Hormone-receptor-positive breast cancer is the most common breast cancer subtype in developed countries, regardless of the age or stage at presentation. Approximately 60% of breast cancers diagnosed in premenopausal women and 75–80% of breast cancers found in postmenopausal women are hormone receptor positive. Recent guidelines from the College of American Pathologist re-defined hormone-receptor-positive breast cancer as expressing estrogen receptor or progesterone receptor at at least 1% by immunohistochemistry . Although not agreed upon by all of the academic community, these guidelines recognize the fact that even at very low levels of estrogen receptor expression, benefit is observed from antiestrogen therapy.
Endocrine therapy for breast cancer has been the cornerstone of treatment for over a century since the discovery of the regressive effect of oophorectomy on ‘cancer of the mamma’ by Beatson in 1896 . Despite its central role in treatment, and although it is indeed the first ‘targeted therapy’, few advances have been made until very recently. Decades of research on endocrine resistance and discovery of new genomic targets have led to new hormonal targets, combinations of hormonal therapy with biologic agents, and with duel hormonal therapies. This is indeed a ‘hormonal renaissance’ for breast cancer, and not a moment too soon as much progress has been made in other breast cancer subtypes.
This review will address the recent studies in the prevention and treatment of hormone-receptor-positive breast cancer and their impact on clinical practice.
ENDOCRINE TREAMENT OF METASTATIC BREAST CANCER
Endocrine therapy is considered the first-line treatment for women with estrogen receptor and progesterone receptor positive breast cancer for both premenopausal and postmenopausal women, provided the pace or burden of disease does not indicate the need for chemotherapy. There are differences in the treatment of premenopausal and postmenopausal patients, as the endocrine environment in the menopausal state leads to variability in drug activity. The following paragraphs describe the standard and new approaches for each type of patient.
Endocrine therapy in metastatic postmenopausal women
Aromatase inhibitors such as anastrozole, letrozole, and exemestane are considered the first-line endocrine treatment for postmenopausal women because of their proven superiority over tamoxifen [3–5]. Fulvestrant is an analog of estradiol that downregulates the estrogen receptor by disrupting the estrogen receptor dimerization and accelerating degradation of the unstable fulvestrant–estrogen receptor complex. It is typically used after aromatase inhibitor therapy, although newer studies suggest an earlier line may be reasonable [6,7].
Several studies have evaluated the timing of single and combination therapies in the first and second line setting which are reviewed in Table 1. It should be noted that in many of these trials, the patients who experience the most benefit had not received prior endocrine therapy or had de novo metastatic disease. On the basis of the results of these studies, the optimal order of exposure to hormonal agents in the advanced setting still needs to be determined as well as the true benefit of combination endocrine therapy in the first-line metastatic setting.
Endocrine therapy in premenopausal women
For premenopausal women with estrogen receptor and progesterone receptor positive metastatic breast cancer, a luteinizing hormone releasing hormone (LHRH) agonist plus tamoxifen remains the standard of care based on trials showing a survival advantage for the combination . This practice has not changed significantly in the recent years. Patients then are typically treated as postmenopausal upon progression. It should be noted there is no evidence that using an aromatase inhibitor with a LHRH agonist is superior to tamoxifen with a LHRH agonist and should be reserved for progression of disease.
Novel targeted therapies for metastatic breast cancer
Unfortunately, not all patients will have a response to first-line endocrine therapy (de novo resistance) and patients who respond will eventually progress (acquired resistance). In the last 2 decades, there have been major efforts to better understand the various biological mechanisms responsible for the development of endocrine resistance with the aim of identifying new therapeutic strategies. Preclinical data show a benefit in blocking the mammalian target of rapamycin (mTOR) pathway in endocrine-resistant tumors because the mTOR complex has the ability to directly active the estrogen receptor. Bolero-2 (Breast Cancer Trials of Oral Everolimus) was a randomized phase 3 trial comparing everolimus and exemestane vs. exemestane and placebo in 724 patients with hormone-receptor-positive advanced breast cancer that had a recurrence or progression while receiving therapy with a nonsteroidal aromatase inhibitor in the adjuvant or advanced disease setting [15▪▪]. Everolimus combined with an aromatase inhibitor improved progression-free survival (PFS) in patients previously treated with nonsteroidal aromatase inhibitors (10.6 vs. 4.1 months; 95% confidence interval 0.35–0.54; P < 0.001). The results of this study was also supported by, Tamoxifen plus Everlimus, a phase 2 randomized study involving 111 postmenopausal women with estrogen-receptor-positive advanced breast cancer previously treated with an aromatase inhibitor [16▪]. The combination of everolimus and tamoxifen was associated with improved PFS (8.6 vs. 4.5 months, P = 0.002) and with significantly improved overall survival (OS). These studies suggests that everolimus plays a role in the treatment of patients with endocrine-resistant disease.
New endocrine targets for therapy
Two novel endocrine targets currently being studied in the clinical trial setting are the androgen receptor and the LHRH receptor. The androgen receptor (AR) is expressed in 70–90% of all breast cancers . During the first half of the 20th century, postmenopausal women were treated with androgen therapy. However, in the 1970s, the use of androgen therapy stopped with the development of tamoxifen. Emerging data suggest that the androgen receptor may play a role in breast cancer pathogenesis and may serve as a potential therapeutic target, especially in more difficult-to-treat triple-negative breast cancers . A recent study conducted in AR-positive, estrogen-receptor-negative metastatic breast cancer patients treated with bicalutamide (an oral antiandrogen therapy) showed a clinical benefit of 21%, making this an interesting potential therapeutic target especially for patients with endocrine-resistant disease or triple-negative breast cancer .
The LHRH also known as gonadotropin-releasing hormone (GnRH) was identified in the early 1970s. LHRH binds to its specific receptor, known today as type 1 LHRH receptor. Approximately 40–50% of breast cancer expresses the LHRH receptor, suggesting that it may be a useful therapeutic target. AEZS-108 is a LHRH agonist–cytotoxic hybrid drug with doxorubicin. In preclinical studies, AEZS-108 was found to inhibit breast cancer in mouse models with minimal side-effects. Currently, there is a phase II clinical trial examining the benefit of AEZS-108 in chemotherapy-resistant triple-negative breast cancer that expresses the LHRH receptor [20▪▪].
ENDOCRINE THERAPY FOR EARLY-STAGE BREAST CANCER
Endocrine therapy in the adjuvant setting can consist of treatment with tamoxifen, ovarian suppression, or aromatase inhibitors. Again, variability in menopausal hormone environment leads to different indicated treatment.
The benefits of adjuvant tamoxifen therapy have been repeatedly demonstrated. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published a recent collaborative meta-analysis of individual patient data from 20 trials with a median follow-up of 13 years and showed that 5 years of adjuvant tamoxifen therapy reduced the 15-year risk of breast cancer recurrence and death . Tamoxifen continues to be the standard of care for adjuvant hormonal therapy in premenopausal women as aromatase inhibitors are not active in this population.
The duration of endocrine therapy remains an important clinical question. The Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial assessed the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years [22▪▪]. This trial accrued 12 894 women with early breast cancer who had completed 5 years of treatment with adjuvant tamoxifen therapy and they were randomly assigned to continue tamoxifen to 10 years or stop at 5 years. After a median follow-up of 7.6 years, they found that continuing tamoxifen reduced the risk of breast cancer recurrence (P = 0.002), reduced breast cancer mortality (P = 0.01) and reduced overall mortality (P = 0.01). Ten years of tamoxifen therapy produced a further reduction in recurrence and mortality, particularly after year 10. Longer therapy was associated with an increased risk for pulmonary embolism, and endometrial cancer, although this risk was lower in premenopausal women. No increase in the incidence of stroke was seen with 10 vs. 5 years and a decrease in the incidence of ischemic heart disease was noted. The UK adjuvant aTTom (Adjuvant Tamoxifen treatment-to offer more) trial randomly allocated 7000 women, most with unknown estrogen receptor status, to continue tamoxifen to 10 years or stop at 5 years [23▪▪]. This study confirmed the reduction in recurrence and death seen with extended endocrine therapy. On the basis of the results of the above studies, a new standard of care for premenopausal women with estrogen-receptor-positive tumors is now 10 years of adjuvant tamoxifen therapy.
Ovarian suppression or ablation
Estrogen receptor expression is a powerful positive predictive factor for antiestrogen therapy. However, estrogen receptor expression may also be a negative predictive factor for benefit from chemotherapy. The EBCTCG examined the effects of ovarian ablation on recurrence and death and showed that in women less than 50 years of age, ablation of functioning ovaries significantly improved the long-term survival in the absence of chemotherapy .
This led to a number of studies that have evaluated ovarian suppression vs. chemotherapy and combination chemotherapy and ovarian suppression therapy in estrogen-receptor-positive premenopausal women which are illustrated in Table 2. The IBCSG (International Breast Cancer Study Group) II-93, IBCSG VIII, and Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) studies show that a subset of premenopausal women have benefit from adjuvant ovarian suppression without systemic chemotherapy. In addition, younger women who do not experience chemotherapy-induced amenorrhea may benefit from ovarian suppression with goserelin plus tamoxifen as illustrated by the INT (Intergroup) 0101 and IBCSG VIII studies.
A recent Cochrane review examined the role of LHRH agonists as ovarian suppression treatment for early breast cancer in premenopausal women and included 14 randomized trials that involved over 13 000 premenopausal women . They concluded that LHRH agonists show clinical benefit in the adjuvant setting for premenopausal women; however, definitive comparisons against third-generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. Also, the American Society of Clinical Oncology (ASCO) review panel stated that ovarian suppression is not recommended either as addition to systemic therapy or as an alternative to systemic therapy and reiterated that the difficulty with the available data is that ovarian function suppression has not been compared with many systemic treatment options (anthracycline-based and taxane-based chemotherapy, aromatase inhibitors) in use today . They stated that ovarian suppression should be considered only for women who will not receive systemic treatment (e.g., those patients who cannot tolerate or refuse systemic therapy). However, if treatment with cyclophosphamide, methotrexate, and fluorouracil (CMF) is being considered, there is available evidence to suggest that ovarian suppression is a reasonable alternative.
More definitive information will be forthcoming when the results of two ongoing studies are available. One such trial is the Suppression of Ovarian Function Trial (SOFT) that will assess the role of ovarian suppression in combination with an aromatase inhibitor (exemestane) compared with ovarian suppression plus tamoxifen or tamoxifen alone as adjuvant therapy . The Tamoxifen and EXemestane Trial (TEXT) trial will assess the benefit of an LHRH agonist with the additional of either tamoxifen or exemestane for 5 years from the start of adjuvant therapy . In the TEXT trial, adjuvant systemic chemotherapy was optional and lymph node status was found to be the predominant determinant of chemotherapy use . The results of both of these trials are anticipated in 2014 and may greatly impact our current treatment approaches.
Premenopausal women who undergo ovarian function suppression may be treated with aromatase inhibitors. The ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group Trial-12) randomized early-stage premenopausal women receiving goserelin to either anastrozole or tamoxifen with or without zoledronic acid . At a median follow-up of 62 months, there was no difference seen in disease-free survival between patients receiving anastrozole or tamoxifen, but those on anastrozole alone had an inferior OS.
Many premenopausal women with early breast cancer develop amenorrhea after chemotherapy, and in the majority of those older than age 40, this is permanent. Some oncologists have started extending the use of aromatase inhibitors to women older than age 40 with chemotherapy-induced ovarian failure. Aromatase inhibitors must be used with caution in premenopausal women who have had chemotherapy-induced amenorrhea because they can be associated with return of ovarian function and pregnancy. On the basis of the results of the available data, we would recommend continued use of tamoxifen in the adjuvant setting in premenopausal women. However, if a premenopausal woman develops amenorrhea after chemotherapy and her hormone levels are reflective of a postmenopausal setting, an aromatase inhibitor could be used with close monitoring. The results of the SOFT and the TEXT trial will provide further recommendations for the role of aromatase inhibitors in premenopausal women.
In postmenopausal women, 5 years of adjuvant aromatase inhibitors when compared with tamoxifen significantly lowered the recurrence rates; however, no clear survival benefit has been demonstrated until recently. The Breast International Group (BIG) 1-98 trial was updated with a median follow-up of 8.1 years and a survival benefit was noted with letrozole monotherapy [37▪].
The optimal duration of adjuvant endocrine therapy for postmenopausal women is currently unknown. The MA17 trial examined the effect of adding an aromatase inhibitor after 5 years of tamoxifen therapy in postmenopausal women and benefit has been seen with the addition of an aromatase inhibitor . The results of the ATLAS trial, discussed earlier, showed a benefit to extended endocrine therapy using tamoxifen, suggesting that this strategy may be useful; however, no trial has evaluated 10 years of aromatase inhibitor therapy. There are several ongoing studies comparing extended vs. 5 years of aromatase inhibitor therapy and results are anxiously awaited! On the basis of the available data, standard of care is monotherapy with an aromatase inhibitor for 5 years or sequential therapy with tamoxifen for 2–5 years followed by an aromatase inhibitor for 5 years. However, if a woman is at high risk for relapse, it may be beneficial to extend aromatase inhibitor therapy beyond the 5-year mark.
ROLE OF ENDOCRINE THERAPY IN PRIMARY PREVENTION OF BREAST CANCER
Tamoxifen and raloxifene are currently approved for risk reduction in women at least 35 years of age at greater than 1.2-fold increased risk of breast cancer . In MAP-3 (Mammary Prevention.3 trial), exemestane was given to postmenopausal women at risk for developing invasive breast cancer, and after 3 years of follow-up, exemestane was found to significantly reduce invasive breast cancer with no serious toxic side-effects . Results of the International Breast Cancer Intervention Study 2 trial (IBIS-2) evaluating anastrozole in the prevention setting will be available in 2013.
Endocrine therapy continues to be the mainstay of treatment for hormone-receptor-positive breast cancer at all stages and ages. Results of the recent clinical trials demonstrate the benefit of 10 vs. 5 years of tamoxifen in the adjuvant setting for premenopausal women and have examined the benefit of combination endocrine therapy in the first-line and second-line setting. In addition, targeted therapy has been developed and validated as a useful approach to overcoming resistance to endocrine therapy. These studies will lead to practice change for hormone-receptor-positive breast cancer. They also pose new clinical questions and will guide future research in order to determine the optimal duration of adjuvant endocrine therapy, the most beneficial sequence of endocrine therapy in the metastatic setting and how to continue to overcome endocrine resistance.
Conflicts of interest
L.N.H. and N.W. have no conflicts of interest to report.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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This clinical trial is attempting to see whether a LHRH-R agonist produces a clinical response in patients with LHRH-R breast cancer.
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This is the first study to show decreased risk of recurrence and improved mortality with 10 years of adjuvant tamoxifen therapy.
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This abstract also shows the benefit of 10 years of adjuvant tamoxifen therapy vs. 5 years of tamoxifen therapy.
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34. Suppression of Ovarian Function Plus Either Tamoxifen or Exemestane Compared with Tamoxifen Alone in Treating Premenopausal Women with Hormone-Responsive Breast Cancer (SOFT).
ClinicalTrials.gov Identifier: NCT00066690
35. Triptorelin with Either Exemestane or Tamoxifen in Treating Premenopausal Women with Hormone-Responsive Breast Cancer (TEXT).
ClinicalTrials.gov Identifier: NCT00066703
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