This year alone, more than 215,000 women in the United States will bediagnosed with, and over 40,000 will die from, invasive breast cancer.Recently, mortality from female breast cancer has declined despite anincrease in its incidence. This decline corresponds with improved screeningfor prompt tumor detection, and advances in the treatment of earlydisease. Of these, endocrine therapy has played a prominent role. Forwomen with estrogen receptor (ER)-positive and/or progesterone receptor(PR)-positive breast cancers, endocrine therapy has proven to be amajor component of adjuvant therapy, but it is not effective in womenwhose breast cancers lack ERs and PRs. The selective estrogen-receptormodulator (SERM) tamoxifen has been well established as safe and effectivein the adjuvant care of both pre- and postmenopausal women withhormone-receptor–positive early breast cancer. For premenopausalwomen, ovarian suppression is an important option to be considered.Additionally, the aromatase inhibitors have recently demonstrated utilityin postmenopausal women. The ideal sequencing of treatment withtamoxifen and/or an aromatase inhibitor is the subject of several ongoingstudies. Factors involved in selecting an appropriate endocrine regimenhave grown considerably over the past decade. It is becoming more importantfor those caring for women with breast cancer to fully understandthe available endocrine treatment options and the prognostic and predictivefactors available to help select the most appropriate treatment. Thegoal of this article is to assist clinicians in making decisions regardingadjuvant hormonal therapy and to provide information regarding availableclinical trials. To achieve this, the therapeutic options for hormonaltherapy will be reviewed, as will prognostic and predictive factors used inmaking decisions. Finally, four cases illustrating these difficult decisionswill be discussed, with recommendations for treatment.
This year alone, more than 215,000 women in the United States will be diagnosed with, and over 40,000 will die from, invasive breast cancer. Recently, mortality from female breast cancer has declined despite an increase in its incidence. This decline corresponds with improved screening for prompt tumor detection, and advances in the treatment of early disease. Of these, endocrine therapy has played a prominent role. For women with estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancers, endocrine therapy has proven to be a major component of adjuvant therapy, but it is not effective in women whose breast cancers lack ERs and PRs. The selective estrogen-receptor modulator (SERM) tamoxifen has been well established as safe and effective in the adjuvant care of both pre- and postmenopausal women with hormone-receptor–positive early breast cancer. For premenopausal women, ovarian suppression is an important option to be considered. Additionally, the aromatase inhibitors have recently demonstrated utility in postmenopausal women. The ideal sequencing of treatment with tamoxifen and/or an aromatase inhibitor is the subject of several ongoing studies. Factors involved in selecting an appropriate endocrine regimen have grown considerably over the past decade. It is becoming more important for those caring for women with breast cancer to fully understand the available endocrine treatment options and the prognostic and predictive factors available to help select the most appropriate treatment. The goal of this article is to assist clinicians in making decisions regarding adjuvant hormonal therapy and to provide information regarding available clinical trials. To achieve this, the therapeutic options for hormonal therapy will be reviewed, as will prognostic and predictive factors used in making decisions. Finally, four cases illustrating these difficult decisions will be discussed, with recommendations for treatment.
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]
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.
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.
Clinical Trials The results of recent clinical trials have given us many options to consider when making choices of adjuvant hormonal therapy; however, many questions remain. These questions are the subject of four ongoing clinical trials.
Prognostic and Predictive Factors "Prognostic factors" are used to predict disease outcome, whereas "predictive factors" refer to the likelihood of response to a specific treatment. The most important predictor of response to hormonal therapy is ER and PR expression. Patients with invasive breast cancer totally lacking expression of these hormone receptors will not benefit from hormonal therapy. Receptor status has often been poorly reported, and criteria for defining a receptor as "positive" are not well standardized. Some data suggest that even patients with 1% of cells staining positively for hormone receptors may derive benefit from adjuvant hormonal therapy. Thus, it is important to understand the method of reporting receptor status, as many laboratories continue to report staining of less than 10% as negative. Well-validated prognostic factors for breast cancer include lymph node status, tumor stage, tumor grade, and patient age. The number of lymph nodes containing tumor remains the most important prognostic factor. In addition, the extent of tumor involvement of the lymph node is important. The prognosis of micrometastasis (< 2 mm) is similar to that of uninvolved lymph nodes, and tumor deposits less than 0.2 mm are considered node-negative. Additionally, the presence of lymphovascular invasion within the breast has been correlated with lymph node status and may be an independent prognostic marker. The significance of lymph node status is demonstrated in the most recent National Comprehensive Cancer Network (NCCN) recommendations. These guidelines recommend adjuvant chemotherapy for anyone with even a single macroscopically positive lymph node and propose "consideration" for adjuvant therapy for those with micrometastasis.[ 57] Tumor size is another important prognostic factor, with larger tumors being more likely to recur than their smaller counterparts. Chemotherapy has been associated with a survival benefit in women who have tumors greater than 1 cm. The NCCN guidelines recommend adjuvant hormonal therapy for receptor-positive tumors greater than 1 cm and consideration of hormonal therapy for tumors smaller than 1 cm. Histologic grade is also of importance. Although there can be interexaminer variability, at the extremes of the grading system there is likely to be greater agreement. Patients with grade 1, node-negative tumors have been reported to have a 97% 5-year disease-free survival rate, as compared with a 78% 5-year disease-free survival for women with grade 3 nodenegative tumors. Tubular or colloid histology also carries a better prognosis than ductal, lobular, or mixed tumors. Tumor proliferation rates may correlate with a higher tumor grade and, therefore, greater risk of recurrence. Demographic factors such as age may also have prognostic value. Some studies suggest that older women have a poorer survival, whereas other data suggest an inverse correlation between patient age and prognosis.[ 62] However, data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute show no difference in overall survival, after adjustment for stage, in patients 40 to 80 years of age. Ethnic background may also be prognostic. The highest age-adjusted death rates from female breast cancer in the United States for the years 1996 to 2000 were seen in the African-American population, while the lowest were seen in women of Asian/Pacific Island descent. HER2, a tyrosine kinase cell-surface receptor in the epidermal growth factor family, is overexpressed in roughly 25% of breast cancers (30%-40% of all metastatic breast cancers). It has both predictive and prognostic value. Overexpression in node-negative tumors has been associated with a poor prognosis.[ 64] Data suggest that HER2 overexpression may be an indicator of endocrine resistance, especially to tamoxifen. These are provocative data that require confirmation. Currently, HER2 is not recommended for use as a predictive factor to help determine the utility of hormonal therapy. Patients can be grouped as being at either low or high risk of recurrence based on the above discussed prognostic and predictive factors. Patients with an excellent prognosis may derive little benefit from additional therapy. The therapeutic risk vs benefit ratio will vary depending on the side-effect profile of an adjuvant treatment and a patient's comorbidities. Risk Assessment Tools
Expert teams of clinicians and programmers have developed algorithms to define risk and guidelines for treatment recommendations. The two commonly used tools to define risk- Numeracy and Adjuvant!- are available to health-care providers at the following websites: www.mayoclinic.com/calcs (Numeracy) and www.adjuvantonline.com (Adjuvant!).[ 68] Numeracy uses grouped information regarding a patient's age, nodal status, tumor size, and hormonereceptor status and provides baseline prognosis and 10-year outcome estimates based on expert panel assessment.[ 69] Adjuvant! uses the same information as well as evaluation of patient comorbidities and tumor grade incorporated with the Surveillance, Epidemiology, and End Results (SEER) database to arrive at 10-year outcome estimates. A good degree of concurrence for these two methods has been demonstrated. It is important to note that these programs place people in categories and that the statistics they offer refer to populations, not specific patients. The use of gene-expression analysis may prove to be a better way of defining risk of recurrence and response to therapy. This technique has been used to identify distinct patterns of gene expression in breast cancer tissue, which may allow a more accurate typing of breast cancer.[70,71] More recently, the expression of 21 specific genes was demonstrated to predict the risk of relapse in a group of 460 receptor-positive, node-negative patients taking tamoxifen.[72,73] This predictive assay is now commercially available (from Genomic Health Inc; www.genomichealth.com). While available results from this test are provocative, further confirmation in larger numbers of patients is required. Physicians wishing to use this clinical test should be careful not to overinterpret the results, especially for lymph node- positive patients or those taking aromatase inhibitors (as these patients were not included in the data set). Treatment recommendations for breast cancer based on accepted prognostic and predictive factors have been proposed by the NCCN and attendees of the 2003 St. Gallen conference.[ 57,74] Despite these general recommendations, treating oncologists are expected to appropriately integrate prognostic and predictive factors into their treatment recommendations. The four cases below illustrate the use of prognostic and predictive factors in making choices about adjuvant hormonal therapy. Case Studies
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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