Choosing early adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer: Aromatase inhibitors versus tamoxifen

Aims

The aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole have demonstrated superior disease-free survival (DFS) over tamoxifen in several trials. As the choice of adjuvant endocrine treatment for early breast cancer (EBC) is evolving from tamoxifen to the AIs, this review compares the AIs with tamoxifen to help surgeons choose a treatment plan that provides the greatest reduction of recurrence risk for their patients.

Methods

MEDLINE was searched to identify relevant literature on the adjuvant use of tamoxifen and AIs in EBC.

Results

Despite the use of adjuvant tamoxifen, recurrence is a persistent threat to women with hormone-sensitive EBC. Trials of the AIs versus tamoxifen have established that patients benefit from longer DFS, and in some cases distant DFS, after the use of an AI as initial adjuvant therapy, as switch therapy following 2–3 years of tamoxifen, or as extended adjuvant therapy following 5 years of tamoxifen. The AIs are well tolerated, with a different safety profile than that of tamoxifen in all these settings. Trials addressing the optimal regimen and treatment duration for AIs are also underway.

Conclusions

The advantage in DFS associated with AIs over tamoxifen use should prompt physicians and patients to consider the use of an AI as the initial adjuvant endocrine therapy or, alternatively, switching patients who currently take tamoxifen to an AI for the remainder of adjuvant endocrine therapy. Prolonging the period of adjuvant therapy with letrozole after 5 years of tamoxifen reduces recurrence and is associated with a survival advantage in node-positive patients.     

Aromatase inhibitors for breast cancer in postmenopausal women

Third-generation aromatase inhibitors are potent inhibitors of the aromatase enzyme, which catalyzes the last step in estrogen biosynthesis. These agents are active against breast cancer in hormone-na?ve postmenopausal women and in women who have experienced failure of tamoxifen or failure of tamoxifen plus other hormonal therapy. There are two types of aromatase inhibitors, irreversible steroidal activators (e.g., exemestane) and reversible nonsteroidal imidazole-based inhibitors (e.g., anastrozole, letrozole). Recent data suggest that some women who experience failure of one type of aromatase inhibitor can subsequently derive benefit from the other type. The reason for this lack of cross-resistance is unknown. This finding of non-cross-resistance between steroidal aromatase activators and nonsteroidal aromatase inhibitors offers the opportunity to increase the number of lines of hormone therapy before making the inevitable switch to more toxic chemotherapy, thus potentially improving quality of life for postmenopausal women with advanced disease. Data from postmenopausal women with advanced disease suggest that steroidal and nonsteroidal aromatase inhibitors have similar tolerability profiles; however, emerging data suggest that there may be differences in their effects on end organs, which may become evident with longer term use, such as in the adjuvant or prevention settings. Steroidal agents appear to have beneficial effects on lipid and bone metabolism, whereas nonsteroidal agents may have neutral or unfavorable effects. These differences may be attributed to the androgenic effects of steroidal agents; clinical trials are currently under way to confirm these suspicions.     

Aromatase inhibitors as adjuvant therapy for postmenopausal patients with early stage breast cancer

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.     

Aromatase inhibitors and the risk of colorectal cancer in postmenopausal women with breast cancer

BackgroundA large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3 years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer.Patients and methodsUsing the UK Clinical Practice Research Datalink, we identified women, at least 55 years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations.ResultsA total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9 years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100 000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53–1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity = 0.54), and time since initiation (P-heterogeneity = 0.66).ConclusionsIn this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.     

Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.     

Aromatase inhibitors for treatment of postmenopausal patients with breast cancer

The third generation of aromatase inhibitors and inactivators, such as anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin), have become available for treatment of postmenopausal breast cancer patients. Several clinical trials have demonstrated that these new drugs can achieve better treatment results than megestrol acetate (Megace) and may replace tamoxifen for the first-line hormonal therapy for metastatic breast cancer patients. In fact, these drugs are now used in many hospitals and clinics for patients with metastatic breast cancer who were previously given tamoxifen as adjuvant treatment. However, the primary concern is whether they can be used as first-line agents for adjuvant treatment of primary breast cancer or are suitable for breast cancer prevention in view of possible adverse side effects. Recently, the Arimidex and Tamoxifen Alone or in Combination trial demonstrated the superiority in terms of disease-free survival of anastrozole over tamoxifen in adjuvant use for postmenopausal patients with Stage I and II primary breast cancer. The results of this report indicate the potential of anastrozole as an alternative drug in the adjuvant setting, although the mean follow-up time is so far only 47 months. Additional data regarding survival resulting from comparative trials of letrozole and tamoxifen and of exemestane and tamoxifen are expected to be available in a few years. However, limited information is available regarding adverse events caused by long-term administration of aromatase inhibitors. Longer follow-up is needed to determine the efficacy and safety of these new aromatase inhibitors when used for adjuvant treatment of postmenopausal patients with breast cancer.     

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98

The level of circulating insulin-like growth factor 1 (IGF-I) has been shown to be positively associated with breast cancer risk. The expression patterns of the IGF-I and its receptor IGFIR genes in breast tissues and their association with breast cancer survival remain unclear. In the present study, we quantified the mRNA levels of the IGF-I and IGFIR genes in both benign and malignant breast tumor tissues and their adjacent normal tissues. We then evaluated whether the expression patterns of these genes in breast cancer tissues are related to breast cancer survival. Included in the study were samples from 508 patients diagnosed with primary breast cancer, and 206 patients diagnosed with benign breast disease (BBD). Patients with BBD had a significantly higher IGF-I gene expression than patients with breast cancer in both tumor and adjacent non-neoplastic tissues. Among BBD patients, mRNA levels of the IGF-I gene were similar between tumor and tumor adjacent tissues. In cancer patients, however, the expression levels of these genes were substantially higher in tumor adjacent tissues than in tumor tissues. Patients with a high expression of the IGF-I gene in cancer tissues tended to have more favorable overall and disease-free survival. Our findings suggest that the expression of IGF-I and IGFIR genes may undergo substantial change over the course of breast tumorigenesis, and the pattern of changes may be associated with breast cancer prognosis.     

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98

The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point. Patients randomized to letrozole had a 19% improved disease-free survival (hazard ratio [HR]=0.81; P=0.003), due especially to reduced distant metastases (HR=0.73; P=0.001). A 14% risk reduction of fatal events in favor of letrozole was also observed (P=NS). The results from the monotherapy arms alone confirmed the findings from the primary core analysis. Based on the results from this trial, the aromatase inhibitor letrozole (Femara) is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States. A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy.     

Modeling for cost-effective-adjuvant aromatase inhibitor strategies for postmenopausal women with breast cancer.

BACKGROUND: To determine cost-effective (CE) strategies comparing adjuvant upfront aromatase inhibitor (AI) with sequential tamoxifen (TAM) AI in postmenopausal (PM) women with breast cancer (BC). Design: A Markov model was constructed to calculate cumulative costs and quality-adjusted life year (QALY) gains for upfront AI and TAM-AI in a hypothetical cohort of 60-year-old PM women with BC. Costs, utilities and probabilities were derived from the literature. The hazard ratios (HRs) of AI strategies were applied to a baseline cancer recurrence risk (RR) to determine CE strategies at the $50,000/QALY gain threshold. A direct payer perspective is utilized, and costs and benefits were discounted at 3%. RESULTS: Two-way sensitivity analyses are presented to determine CE strategies across a wide range of HRs and in different clinical scenarios including varying RRs (low, average, high and very high). TAM-AI is the preferred CE strategy at low and average RR, while upfront AI is CE at very high RR. The CE strategy in patients with high RR was dependent on the scenario examined. CONCLUSIONS: This model may help health care providers select CE-adjuvant AI strategies in PM women with BC, until further direct evidence is available from randomized clinical trials.     

Aromatase inhibitors in the management of early breast cancer

The adjuvant treatment of patients with endocrine-sensitive breast cancer has been dominated for several decades by the gold-standard tamoxifen. Promising results on the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to the development of these agents in the treatment of early breast cancer. Recent results consistently show the superiority of these agents over tamoxifen, and the therapeutic strategies of AIs in the adjuvant setting are still being discussed. Various approaches have been evaluated, including the following:

1.

upfront 5-year use of an AI instead of tamoxifen for newly diagnosed patients,     

Neoadjuvant tamoxifen for hormone-sensitive non-metastatic breast carcinomas in early postmenopausal women.

BACKGROUND: From 1984 to 1996, 1581 postmenopausal women aged 50-70 years old were treated at Institut Bergonié for an infiltrative non-metastatic breast carcinoma with a positive estrogen and/or progesterone receptor determination. PATIENTS AND METHODS: Among them, 199 were treated with first line tamoxifen. Ninety-seven had operable disease (T2 >30 mm, T3, N0/1) and 102 had T4 tumours. RESULTS: After a mean treatment duration of 5.3 months, 89 T2 and T3 (92%) and 93 T4 (91%) were treated by surgery (conservative or not) with or without irradiation, or by irradiation alone. Conserving treatment levels were 53.6% and 44%, respectively. The other women were treated with either second-line chemotherapy or another hormonotherapy; the remaining patients continued regularly with tamoxifen. Overall survival is analysed with a 83 month median follow-up. CONCLUSIONS: A comparison between neoadjuvant endocrine therapy and surgery seems feasible to assess the concept of neoadjuvant hormonotherapy.     

Hormonal therapy in postmenopausal women with breast cancer

The treatment of postmenopausal women with breast cancer presents a number of challenges. Tamoxifen has had a substantial impact on mortality in women with early-stage, estrogen-receptor-positive tumors. Despite the improvement in the treatment of breast cancer, many patients will ultimately experience a recurrence. Present treatment approaches can provide effective palliation in the advanced disease setting, but, at best, there has been a modest impact on survival. Numerous options are now available to provide effective palliation for patients with advanced disease. These options include antiestrogens, pure antiestrogens, aromatase inhibitors and progestins and LHRH agonists. Recently, several studies have reviewed the efficacy of aromatase inhibitors as first-line agents in postmenopausal women. Anastrozole and letrozole have recently been approved as first-line agents in women with metastatic breast cancer. In addition to their role in metastatic breast, trials investigating the potential of aromatase inhibitors in the early breast cancer, both in the adjuvant and neoadjuvant setting are underway.     

Aromatase inhibitor versus tamoxifen in postmenopausal woman with advanced breast cancer: a literature-based meta-analysis

Clinical trials have reported conflicting results as to whether Aromatase inhibitors (AIs) as first-line hormonal therapy improve outcome over tamoxifen in postmenopausal women with advanced breast cancer. We performed a meta-analysis comparing primary and secondary endpoints of AIs to tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. The event-based odds ratio (OR) with 95% confidence interval (95% CI) were derived, and a test of heterogeneity was applied. Six eligible trials (2560 patients) were selected from 488 studies that initially were identified. A significant difference in favoring AIs over tamoxifen was observed in overall response rate (ORR; OR, 1.56; 95% CI, 1.17-2.07; P = .002) and clinical benefit (CB; OR, 1.70; 95% CI, 1.24-2.33; P = .0009).Whereas the trend toward an improved overall survival (OS) rate was not significant (OR, 1.95; 95% CI, 0.88-4.30; P = .10).Toxicities did not differ significantly except vaginal bleeding (OR, 0.30; 95% CI, 0.16-0.56; P = .0002) and thromboembolic event (OR, 0.47; 95% CI, 0.28-0.77; P = .003). AIs appeared to be effective and feasible compared with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Further prospective, randomized, controlled trials will be necessary.     

Aromatase inhibitor development for treatment of breast cancer

Summary Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue.To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hrurine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS 20267 can be expected to bring improved response rates in the treatment of metastatic hormone-dependent breast cancer without substantial side effects.Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).