Appraising adjuvant aromatase inhibitor therapy

Tamoxifen, once the gold standard adjuvant endocrine therapy for early breast cancer, is being challenged by third-generation aromatase inhibitors (AIs) that have demonstrated improved disease-free survival in a variety of adjuvant settings for early breast cancer. Tamoxifen and AIs have different safety profiles, which should allow physicians to begin to individualize treatment based on a patient's comorbidities and risk factors. Because of its properties as a partial estrogen agonist, tamoxifen has a positive effect on serum lipids and may confer a cardioprotective benefit, as well as a beneficial effect on bone health. However, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major side effect of AIs is increased bone loss, which may heighten the risk for osteoporotic fractures and bone pain. Because of their superior efficacy and manageable side effects, AIs are a cost-effective alternative to tamoxifen, and clinical guidelines now embrace AIs as appropriate adjuvant therapy for hormone-sensitive early breast cancer. The anticipated results of ongoing trials will provide further insights into the long-term safety and application of AI therapy in the adjuvant setting.     

Women and bone health: maximizing the benefits of aromatase inhibitor therapy

Postmenopausal women with early breast cancer (EBC) are already at risk for bone loss, osteoporosis and fracture as they age because of declining estrogen levels. Adjuvant hormonal therapy with aromatase inhibitors (AIs; e.g. letrozole, anastrozole, exemestane) can exacerbate this risk. All three AIs appear to have similar effects on bone, increasing bone turnover and fracture risk in postmenopausal women with EBC. Risk factors for bone loss can be used to assess fracture risk and the need for ongoing assessment and/or treatment in postmenopausal women receiving AIs for EBC. The concomitant, up-front use of intravenous bisphosphonate therapy, such as zoledronic acid, in combination with AIs can inhibit bone loss. In addition, a strong body of evidence suggests an anticancer activity of bisphosphonate therapy with zoledronic acid in EBC in both the pre- and postmenopausal adjuvant setting. Zoledronic acid thus provides a therapeutic option for postmenopausal women with EBC who may be at higher risk for bone loss while on AIs, allowing more patients to receive treatment with effective adjuvant hormonal therapy to prevent recurrence.     

A woman's heart

Adjuvant therapy in postmenopausal women with breast cancer may contribute to the expression of underlying cardiovascular disease or expose the heart to additional toxicities. Tamoxifen remains an important component of endocrine therapy for breast cancer, although major clinical trials of the aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane suggest that these agents are more effective and better tolerated alternatives to tamoxifen. The AIs inhibit the conversion of androgens to estrogen in postmenopausal women; consequently, their mechanism of action differs from that of tamoxifen. Accordingly, although it has been observed that tamoxifen has some favorable effects on cardiovascular risk, such as reducing total cholesterol levels, because of its partial estrogen‐agonist properties, no such effects exist for the AIs. Some studies, particularly those that compare the AIs with tamoxifen, have suggested a less favorable impact of adjuvant AI therapy on cardiovascular risk. Comorbid conditions, including cardiovascular disease, emerge as competing causes of death as women with breast cancer continue to live longer, and the potential impact of adjuvant therapies on cardiovascular risk becomes an increasingly important consideration for clinicians. Cancer 2009. © 2009 American Cancer Society.     

Osteopenia and osteoporosis in women with breast cancer

Osteopenia and osteoporosis are prevalent in women. Epidemiologic studies show that the risk of breast cancer is greater in postmenopausal women with higher bone mineral density (BMD). Standard treatments for breast cancer such as adjuvant chemotherapy or hormonal therapy can increase bone loss, and hence may increase the risk of osteoporosis. Premenopausal women treated with standard adjuvant chemotherapy frequently develop permanent ovarian failure, or early menopause. Ovarian failure is associated with accelerated bone loss, and bisphosphonates may mitigate this bone loss in women treated with adjuvant chemotherapy. Tamoxifen preserves BMD in postmenopausal women; however, in premenopausal women tamoxifen may increase bone loss. Anastrazole, an aromatase inhibitor, is approved for adjuvant treatment of postmenopausal women with early-stage, estrogen receptor-positive breast cancer. With a follow-up duration of less than 5 years, anastrazole-treated women experience increased fractures relative to those treated with tamoxifen. The management of osteopenia and osteoporosis in women with breast cancer generally does not differ from women without breast cancer. Adequate dietary calcium and vitamin D intake, encouraging weight-bearing exercise, and counseling about the relationship between smoking and alcohol and bone loss are all prudent recommendations for overall health and may lessen bone loss and the risk of subsequent osteoporosis. BMD should be measured in women with chemotherapy-induced ovarian failure, and in those on aromatase inhibitors. Bisphosphonates reduce the bone loss associated with chemotherapy-induced ovarian failure, and clinical trials evaluating third-generation bisphosphonates in women with chemotherapy-induced ovarian failure are underway. As many women with breast cancer will be long-term survivors, increasing recognition of maintaining skeletal health is important.     

Adjuvant hormonal therapy in peri- and postmenopausal breast cancer

Tamoxifen has been the mainstay of endocrine treatment for early-stage breast cancer in both premenopausal and postmenopausal women for many years. Since 2001, the results of several large, randomized, clinical trials have provided evidence that aromatase inhibitor (AI) therapy, either upfront or in sequence after tamoxifen, improves disease-free survival and, in certain patients, overall survival for postmenopausal patients with hormone receptor-positive breast cancer. Thus far, with relatively short-term follow-up, AIs have been generally safe and well tolerated among the population of patients treated in these adjuvant trials. However, important side effects such as musculoskeletal and bone-related problems, including the risk for osteoporosis and fractures, remain of concern and warrant continued monitoring and follow-up. Several questions regarding the appropriate AI to use and the timing of AI therapy remain unresolved, and ongoing studies will help address these issues. Caution is warranted in the use of AIs in perimenopausal women, including those that develop chemotherapy-induced amenorrhea, and clinical evidence supports the role for AI use in postmenopausal women only. Areas of active investigation include the mechanisms of resistance to endocrine therapy with tamoxifen and AIs and clinical strategies to overcome this resistance.     

Adverse bone effects during pharmacological breast cancer therapy

The improved survival and cure rate of breast cancer patients leads to increased diagnosis of later occurring side effects to therapy such as osteoporosis. Conventional chemotherapies such as CMF and CEF are known to induce premature menopause, which increases bone loss but these therapies have additional detrimental effects on bone. The loss in bone mass during chemotherapy is substantial and may lead to increased fracture risk. The influence of taxanes on bone is less well known. Whereas tamoxifen has a slight protective effect on bone loss the opposite is true for aromatase inhibitors. Adverse effect reportings show, that adjuvant treatment with aromatase inhibitors in postmenopausal women increases the risk of clinical fractures as compared to tamoxifen. The Danish Bone Society suggests that all women with operable breast cancer have their fracture risk evaluated including a BMD measurement prior to initiation of adjuvant aromatase inhibitor therapy as a part of the standard examination program. If osteoporosis is diagnosed, anti-osteoporosis therapies should be considered. Moreover, all women undergoing adjuvant chemotherapy and endocrine therapy should be informed of the risk of bone loss and should receive life style advice of how to preserve bone. Adjuvant regimens in breast cancer patients improve survival and cure rates. Therefore it is preferable to use such therapies although they increase risk of side effects such as osteoporosis.     

Effects of third-generation aromatase inhibitors on bone

Low oestradiol levels in women are associated with decreased bone mineral density (BMD) and increased fracture risk. The third-generation aromatase inhibitors (AIs; anastrozole, letrozole, and exemestane) are used in the treatment of early and advanced breast cancer and act by substantially reducing oestrogen synthesis in postmenopausal women. However, due to their mechanism of action, there is concern regarding the long-term effects of these agents on bone, particularly when used in the adjuvant setting. In this paper, the currently available data on the effects of the third-generation AIs on markers of bone turnover, BMD, and fracture risk are reviewed, with the emphasis on results in the adjuvant treatment of early breast cancer. These data suggest that both the steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs appear to affect bone turnover. Conclusions regarding any clinically relevant differences between these agents are difficult to make, and further data are awaited from long-term adjuvant use of these three agents in ongoing clinical studies. Postmenopausal women are at increased risk of osteoporosis and fracture, and the increasing use of AIs in the adjuvant treatment of postmenopausal breast cancer patients will require appropriate consideration of fracture risk, with the use of anti-osteoporotic therapies, if necessary.     

Aromatase inhibitors and bone loss

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.     

Strategies for the prevention of treatment-related bone loss in women receiving adjuvant hormonal therapy

More than 220,000 women will be diagnosed with breast cancer this year, and approximately 75% of these women will be long-term survivors of this disease. Survival has improved largely because of advances in adjuvant hormone therapy and chemotherapy, as well as early detection strategies. Because most women will receive adjuvant treatment, and the majority will survive cancer, it is increasingly important to understand the resultant toxicities and to devise monitoring and treatment strategies to avoid adverse long-term effects. Loss of bone mineral density leading to osteoporosis and increased risk of fracture as well as other morbidities is a well known complication of estrogen suppression associated with use of aromatase inhibitors (AIs) in postmenopausal women, and ovarian suppression with GnRH agonists or chemotherapy in premenopausal women. Hormone receptor positivity is increasingly frequent with increasing patient age, so that a large number of women already at risk for osteopenia associated with menopause are at risk for further bone loss caused by adjuvant hormone therapy with AIs. This article will review data on bone mineral density loss and risk of fracture in the large, randomized phase III trials comparing tamoxifen to AIs using the upfront, switching or extended hormone therapy approach. Data from prophylactic bisphosphonate intervention trials in both post- and premenopausal women will be discussed. Ongoing trials are described.     

Adjuvant endocrine therapy in hormone receptor-positive postmenopausal breast cancer: evolution of NCCN, ASCO, and St Gallen recommendations

Endocrine therapy has a firm role in adjuvant treatment of women with hormone receptor-positive invasive breast cancer. Until recently, tamoxifen was the most commonly used adjuvant endocrine therapy in premenopausal and postmenopausal women. Several randomized clinical trials have studied the third-generation selective aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) as adjuvant endocrine therapy in postmenopausal women. These studies compared therapy with an AI alone versus tamoxifen alone; 2 to 3 years of tamoxifen followed by switching to an AI versus continuation of tamoxifen; or extended therapy with an AI after approximately 5 years of tamoxifen therapy. No statistically significant differences in overall survival were observed. A single trial using extended treatment with an adjuvant AI suggests a small, statistically significant survival advantage in women with axillary lymph node-positive disease while showing no statistically significant decrease in survival with the use of an AI. The toxicities of the AIs are generally acceptable, with fewer endometrial cancers, gynecologic complaints, and thromboembolic events, but more bone fractures and arthralgias compared with tamoxifen alone. Three widely disseminated treatment guidelines, the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology, the American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors, and the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, now incorporate AIs in the adjuvant therapy of postmenopausal women with estrogen receptor-positive breast cancer.     

Optimizing endocrine therapy for premenopausal and postmenopausal women with breast cancer

The majority of invasive breast cancer patients present with hormone receptor-positive disease, and modulation of estrogen receptor (ER) activation is an essential component of systemic adjuvant therapy for these women. While tamoxifen has traditionally been the primary adjuvant endocrine therapy for all ER-positive women, recent trials evaluating the use of aromatase inhibitors (AIs) have challenged this standard in postmenopausal women, and ongoing trials are examining the optimal use of endocrine therapy in younger women. Issues regarding the optimal approach to endocrine therapy in both pre- and postmenopausal women are examined in this review.     

Recent advances in endocrine therapy for postmenopausal women with early breast cancer: implications for treatment and prevention.

BACKGROUND: In the treatment of advanced breast cancer, third-generation aromatase inhibitors (AIs) have shown superior efficacy and tolerability compared with tamoxifen and megestrol acetate, the previous standard endocrine therapies in the first- and second-line settings, respectively. AIs are now being assessed in the adjuvant and prevention settings. DESIGN: Literature review (PubMed search). RESULTS: Tamoxifen is currently the only endocrine option available for adjuvant therapy and chemoprevention in postmenopausal women. However, results from the ATAC ('Arimidex', Tamoxifen, Alone or in Combination) trial have shown anastrozole to be more effective than tamoxifen as adjuvant therapy for postmenopausal women with hormone-responsive early breast cancer. Other third-generation AIs, including letrozole and exemestane, are also being investigated as adjuvant therapies. In the chemoprevention setting, tamoxifen is the only available endocrine option for women at high risk of breast cancer but, given that these are healthy subjects, is associated with an unacceptable rate of adverse events. Raloxifene is being further assessed in the STAR (Study of Tamoxifen and Raloxifene) trial, while anastrozole is being evaluated in the second IBIS-II (International Breast Intervention Study II). CONCLUSIONS: AIs, in particular anastrozole, are set to change the way that early breast cancer is treated. Effective and better-tolerated endocrine alternatives for breast cancer prevention may become available in the future.     

Breast cancer adjuvant endocrine therapy

Adjuvant endocrine therapy with the selective estrogen receptor modulator, tamoxifen, has significantly improved mortality from early-stage breast cancer for both pre- and postmenopausal women with hormone receptor-positive breast cancer. Recent large clinical trials have demonstrated a clear and consistent benefit for the incorporation of aromatase inhibitor (AI) therapy within adjuvant endocrine regimens for postmenopausal women. The AIs, which are associated with myalgias, arthralgias, and a reduction in bone mineral density, are generally well tolerated and have lower risks of endometrial carcinoma and thromboembolic events than tamoxifen. Data are awaited from ongoing trials to better define the optimal sequencing strategy, duration, and AI agent. Attempts to further optimize adjuvant endocrine therapy by identifying predictive biomarkers of response, as well as by developing strategies to overcome endocrine resistance are underway. In premenopausal women AI monotherapy is currently contraindicated and tamoxifen remains the standard of care. The role of ovarian function suppression in addition to tamoxifen or combined with AI therapy is being explored. The hope is that continued advances in endocrine therapy will translate into improved survival among both pre- and postmenopausal women with receptor-positive breast cancer.     

The role of aromatase inhibitors in early breast cancer

Opinion statement The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptorpositive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large study showed that at a median follow-up time of 33 months, anastrozole alone results in significant improvement in disease-free survival rates, reduction in contralateral breast cancers, and increased tolerability, compared to tamoxifen in postmenopausal women. Although the long-term effects of AIs are not known, the early positive results of the ATAC trial led to the approval of anastrozole by the US Food and Drug Administration for use as adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive invasive breast cancer. Thus, there is an alternative to tamoxifen for postmenopausal women with relative/absolute contraindications to tamoxifen use or patients who choose not to take tamoxifen because of its side-effect profile. New AIs may challenge the position of tamoxifen as the gold standard for the treatment of early stage breast cancer in postmenopausal women.     

Recent perspectives of endocrine therapy for breast cancer

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.     

Skeletal events of Anastrozole versus Tamoxifen on bone mineral density and bone biomarker osteocalcin in postmenopausal women with early breast cancer

Objective  

Postmenopausal women with breast cancer are at increased risk of bone loss because of age related estrogen deficiency face which accelerated with the use of aromatase inhibitors (AIs). We aimed to study the effect on bone mineral density (BMD) and bone formation biomarker osteocalcin level in postmenopausal breast cancer patients, for the first three years of adjuvant hormonal treatment of both groups Tamoxifen versus Anastrozol.     

Managing bone mineral density with oral bisphosphonate therapy in women with breast cancer receiving adjuvant aromatase inhibition

The use of adjuvant aromatase inhibitors is associated with an increased risk of osteoporosis and fractures. The oral bisphosphonate, risedronate - dosed as the US Food and Drug Administration approved for the treatment or prevention of postmenopausal osteoporosis - appears to mitigate bone loss associated with 2 years of adjuvant anastrozole in women with early-stage breast cancer.     

Musculoskeletal events associated with the management of endocrine-responsive breast cancer

Musculoskeletal symptoms have been reported in patients treated with third generation aromatase inhibitors (AIs) and with blockers of hypothalamic–pituitary gonadal axis. AIs act by suppressing postmenopausal estrogen biosynthesis through inhibition of the enzyme aromatase, which is responsible for the conversion of androgens to estrogens in many tissues. Maximal estrogen and/or androgen deprivation is beneficial for cancer growth suppression but could be associated with side effects such as accelerated bone loss and osteoporotic fractures which are extensively reported. Musculoskeletal events, another group of adverse events, have been studied to a lesser extent and are usually commonly reported as arthralgia and myalgia. Furthermore, the pathogenesis and anatomical findings of musculoskeletal symptoms have not been adequately elucidated. In this communication, we review recent information related to musculoskeletal symptoms in breast cancer and speculate on possible explanations for musculoskeletal pain related to hormone deprivation. We outline treatment options for control of arthralgia and myalgia due to hormonal therapy. More knowledge about the etiology and management of musculoskeletal adverse effects breast cancer during endocrine therapy is needed because discontinuation of the treatment due to intolerant symptomatology may result in disruption of the treatment schedule.     

Symptômes musculosquelettiques liés aux inhibiteurs de l’aromatase

Aromatase inhibitors (AIs) are widely used as adjuvant endocrine treatment in postmenopausal women with a breast cancer at early stage, with the presence of estrogen receptor. However an elevated incidence of musculoskeletal symptoms has been observed as associated with AIs treatment. Musculoskeletal symptoms can be observed with every AI and are considered a class effect of AIs. These manifestations are related to the effect of estrogen deprivation on cartilage and periarticular tissues. Patient education regarding the possibility of experiencing arthralgia, and effective management of potential symptoms are important to promote patients’ adherence to AI treatment.     

The causes and treatment of bone loss associated with carcinoma of the breast

Despite an increasing incidence, the outlook for women with early breast cancer has improved considerably over recent years with a steady fall in the death rate in most western countries. This is due, at least in part, to the widespread use of adjuvant systemic therapy. However, some of these treatments have adverse effects on bone metabolism with increased bone loss which may result in osteoporosis and associated fractures. Most of the effects on bone are mediated by endocrine changes, either induction of an early menopause by chemotherapy and ovarian ablation, or further suppression of postmenopausal circulating oestrogens by aromatase inhibitors. There may also be direct effects of chemotherapy on bone cell function. The pathophysiology of osteoporosis in breast cancer patients, the methods of assessment and treatment options are reviewed. Bone health is a highly topical issue in breast cancer with the emergence of data supporting the use of several years of treatment with aromatase inhibitors. Guidelines on who and how to screen for bone loss, and simple, safe strategies for treatment to prevent osteoporosis are presented.