The incidence of female breast cancer in the United States has been rising, with an estimated 215,990 new cases in 2004. Despite this, there has been a decline in breast cancer mortality. This decline in mortality is paralleled by an increasing use of adjuvant hormonal therapy, which is associated with an increase in survival. Selecting an appropriate endocrine regimen has become more complex as choices of endocrine therapy expand. Until that time when we can identify with certainty the specific patients who benefit from adjuvant care, meaningful counseling will require not only an understanding of the risks and benefits of the various treatments, but also an appreciation of the patient's perspective. Issues regarding reproduction, body image, sexuality, and timing of side effects are part of the quality-of-life decisions facing women with breast cancer and those who would advise them. Since Beatson first reported the benefit of surgical oophorectomy in the management of breast cancer over a century ago, the role of endocrine therapy has evolved. Synthetic estrogen use was first reported by Haddow et al in 1944. Shortly thereafter, adrenalectomy and hypophysectomy in women with metastatic breast cancer were shown to have a benefit in postmenopausal women.[7,8] Advances in our understanding of the endocrine pathways have since revealed the mechanisms by which these early surgical methods function. There are now multiple options for blocking the hormonal stimulation of tumors by estrogens, the basis of adjuvant hormonal therapy. These options include selective estrogen-receptor modulators (SERMs), aromatase inhibitors, and medical oophorectomy with luteinizing hormone-releasing hormone (LHRH) agonists. In this article, we will review the various options available and discuss their efficacy, side effects, and relevant ongoing clinical trial options. We will also review the prognostic and predictive factors that can be used to make informed decisions regarding adjuvant therapy. We will present four cases that illustrate difficulties in choosing adjuvant therapy and finally summarize our recommendations and the major consensus for adjuvant hormonal therapy (Table 1). Treatment Options Optimum use of adjuvant hormonal therapy is dependent on menopausal status. Ovarian ablation-either permanent (using surgical or radiotherapeutic ablation) or temporary (using pharmacologic agents such as LHRH agonists)-is a potential strategy for premenopausal women. The aromatase inhibitors are appropriate only for postmenopausal women and can be used in conjunction with LHRH agonists. SERMs such as tamoxifen are a viable option regardless of hormonal status. Table 2 reviews all endocrine therapies used in the treatment of breast cancer. This article will focus only on those treatments indicated for use in adjuvant therapy. Selective Estrogen-Receptor Modulators
The SERMs have varying estrogenic or antiestrogenic effects, depending on type and target tissue. The most widely studied SERM, tamoxifen, has become a treatment standard backed by several well-constructed clinical trials as well as the overview analysis.[ 3] Tamoxifen is the only SERM currently approved by the US Food and Drug Administration (FDA) for use in the adjuvant setting. Women with estrogen receptor (ER)-positive breast tumors who have completed 5 years of tamoxifen will derive a 47% reduction in annual rate of relapse and a 26% reduction in annual rates of breast cancer-related death, regardless of menopausal status. Women with node-positive disease achieve greater absolute benefit from tamoxifen at 10 years (15.2% decrease in recurrence and 10.9% reduction in mortality) compared to nodenegative women (14.9% decrease in recurrence and 5.6% reduction in mortality). The optimal duration of adjuvant tamoxifen therapy is probably 5 years. Adjuvant tamoxifen use for 1, 2, and 5 years has been associated with relative recurrence reductions of 21%, 29%, and 47%, respectively, and relative mortality reductions of 12%, 17%, and 26%. Current data suggest no additional benefit from treatment with more than 5 years of tamoxifen, and in lymph node- negative breast cancer patients, there may be a disadvantage to longer treatment periods.[10,11] Importantly, no significant decrease in cancer recurrence or improvement in survival is seen when tamoxifen is given to women with ER-negative tumors. Adjuvant tamoxifen for 5 years has also been shown to reduce the risk of contralateral breast cancer by 47%. While patients treated with tamoxifen have a higher proportion of ER-negative second primary breast cancers as compared with those who did not receive tamoxifen, the absolute numbers of ER-negative second primary tumors are the same and patient survival does not appear to be significantly impaired. Whether tamoxifen is effective in reducing the incidence of contralateral breast cancers in women with ERnegative primary tumors remains a matter of debate. The Early Breast Cancer Trialists' Collaborative group overviews from 1998 and 2001 demonstrated a decreased rate of contralateral breast cancer when all patients, irrespective of tumor ER status, took tamoxifen for 5 years.[3,13] Other studies performed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Southwest Oncology Group (SWOG) showed no decrease in contralateral breast cancers with the addition of tamoxifen for women with high-risk, ER-negative, node-negative tumors.[14-16]
- Side Effects-The side-effect profile of SERMs is in great measure a function of their relative agonist and antagonist properties. Agonist effects on bone allow tamoxifen to attenuate osteoporosis in postmenopausal women. Paradoxically, it can increase calcium loss in premenopausal women. In the liver, the use of tamoxifen can improve the lipid profile. Tamoxifen is associated with a two- to threefold increased risk of thrombosis, which is more pronounced for older women. Although the mechanism is not well understood, reduced levels of antithrombin III and protein S have been seen in women on tamoxifen. Effects on the hypothalamicgonadal axis contribute to the problematic vasomotor symptoms (hot flashes). Additionally, there is a 10% increased absolute risk of menopause over the first year of use for women over 45 years old. Women younger than age 45, however, have no significant increased risk of premature menopause during this period. Tamoxifen's stimulatory effect on the endometrium of postmenopausal women is associated with an increased risk of endometrial cancer and, rarely, endometrial sarcoma. For postmenopausal women, the relative risk of developing endometrial cancer after 5 years of tamoxifen is approximately 1%.[21,22] Endometrial hyperplasia, polyps, and ovarian cysts are also seen. Tamoxifen has also been associated with retinopathy, macular edema, and subcapsular cataracts. Annual eye exams, screening pelvic exams, and Pap smears are recommended for women while receiving tamoxifen therapy and for 1 year upon completion of treatment.
Oophorectomy has been shown to be of benefit in the adjuvant setting for premenopausal women with hormone- receptor-positive breast cancer.[ 24,25] There are now several options for ovarian suppression or ablation. Permanent ablation can be achieved surgically or with irradiation, and temporary suppression can be achieved using one of several LHRH agonists. Surgical oophorectomy is irrevers ible and, when performed laproscopically, carries minimal risk. It also provides a 90% decrease in the risk of ovarian cancer for all women, and for premenopausal women with germ-line abnormalities in BRCA1/2, oophorectomy may confer a 50% reduction in the risk of breast cancer.[26,27] It is important to note that oophorectomy, in this setting, should be discussed with a gynecologist who is familiar with the issues of ovarian cancer risk reduction to consider complete hysterectomy or just the removal of fallopian tubes and ovaries. Ovarian irradiation, on the other hand, may appeal to many by avoiding surgery. Such therapy can be accomplished with the use of either single or multiple fractions; however, on rare occasions, menses may return. The LHRH agonists triptorelin (Trelstar), goserelin (Zoladex), or leuprolide may also be utilized to achieve ovarian suppression. These agents downregulate LHRH receptors, causing a decline in leuteinizing hormone (LH) and follicle-stimulating hormone (FSH) release from the pituitary, with a subsequent drop in systemic estrogen levels. Adverse side effects are those of menopause and include headache, vasomotor symptoms, depression, emotional lability, sexual dysfunction, and vaginitis. This abrupt menopause may be poorly tolerated. Monitoring of bone mineral density for the treatment of osteoporosis is required with ovarian ablation. Bone loss occurring with ovarian suppression is likely to be reversible or attenuated with bisphosphonate therapy.
- Ovarian Suppression vs Chemotherapy- Adjuvant ovarian ablation in women with hormone-receptor- positive breast cancer has been associated with a significant reduction in the annual risk of relapse (25%) and of dying of breast cancer (24%). However, no significant difference has been observed when ovarian ablation is added to chemotherapy.[24,25] It may be that much of the observed benefit from adjuvant chemotherapy is derived from its ability to induce menopause in these trials, dampening the likelihood of observing a further reduction in relapse. The incidence of chemotherapy-induced amenorrhea is a function of both patient age and chemotherapy regimen, with reported rates of 40% to 70%.[29,30] Increases in both relapse-free and overall survival have been demonstrated for women who become amenorrheic after chemotherapy over those with continued menses.[31,32] Other studies have failed to demonstrate similar benefits of chemotherapyinduced amenorrhea.[33,34] Several trials have compared ovarian inhibition vs polychemotherapy and demonstrated similar efficacy in disease-free and overall survival in premenopausal woman with hormone-receptor-positive tumors.[35-37] However, these investigations did not use anthracycline- or taxane-based therapy, and thus, ovarian suppression has not been compared to current optimal chemotherapy. Quality of life may be better with ovarian suppression as compared to chemotherapy. Therefore, it is important to compare ovarian suppression to current, more effective chemotherapy regimens. Given the risk of amenorrhea with chemotherapy, women hoping to maintain fertility may opt for ovarian suppression with LHRH agonists. To reduce the risk of permanent amenorrhea and provide adjuvant ovarian suppression therapy, an LHRH agonist could be started 1 month prior to initiation of chemotherapy.[ 38] Currently, this strategy should be used with caution and considered experimental. Return of menses after an LHRH agonist may not be equivalent to fertility, and the estrogen withdrawal associated with LHRH agonists may theoretically slow tumor cell growth, resulting in loss of chemosensitivity.
In postmenopausal women and in women for whom an early menopause has been induced with ovarian ablation, aromatase inhibitors may represent the most effective endocrine option. Aromatase converts testosterone to estrogen and androstenedione to estrone in adipose, muscle, breast, and breast cancer cells. By blocking this conversion, estrogen levels are decreased by more than 90%. The aromatase inhibitors have been grouped into three generations. The first generation includes aminoglutethimide (Cytadren), originally used in breast cancer management as a means of medical adrenalectomy. It has significant toxicity, causing it to be mostly of historical significance. The second-generation agents include the nonsteroidal rogletimide and fadrozole (approved for use in Japan) and the steroidal formestane (administered intramuscularly). Selective antiaromatase drugs comprise the third generation of aromatase inhibitors and are currently the aromatase inhibitors of choice. These include the steroidal, irreversible "suicide" inhibitor exemestane (Aromasin) and the nonsteroidal reversibly binding anastrozole (Arimidex), letrozole (Femara), and vorozole (R83842). Despite an increased risk of bone demineralization and frequent myalgias/ arthralgias, the aromatase inhibitors are generally well tolerated.[ 39,40] Anastrozole is associated with lower rates of thromboembolic events than tamoxifen. However, higher rates of ischemic cardiovascular events were reported with anastrozole than with tamoxifen, although this difference was not statistically different.[ 41] Lower rates of endometrial cancer and vaginal bleeding are seen with aromatase inhibitors.
- First-Line/Neoadjuvant Setting- As first-line agents in postmenopausal women with metastatic hormonereceptor- positive breast cancer, the aromatase inhibitors have demonstrated equal to superior time to progression and response rates when compared with tamoxifen,[42-44] and in the neoadjuvant setting, a decreased time to response. In fact, some investigators maintain that aromatase inhibitors may be superior to chemotherapy for the neoadjuvant management of hormone-receptor-positive tumors by causing uniform, concentric tumor shrinkage with less multifocal residua and a greater likelihood of complete tumor excision at surgery. Furthermore, neoadjuvant chemotherapy may be less effective in ER-positive tumors than ER-negative tumors (the inverse of which is true for neoadjuvant hormonal therapy).
- Adjuvant Setting-The benefit of the aromatase inhibitors in the firstline and neoadjuvant settings has led to the question of possible superiority to tamoxifen in the adjuvant setting. Results reported by the Arimidex, Tamoxifen Alone or in Combination (ATAC) trialists' group after a median follow-up of only 47 months demonstrate that anastrozole provides a 14% reduction in relative risk of recurrence and 46% reduction in relative risk of a second primary compared to tamoxifen.[39,40] Further followup of this and other studies of adjuvant therapy should help us compare the relative risks and benefits of tamoxifen vs anastrozole, letrozole, and exemestane. Additional studies have focused on the role of adjuvant aromatase inhibitor therapy subsequent to tamoxifen; results from four of these trials have been released.[48-51] Early closure of the letrozole trial led by the National Cancer Institute of Canada (NCIC) was recommended after a median follow- up of 2 years. Interim analysis demonstrated a significant increase in event-free survival for women randomized to letrozole after tamoxifen (compared to placebo). Two additional trials have recently been reported-one using anastrozole[ 50] and another, exemestane begun after 2 to 3 years of tamoxifen, to complete a 5-year adjuvant treatment course, compared to tamoxifen alone for 5 years. Both of these studies confirmed an increase in diseasefree survival with transition to an aromatase inhibitor. Of note, a trial of sequential aminoglutethimide following 2 years of tamoxifen vs tamoxifen for 5 years (the predecessor to the above anastrozole study) demonstrated a mortality benefit with sequential therapy. However, owing to the poor sideeffect profile of aminoglutethimide and the advent of the third-generation aromatase inhibitors, this trial failed to recruit its planned number of patients, and its results should be considered preliminary. More recently, in a presentation updating the above NCIC MA.17 letrozole trial, a significant increase in overall survival was observed for the node-positive subset of patients (personal communication, H.B. Muss, 2004). The current role of aromatase inhibitors in the adjuvant setting is controversial. The four trials discussed above include over 16,000 women and although the follow-up is short, all show decreased relapse rates of breast cancer for women on aromatase inhibitors compared to tamoxifen. Not only are these data compelling, but they confirm what we already know regarding the superiority of aromatase inhibitors in the metastatic setting. It is, therefore, reasonable to consider using aromatase inhibitors for the majority of postmenopausal women except for those at lowest risk of recurrence, in whom survival data associated with tamoxifen are an important part of the risk/benefit ratio. For women currently on tamoxifen, it is reasonable to consider changing to an aromatase inhibitor, again for those at higher risk of recurrence or intolerant of tamoxifen. We suggest specific aromastase inhibitor selection be determined by the currently available trial information. That is, anastrozole as first-line adjuvant therapy, exemestane after 2 to 3 years of tamoxifen, and letrozole after 5 years of tamoxifen.
Dr. Muss has ownership interest in Amgen and Enzon, has received research grants from Aventix, Pfizer, Celgene, Coley Pharmacia, Immunex, Schering, Merck, AstraZeneca, Imclone, Ligand, Lilly, Genentech, Bristol-Myers Squibb, Ortho-Biotech, Novartis, Genetics Institute, and Tibotech; fellowship support from Ortho, Amgen, and Aventis; honoraria from Network Oncology Communication, Neil Love Communications, and Medidigm; and is on the board of directors or advisory committees of the Amercian Society of Clinical Oncology.
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