In Brief

Article Outline

• Copyright

Endocrine therapies have been used in the treatment of carcinoma of the breast for more than 100 years. Historically, endocrine therapy consisted largely of surgical ablative approaches including adrenalectomy, hypophysectomy, and oophorectomy. There are now numerous pharmacologic agents available to clinicians for use in treatment of all stages of breast cancer and these have been extended into the field of breast cancer prevention as well. The therapeutic approach depends both on the clinical setting and the menopausal status of the patient. In premenopausal women the major source of estrogens is from the ovaries while in postmenopausal women it is produced in peripheral tissues and through the aromatization of adrenal androgens. Approximately 75% of all breast cancers will express hormone receptors, that is, estrogen receptor or progesterone receptor or both. The Early Breast Cancer Trialists Collaborative Group review of the randomized trials has demonstrated that adjuvant endocrine therapy can reduce the risk of recurrence and risk of death from breast cancer by as much as 35%.

The estrogen receptor (ER) was first described in 1969 and subsequently methods of measuring the amount of ER expression in the primary tumor tissue have been refined. The biochemical method that previously required significant amounts of tissue for processing has been replaced with immunohistochemical techniques that can be performed on sections from paraffin blocks. It is now widely accepted that the amount of hormone receptor expression dictates the degree of response to endocrine therapies and patients whose tumors express both ER and progesterone receptor (PR) expect the greatest benefit.

The effects of estrogen on breast tissue can be counteracted by interfering with the interaction of estrogen with the estrogen receptor and its subsequent downstream signaling, or by decreasing the amount of estrogen available to bind to the estrogen receptor. Tamoxifen is a selective estrogen receptor modulator and competes with estrogen for binding to its receptor. Tamoxifen can be used in both premenopausal and postmenopausal patients. Aromatase inhibitors (AIs) act by inhibiting the aromatization of androgens to estrogens in peripheral tissues. AIs can be used only in postmenopausal patients and can reduce estrogen levels to almost undetectable levels. These agents can be used in the palliative treatment of metastatic breast cancer, the adjuvant or neoadjuvant setting for operable and locally advanced disease and in primary breast cancer chemoprevention.

The idea of using hormonal therapies to prevent the development of breast cancer came from the knowledge that women who received adjuvant hormonal therapy as part of their breast cancer treatment developed fewer contralateral breast cancers. The proposal to treat healthy women without a breast cancer diagnosis with drugs that could prevent the development of breast cancer, but also lead to side effects and potential serious toxicities, was initially met with significant resistance. The National Surgical Adjuvant Breast and Bowel Project (NSABP) published results of their landmark trial NSABP P-1 in 1998 demonstrating that tamoxifen administered daily for 5 years could reduce the incidence of invasive and noninvasive breast cancer events by as much as 50% in a high-risk population. Although 2 smaller European trials did not show the same degree of risk reduction, another large randomized trial, International Breast Cancer Intervention Study I (IBIS-I), reported a 32% reduction in breast cancer events and more recently published that this risk reduction was durable up to 10 years after the therapy was discontinued. The benefit from tamoxifen has been shown in all age groups and across all risk categories; however, this effect is largely through the reduction in incidence of ER-positive tumors without any significant impact on development of ER-negative disease. It is also unclear whether patients who are mutation carriers of the BRCA1 or BRCA2 breast cancer susceptibility genes benefit from tamoxifen as a preventative agent.

It is important to note that the use of tamoxifen is associated with risks, especially in women older than 50 who had a 4-fold increase in stage I endometrial cancer, increased rates of stroke, pulmonary embolism and deep vein thrombosis, and a significant increase in the incidence of cataract formation. The U.S. Food and Drug Administration (FDA) approved tamoxifen as an agent for prevention of breast cancer in women at high risk, with high-risk population being defined as those women who have a 5-year projected risk for breast cancer of 1.66% or greater according to the Gail model and those with a diagnosis of lobular carcinoma in situ (LCIS). A risk-benefit profile should be developed for each individual with the decision to use tamoxifen being an informed decision after appropriate counseling.

Publication of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial results demonstrating that raloxifene resulted in a significant reduction in the incidence of breast cancer in postmenopausal women led to the development of the second NSABP prevention trial, NSABP P-2 (STAR). Early results from the STAR trial were released in April 2006, showing that both raloxifene and tamoxifen reduced the risk of developing invasive breast cancer in postmenopausal women who are at increased risk of the disease by about 50%. Raloxifene did not significantly reduce the incidence of noninvasive breast cancers. The incidence of uterine cancer was 38% lower in the raloxifene arm and women had 30% fewer deep vein thromboses and pulmonary embolisms than the women who received tamoxifen. There was also a lower incidence of cataracts and reduced need for cataract surgery. Raloxifene is now a second option for the chemoprevention of breast cancer in postmenopausal women at high risk for the disease.

With the effectiveness of AIs reported from both adjuvant and neoadjuvant trials in patients with hormone receptor-positive breast cancer, there has been significant interest in using these agents in the prevention setting. The ongoing IBIS-II trial is evaluating the impact of anastrozole versus placebo on risk reduction whereas the NSABP P-4 trial (STELLAR) proposes to compare letrozole with raloxifene.

The Early Breast Cancer Trialists Collaborative Group (EBCTCG) has performed a meta-analysis of all of the randomized trials evaluating tamoxifen as adjuvant therapy and confirmed that 5 years of tamoxifen is efficacious in patients with ER-positive tumors and this effect is independent of age, nodal involvement, menopausal status, or use of chemotherapy. Adjuvant treatment with tamoxifen resulted in a reduction of 40% in disease recurrence and a mortality reduction of 34%. These data were reported to the 2000 U.S. National Institutes of Health Consensus Development Conference and led to the recommendation that adjuvant tamoxifen therapy be recommended for women with ER-positive breast cancer regardless of age, menopausal status, nodal status, or tumor size.

Ovarian ablation has also been firmly established by the EBCTCG to result in significant improvements in relapse-free and overall survival in women younger than 50 years of age. More recently, there has been an interest in suppressing ovarian function through pharmacologic means with luteinizing hormone-releasing hormone (LHRH) agonists. In premenopausal women ovarian function suppression plus chemotherapy or in combination with AIs is being evaluated in the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial and in the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) trials.

In premenopausal women the primary source of estrogens is from the ovaries and in postmenopausal women the aromatase enzyme converts androgens to estrogens in the peripheral tissues and provides circulating estrogen. AIs interfere with this conversion of androgens and dramatically reduce estrogen levels in postmenopausal women. AIs are not able to suppress the action of ovarian aromatase and there is some concern that AIs may in fact cause an increase in ovarian aromatase activity resulting in even higher estrogen levels. Therefore AIs are not recommended in younger women unless the clinician can confirm the patient is postmenopausal by testing hormone levels.

AIs were first tested in the metastatic setting and were found to be more effective than megestrol acetate (Megace) and at least as effective as tamoxifen, with an improved toxicity profile. These findings led to the development of several large randomized trials evaluating the efficacy of the AIs in the adjuvant setting compared with tamoxifen. Although the trial designs and agents used in each of these adjuvant trials were different, the majority of these studies showed an improvement in disease-free survival with the use of AIs. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial showed that anastrozole was better than tamoxifen alone or in combination with anastrozole at reducing recurrence, distant metastases, and contralateral breast cancers. The ABCSG/ARNO95 and Italian Tamoxifen Anastrozole Trials all showed an improvement with anastrozole over tamoxifen with a reduction in adverse events. The initial analysis from the BIG 1-98 trial revealed that patients receiving letrozole had a significant improvement in disease-free survival compared with those receiving tamoxifen. The MA-17 trial showed that women who received letrozole after 5 years of tamoxifen had an improvement in disease-free survival over those receiving placebo. There is a second randomization evaluating the impact of 10 years of therapy. Finally, the International Exemestane Study (IES) reported that the use of the steroidal AI exemestane resulted in a 4.9% absolute benefit in disease-free survival over tamoxifen.

Although no clear advantages have been documented in overall survival with the use of AIs, the data support the use of AIs over tamoxifen in postmenopausal women. The American Society of Clinical Oncology (ASCO) recently issued a technology assessment on the use of AIs, stating that “adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an AI to lower the risk of tumor recurrence.”

Although AIs have demonstrated significant improvements in terms of disease-free survival and prevention of contralateral breast cancers, the optimal duration of therapy and the appropriate AI to use in each clinical situation still remain to be answered. Trials exploring the use of endocrine agents in the neoadjuvant setting may provide answers to these questions without the large numbers of patients required and the prolonged follow-up necessary in adjuvant therapy trials. Once used only for the frail and elderly patients, neoadjuvant endocrine therapy has demonstrated benefits in terms of reducing the need for mastectomy and providing an assessment of clinical and radiographic response to different agents. While it generally takes 3 to 4 months to demonstrate a significant clinical or radiographic response that would result in a meaningful reduction in tumor size to allow a change in surgical management, the use of proliferation markers such as Ki67 may be useful in terms of predicting activity even after 2 weeks of therapy.

Measuring gene expression profiles from the primary tumor can separate hormone receptor-positive tumors into good prognosis and poor prognosis groups. The Oncotype DX assay has been shown to be a good indicator of prognosis in ER-positive, lymph node-negative patients. The ability of the Oncotype DX assay to predict response to therapy is currently being tested in the TAILORx [Trial Assigning Individualized Options for Treatment (Rx)] trial. In the ongoing neoadjuvant AI trial, ACOSOG Z1031, gene expression profiles are being created in addition to comparative genomic hybridization analyses that will be used to identify chromosomal anomalies that can explain endocrine resistance. This will allow a more individualized approach to the management of hormone responsive breast cancer than can currently be provided through measurements of ER, PR, and HER2 status.

Use of endocrine therapy as first-line therapy in metastatic breast cancer allows treatment with minimal toxicity and allows the patient to maintain a high quality of life. The tumor response to first-line therapy is predictive of future responses to second-line and third-line agents. Several types of endocrine therapy are available for use in managing metastatic breast cancer, including ovarian ablation, hormonal agonists, synthetic agents, and selective AIs. Tamoxifen or LHRH agonists are used as first-line therapy in premenopausal women with metastatic breast cancer. On disease progression, second-line therapy then usually involves ovarian ablation. First-line therapy in postmenopausal women is either tamoxifen or AIs, depending on the time interval between completion of adjuvant therapy and which agents were used in that setting. The treatment of patients with metastatic breast cancer is palliative. Although there may be many options for therapy, the best approach is one that offers the best response while maintaining the best quality of life.