywide) adjuvant therapy that are useful in women with breast cancer: hormone therapy, chemotherapy, and targeted therapy using the monoclonal antibody trastuzumab (Herceptin®). The choice of hormone therapy, chemotherapy, Herceptin, or a combination of these treatments is mainly dependent upon whether a woman's breast cancer is hormone-responsive, and whether it makes a protein called HER2.

In general: When adjuvant systemic therapy is indicated, hormone therapy is used for women with ER/PR-positive breast cancer, while chemotherapy is recommended for women whose breast cancers are ER/PR-negative. Chemotherapy may be recommended in addition to hormone therapy for women with ER/PR-positive breast cancer, particularly if they have node-positive disease, a large tumor size, or other features that suggest a higher risk for a cancer recurrence. The protein tumor marker HER2 indicates which women might benefit from treatment with Herceptin. In addition, preliminary studies suggest that HER2 may help to identify women who are most likely to benefit from specific types of chemotherapy. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").

AVAILABLE TREATMENT OPTIONS — The goal of adjuvant hormone therapy is to prevent breast cancer cells from receiving stimulation from estrogen. There are several ways in which this can be accomplished. Choices for hormone therapy in postmenopausal women with early breast cancer include the drug tamoxifen (which blocks the hormone receptors on breast cancer cells, thus preventing the body's estrogen from interacting with the receptors) and a class of drugs called aromatase inhibitors (AIs).

In contrast, premenopausal (menstruating) women are not routinely offered AIs. Because a premenopausal woman's ovaries are still functioning and making hormones, AIs will cause the ovaries to produce more male rather than female hormones, which is usually not desirable. Instead, the available options for hormone therapy in premenopausal women include the drug tamoxifen and disruption of the ovaries' ability to make estrogen (termed ovarian function suppression) (see "Ovarian function suppression" below).

Tamoxifen — Tamoxifen (Nolvadex®) is a member of a drug class called selective estrogen receptor modulators, or SERMs. SERMs appear chemically similar to estrogen, but are in fact very different. Tamoxifen and other SERMs prevent estrogen from binding to the ER (and thereby preventing it from stimulating growth of the cells). Tamoxifen also interacts directly with the ER, disrupting the normal function of breast cancer cells and the cells of other organs as well. Thus, tamoxifen is associated with effects on bones, the heart, blood clotting, and the uterus. Some of these effects are beneficial, while others are detrimental.

Effects on breast cancer and other organs — The interaction of SERMs with the ER can affect the cells of different organs in ways that mimic the effects of estrogen (referred to as estrogenic effects), or block the effects of estrogen (referred to as antiestrogenic effects). In the same person, SERMs can be antiestrogenic in some tissues and estrogenic in others (show figure 1): Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, in women at high risk for developing breast cancer, taking tamoxifen can prevent new breast cancers. Tamoxifen also has antiestrogenic activity on certain parts of the brain. This can lead to detrimental effects, because it is thought to be the cause of many of the menopausal symptoms (eg, hot flashes, sweating, insomnia) that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in the bones of postmenopausal women, preventing progression of osteoporosis. Tamoxifen is also estrogenic in the liver, and increases the liver's production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during tamoxifen use, particularly in women who are otherwise at high risk for these events (ie, smokers, those with a past history of blood clots). Higher levels of clotting proteins also increase the risk of blood clots in the major veins of the leg (deep vein thrombosis) and migration of such a blood clot to the lungs (pulmonary embolus). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). Although most abnormal uterine growths are benign (eg, thickening of the lining of the uterus, or polyps), the risk of cancer of the uterus is increased by two- to threefold in women taking tamoxifen.

Benefits — Tamoxifen is effective adjuvant treatment for women of all ages who have hormone responsive breast cancer, whether they have involved lymph nodes (node-positive) or not (node-negative) [1]. The amount of benefit can best be illustrated in results from the Early Breast Cancer Trialists Collaborative Group (EBCTCG), an international group that evaluates the worth of adjuvant therapy for early breast cancer.

Studies have suggested that five years of tamoxifen (compared to no adjuvant treatment) reduces the risk of a breast cancer recurrence by about 40 percent, and the risk of death by about 30 percent [1]. This is a 12 percent reduction in the chance of a breast cancer recurrence within 15 years after treatment, and a 9 percent reduction in the risk of a breast cancer-related death [1].

In addition to reducing the chance of a breast cancer recurrence and death from breast cancer, tamoxifen also decreases the chance that a woman will develop a breast cancer in the opposite breast (contralateral breast cancer) by about one-half.

Duration of therapy — The standard duration of adjuvant tamoxifen is five years. Taking tamoxifen for more than five years does not add further benefit, and the risk of side effects such as uterine cancers increases with longer treatment.

Side effects — Tamoxifen therapy may increase the risk of the following, all of which are more common in women over the age of 50: Cancer of the uterus (endometrial cancers and sarcomas) Blood clots within deep veins, usually in the legs (deep vein thrombosis), which can travel to the lungs (pulmonary embolism) (See "Patient information: Venous thrombosis"). Stroke

Although concerning, this information must be placed in appropriate context for women who are considering tamoxifen for early breast cancer. For most women, the benefits of tamoxifen in preventing a recurrence of breast cancer far outweigh the risks of uterine cancer, blood clots, or other long-term effects. However, the risks may be higher for women with risk factors for blood clots (eg, prior history of blood clots in the leg or lung, history of smoking), and for those who take tamoxifen for longer than five years.

Tamoxifen therapy may also cause other more minor but still bothersome side effects, particularly hot flashes, vaginal discharge, and menstrual irregularities.

Ovarian function suppression — Ovarian function suppression, which disrupts the ability of the ovaries to make estrogen, can be accomplished in several ways: Surgical removal of the ovaries (called oophorectomy) or radiation treatment of the ovaries, both of which stop the production of hormones permanently The production of estrogen by the ovaries can be temporarily blocked with drugs called gonadotropin releasing hormone (GnRH) agonists. The most commonly used drug in this class is goserelin (Zoladex®), which is given as a monthly injection

In addition, chemotherapy also provides some hormonal effects; many women who receive it become menopausal (ie, their ovaries no longer function), particularly if they are over the age of 40 at the time of treatment. Some physicians believe this is one of the reasons chemotherapy seems to be more beneficial in younger (premenopausal) women. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").

Suppression of ovarian function appears to be as effective as tamoxifen in premenopausal women with early breast cancer. However, in the United States, it is used less often than tamoxifen.

Unlike tamoxifen, ovarian function suppression is not associated with a higher risk of blood clots, stroke, or uterine cancers. However, all forms of ovarian function suppression cause a rapid onset of menopause symptoms (hot flashes, night sweats, mood swings, vaginal dryness), which can be severe. However, women who take GnRH analogs such as goserelin generally resume menstruating when drug treatment is discontinued, causing menopausal symptoms to disappear.

Some trials suggest that combining tamoxifen and ovarian function suppression provides better outcomes than can be achieved by using either treatment alone. However, the best form of adjuvant hormone therapy in premenopausal women is currently unknown. Several important international clinical trials are underway that will help to address the issue of which hormone therapy is best in young women (show table 1). Eligible patients are encouraged to enroll in these trials (www.cancer.gov/clinicaltrials).

Hormone therapy versus chemotherapy versus both — Whether hormone therapy (tamoxifen, ovarian function suppression, or both) is as good as adjuvant chemotherapy in premenopausal women is another controversial issue. Most doctors agree that hormone therapy alone is adequate systemic adjuvant therapy for premenopausal women with node-negative, hormone-responsive breast cancer, as long as the tumor size is small (less than 1 to 2 centimeters) and has no other high-risk features [2,3].

Whether hormone therapy alone is as good as adjuvant chemotherapy for premenopausal women with higher risk ER-positive breast cancers (ie, those with involved lymph nodes, tumor size larger than 2 centimeters, or unfavorable pathologic features) is more controversial, since most of the trials studying this issue have not used the best available chemotherapy regimens. As a result, at least in North America, premenopausal women with node-positive (or higher-risk node-negative) breast cancers are more likely to be offered chemotherapy plus hormone therapy rather than hormone therapy alone.

However, the benefit of chemotherapy for women with ER-positive breast cancer has been called into question by an analysis of three studies carried out by one of the National Cancer Institute's Cooperative Cancer Groups [4]. When these investigators reviewed the results of newer adjuvant chemotherapy regimens that have been developed over the last 20 years, women with hormone receptor-negative breast cancer benefit the most, while the benefits were marginal (but not zero) for women with hormone-responsive tumors. As a result, the recommendations for chemotherapy in women with ER-positive breast cancer are difficult to define at present.

It is particularly difficult to know whether the benefits of adding chemotherapy to adjuvant hormone therapy outweigh the risks for women with small ER-positive, node-negative breast cancers.

Recommendations of expert groups — The uncertainty of benefit for adding chemotherapy to hormone therapy for women with hormone receptor-positive breast cancer is reflected in the differing recommendations of two major consensus groups, the National Comprehensive Cancer Network (NCCN [2]) and the International Consensus Group [3]. NCCN guidelines suggest adjuvant chemotherapy for patients with tumor size >1 cm or node-positive breast cancer, regardless of hormone receptor status The International Consensus Group guidelines recommend hormone therapy alone for ER-positive node-negative tumors 2 cm as long as they have favorable features, and for some node-positive tumors with fewer than three involved lymph nodes that do not have high risk features (such as HER2).

For higher-risk disease, or in cases where the hormone responsiveness of the tumor is uncertain (for example, if the amount of hormone receptors on the tumor is very small), the addition of chemotherapy is suggested.

Oncotype DX assay — Some experts feel that a new test, the Oncotype DX assay, may be useful in selecting those women with ER-positive, node-negative breast cancer who will benefit the most from adding chemotherapy to hormone therapy. This test, which is performed by pathologists on a specimen of the breast tumor, uses unique features of an individual woman's breast cancer to estimate her risk of a cancer recurrence [5]. If the recurrence score indicates that the patient is in a low-risk category, hormone therapy alone may be sufficient, while for patients whose recurrence score puts them in a high-risk category, chemotherapy followed by hormone therapy may provide a better outcome. This test has not been studied in women with ER-positive node-positive tumors, and should not be used in this group.

Whether the information gained from the Oncotype DX assay should be used for clinical decision making regarding the need for adjuvant chemotherapy at this time is controversial. In the opinion of the author, use of this test to select women for adjuvant chemotherapy is still experimental, although the information gained may be used in conjunction with other data when estimating a woman's level of risk of having a breast cancer recurrence.

A web-based assessment program (Adjuvant! Online, www.adjuvantonline.com) can assist in estimating the relative risks and benefits of chemotherapy and hormone therapy in individual women based upon their prognostic profile. Particularly for women who are considering undergoing hormone therapy alone, calculation of the absolute expected survival benefit of adding chemotherapy to hormone therapy using a program such as Adjuvant! Online is recommended by many oncologists [6]. The results are useful in providing complete information regarding the potential benefits she may be giving up if she decides to avoid chemotherapy due to its potential risks. A version of Adjuvant! Online is available that incorporates information derived from the Oncotype DX assay.

SURVEILLANCE AFTER TREATMENT — A summary of the American Society of Clinical Oncology's recommendations for surveillance after breast cancer treatment is provided in table 2 (show table 2).

SUMMARY AND RECOMMENDATIONS — The many options for the adjuvant therapy of breast cancer can be very confusing. General guidelines help clarify which therapies are likely to be most appropriate for specific groups of women. However, because individual factors strongly influence the choice of therapy, each woman should discuss the options for adjuvant therapy with her doctor to determine which therapy is best for her.

Adjuvant treatment should be selected based upon the estimated risk of a breast cancer recurrence, and an estimate of the benefits to be achieved using hormone therapy, chemotherapy, or a combination of both approaches. The following represent our general recommendations for adjuvant systemic therapy in women with hormone-responsive breast cancer. The best adjuvant treatment strategy for premenopausal women with hormone responsive early breast cancer is unknown. We encourage eligible women to enroll in one of the international clinical trials studying this issue (show table 1) [7]. For women who are either not eligible to participate in these trials or who choose not to enroll, international guidelines for breast cancer treatment suggest adjuvant hormone therapy alone for those with ER-positive, node-negative tumors 2 cm as long as they have favorable features. Hormone therapy alone is also recommended for some node-positive tumors with fewer than three involved lymph nodes that do not have high risk features (such as HER2 production).

On the other hand, in the United States, most clinicians follow guidelines from the National Comprehensive Cancer Network, which recommend that hormone therapy alone is appropriate only for women with node-negative tumors, 1 cm or less in size [2].

Particularly for women who are considering treatment with hormone therapy alone, calculation of the absolute expected survival benefit of adding chemotherapy to hormone therapy using a program such as Adjuvant! Online is recommended by many oncologists [6]. The results should be used to fully inform each patient regarding the potential benefits she might be foregoing to avoid the risks of chemotherapy. The optimal hormone therapy (tamoxifen or ovarian function suppression) is controversial. For women who are not eligible or who choose not to participate in a clinical trial, we suggest five years of tamoxifen.

An alternative approach is to use ovarian function suppression; if goserelin is chosen rather than surgical removal of the ovaries, the optimal duration is not known. A combination of tamoxifen and ovarian function suppression is not currently recommended, although this recommendation is also controversial. Gene expression analysis on an individual tumor (ie, the Oncotype DX assay) may be useful to select those women with ER-positive, node-negative breast cancers whose risk of recurrence is low enough to avoid adjuvant chemotherapy. However, due to the scant amount of data available to support the value of this approach, we suggest not basing treatment decisions on the results of the Oncotype DX assay until further data become available. However, many physicians disagree and routinely use this test to assist in the decision-making process.

Two clinical trials are ongoing (the North American TAILORx and European MINDACT trials) to determine the benefit of using gene expression analysis to select the adjuvant treatment strategy; eligible women are encouraged to enroll [8,9]. For higher-risk (ie, node-positive, tumor size >2 cm, adverse pathologic features) early stage breast cancers, or if endocrine responsiveness is uncertain, we recommend hormone therapy in addition to chemotherapy. If combined therapy is chosen, tamoxifen therapy should not be started until after chemotherapy is completed because of concerns that giving both at the same time could decrease the effectiveness of the chemotherapy. Furthermore, there is an increased risk of a blood clot in the legs or lungs when chemotherapy and tamoxifen are given together.

Although the timing of ovarian function suppression is less clearly defined, we suggest waiting until after the completion of chemotherapy to start it as well. A web-based assessment program (Adjuvant! Online) is available (www.adjuvantonline.com) that can assist in estimating the relative risks and benefits of chemotherapy (as well as hormone therapy) in individual women based upon their prognostic profile. A version is available that incorporates information derived from the Oncotype DX assay.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus)
Adjuvant! Online

(www.adjuvantonline.com/)
Susan G. Komen Breast Cancer Foundation

(www.komen.org)



Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.
2. National Comprehensive Cancer Network (NCCN) Guidelines available at www.nccn.org/patients/patient_gls.asp.
3. Goldhirsch, A, et al. Meeting highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 2005; 16:1569.
4. Berry, DA, Cirrincione, C, Henderson, IC, et al. Estrogen receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006; 295:1658.
5. Paik, S, Shak, S, Tang, G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:2817.
6. Adjuvant! Online program available online at www.adjuvantonline.com (accessed September 6, 2006).
7. Enrollment information for the TEXT, SOFT, and PERCHE trials summarized at www.youngsurvival.org/research/current-studies/clinical-trial-listing/ (Accessed September 6,2006).
8. Information on the TAILORx trial available online at www.cancer.gov/clinicaltrials/ECOG-PACCT-1. (Accessed Spetember 6,2006).
9. Information on the MINDACT trial available online at www.eortc.be/services/unit/mindact/default.asp (accessed September 6,2006).