Bisphosphonates as adjuvant therapy for breast cancer

Breast cancer is the most common malignancy among women worldwide. Emerging results from clinical trials in patients with breast cancer suggest that, in addition to preventing cancer treatment-induced bone loss, bisphosphonates may improve disease-free survival (DFS). Although the first adjuvant studies using the early generation oral bisphosphonate clodronate suggested potential reductions in distant recurrence versus placebo in patients with early breast cancer, subsequent results with clodronate were inconsistent, and oral pamidronate produced no disease recurrence benefits versus chemotherapy alone in this setting. In contrast, addition of the newer bisphosphonate zoledronic acid to adjuvant therapy reduced disease recurrence rates and improved DFS compared with adjuvant endocrine therapy alone in two phase 3 studies in postmenopausal women with early breast cancer. Adjuvant zoledronic acid also significantly improved DFS compared with endocrine therapy alone in premenopausal women with breast cancer. Data from ongoing and future trials will further define the role of bisphosphonates in the adjuvant breast cancer setting.     

Should bisphosphonates be utilized in the adjuvant setting for breast cancer?

Adjuvant therapies for early breast cancer are associated with substantial decreases in bone mineral density. Bisphosphonates are antiresorptive agents that have an established role in preventing skeletal morbidity in patients with bone metastases and in the treatment of osteoporosis. Recently, several trials have demonstrated the efficacy of bone-directed agents for prevention of cancer treatment-induced bone loss in both premenopausal and postmenopausal women with early stage breast cancer. Moreover, it is now becoming evident that bisphosphonates may also exert anticancer effects in the adjuvant setting. For example, long-term follow-up of a study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for clodronate versus placebo, and an ongoing large trial may provide further insights. Addition of twice-yearly zoledronic acid to standard adjuvant endocrine therapy significantly improved disease-free survival and decreased disease recurrence compared with standard therapy alone in 3 clinical trials involving nearly 3,500 patients with stage I-IIIA breast cancer, and monthly zoledronic acid during neoadjuvant therapy decreased residual tumor volume and improved pathologic response in patients with stage II/III breast cancer. Overall, a large and growing body of evidence suggests the potential adjuvant benefits of bisphosphonates in early breast cancer.     

Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer.     

Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer.     

Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures. Many small studies have demonstrated that cancer therapy—induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting. Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of earlystage breast cancer. Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.     

Managing bone loss in women with early-stage breast cancer receiving aromatase inhibitors

Third-generation aromatase inhibitors (AIs; anastrozole, letrozole, exemestane) have replaced tamoxifen as the adjuvant treatment of choice for postmenopausal women with hormone receptor-positive early-stage breast cancer. Because bone loss is a predictable adverse event of AI therapy, early recognition, prevention, and/or treatment of AI-induced bone loss is needed. One to 5 years of AI therapy causes a bone mineral density (BMD) loss of up to 7.2% in postmenopausal women; however, current clinical guidelines do not recommend initiating bisphosphonate therapy for the treatment of BMD loss until fragility fractures or frank osteoporosis occur. Results of recent trials evaluating the use of intravenous (I.V.) zoledronic acid as prevention and treatment of AI-induced bone loss in women with early-stage breast cancer receiving letrozole suggest a potential benefit to the concurrent use of zoledronic acid and letrozole. To our knowledge, clinical trials assessing oral or other I.V. bisphosphonates for these indications have not been published. Recently, concerns of bisphosphonate-induced renal safety and osteonecrosis of the jaw have emerged. Studies evaluating bisphosphonates in women with breast cancer have reported lower rates of renal dysfunction than those reported in patients with metastatic cancer receiving bisphosphonates, and no cases of jaw osteonecrosis. The use of bisphosphonates in this population requires further study to more clearly define the most appropriate timing and length of therapy as well as the long-term efficacy and safety of these drugs. Until these data become available, balancing the safety concerns with the potential benefits of I.V. bisphosphonates to minimize or prevent AI-induced bone loss in women with early-stage breast cancer is required.     

Bone health in women with early-stage breast cancer

Bone health is an increasingly important concern in breast cancer survivors because in postmenopausal women, bone-sparing tamoxifen is being replaced by aromatase inhibitors, whereas in premenopausal women, ovarian suppression is playing an increasing role in adjuvant management. Estrogen reduction resulting from aromatase inhibition and ovarian suppression are associated with loss in bone mineral density (BMD) and an increase in fracture risk. These side effects must be placed in context of the overall risks and benefits seen with these interventions. The American Society of Clinical Oncology has outlined a management strategy for bone health maintenance in breast cancer survivors with early-stage disease that incorporates baseline and ongoing screening for BMD and treatment based on BMD results. Limited but consistent data suggest bisphosphonate therapy represents a treatment option for this condition. A variety of interventions to maintain bone health in breast cancer survivors are undergoing clinical evaluation and include the oral bisphosphonates risedronate and clodronate, the intravenous bisphosphonate zoledronic acid, the receptor activator of nuclear factor-kB ligand inhibitor AMG-162, and the hormonal agent tibolone. Current information suggests bone loss associated with estrogen reduction in breast cancer survivors may represent a preventable and treatable condition. Ongoing clinical trials will definitively evaluate this hypothesis.     

Adjuvant bisphosphonates in endocrine-responsive breast cancer: what is their place in therapy?

Recent advances in the treatment of early breast cancer have improved clinical outcomes and prolonged survival, especially in women with endocrine-responsive disease. However, cancer therapies including cytotoxic chemotherapy, ovarian suppression, and aromatase inhibitors can drastically reduce circulating estrogen, increasing bone loss and fracture risk. Because most women with early breast cancer will live for many years, it is important to protect bone health during cancer therapy. Several recent clinical trials combining adjuvant endocrine therapy with bisphosphonates have demonstrated efficacy for preventing cancer treatment-induced bone loss in pre- and postmenopausal women with early breast cancer. The largest body of evidence supporting the use of adjuvant bisphosphonates comes from studies with zoledronic acid; however, studies with risedronate, ibandronate, and denosumab (a biologic agent) have also demonstrated efficacy for preventing bone loss. Adding zoledronic acid to endocrine therapy prevents bone loss and improves bone mineral density (BMD). In addition, preclinical studies suggest that bisphosphonates have direct and indirect antitumor activity, such as inducing tumor cell apoptosis, reducing tumor cell adhesion and invasion, reducing angiogenesis, activating immune responses, and synergy with chemotherapy agents, among others. Clinical trials have demonstrated significantly improved disease-free survival in patients receiving adjuvant endocrine therapy plus zoledronic acid compared with endocrine therapy alone. Ongoing studies will further define the role of adjuvant bisphosphonates in maintaining bone health and improving clinical outcomes. The available evidence suggests that pre- and postmenopausal patients may receive clinical benefit from including bisphosphonates as part of their adjuvant treatment regimen for endocrine-responsive early breast cancer.     

Evolving role of bisphosphonates in women undergoing treatment for localized and advanced breast cancer

Breast cancer commonly metastasizes to bone, producing hypercalcemia, pathologic fractures, spinal compression, and pain that increase morbidity and affect the patient's mobility and quality of life. The use of bisphosphonates like pamidronate and zoledronic acid inhibits osteolytic activity caused by bone metastases. The use of bisphosphonates to prevent bone loss and preserve bone health in the adjuvant setting in women with breast cancer undergoing hormonal therapy with aromatase inhibitors or ovarian suppression is being actively investigated. Interestingly, clodronate, an oral bisphosphonate, has been shown in 2 trials to decrease the risk of recurrence in women with early-stage breast cancer, suggesting a direct or indirect antitumor effect of bisphosphonates. Trials to confirm the antitumor effects of bisphosphonates are currently ongoing. Prolonged intravenous bisphosphonate use has been associated with a rare risk of osteonecrosis of the jaw. Recommendations for management of this condition are discussed.     

Antiresorptive therapies in oncology and their effects on cancer progression

Bone health is an emerging concern in the early breast cancer setting. Current adjuvant therapies, especially hormonal therapies in premenopausal patients (e.g. goserelin) and aromatase inhibitors in postmenopausal patients, have been associated with substantial decreases in bone mineral density that may place patients at risk for fractures. Bisphosphonates--and the recently approved anti-RANKL antibody, denosumab--have both demonstrated activity for the treatment of postmenopausal osteoporosis and cancer treatment-induced bone loss (CTIBL) in breast cancer patients, although neither has received widespread approval specifically for CTIBL. However, some bisphosphonates, especially the nitrogen-containing bisphosphonate zoledronic acid, have also demonstrated clinically meaningful anticancer effects in patients receiving adjuvant hormonal therapy for breast cancer and in other oncology settings. The effects of denosumab on cancer disease outcomes in the adjuvant setting remain to be established. This discrepancy has created a dilemma in terms of how to evaluate the complete benefit:risk profile of bone-health management options in the adjuvant breast cancer setting. This review summarises the current data on the course of cancer in clinical trials of the antiresorptive agents and provides important insight into the relative anticancer potential of the various therapies.     

Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel

Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18 000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.     

Prevention of bone metastases and management of bone health in early breast cancer

Treatment options for women with early-stage breast cancer have never been better, and the addition of bisphosphonates to adjuvant therapy is a valuable new tool capable of substantially improving clinical outcomes for these women. Several recent studies demonstrated that the anticancer activity of bisphosphonates is not limited to bone, and can translate into a reduction in disease recurrence, including reductions in locoregional and distant metastases. In addition, bisphosphonates maintain bone health during adjuvant therapy; this may be especially important for women who are at high risk for fracture.     

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.     

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.     

Exploring novel targets of basal-like breast carcinoma by comparative gene profiling and mechanism analysis

Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms “breast,” “cancer,” “neoplasm,” “Tamoxifen,” “Aromatase Inhibitor,” “chemotherapy,” “hormone therapy,” “alveolar bone loss,” “postmenopausal bone loss,” “estrogen,” “SERM,” “hormone replacement therapy,” and “quality of life.” We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship.     

Bisphosphonates and bone metastases]

Bisphosphonates, potent inhibitors of bone resorption have been emerging as the standard treatment of tumor-induced hypercalcemia during the 90's. All uncontrolled phase II studies up to 1992 had demonstrated efficacy in reducing morbidity in terms of bone pain, fracture and hypercalcemia. Other studies on intravenous bisphosphonates, with no other anti-tumor treatment, even demonstrated sclerosis of osteolytic breast cancer bone metastases. Randomised phase III studies only began after 1992. In multiple myeloma, one study with oral clodronate has reported a decrease in bone events and two other studies, one with intravenous pamidronate and the other with oral clodronate have both reported a decrease in skeletal events and bone pain. In breast cancer patients with bone metastases, five large studies have been reported: three with intravenous pamidronate, one with oral pamidronate and one with oral clodronate. All these studies have demonstrated the superiority of bisphosphonates over placebo on both bone pain and bone events, but have failed to show an increase in duration of survival. Bisphosphonates should therefore be considered as an important part of the palliative treatment in breast cancer patients with bone metastases. On the other hand, no definite conclusion can be drawn on the role of bisphosphonates in the treatment of prostatic carcinoma bone metastases yet. However, bisphosphonates should be considered as part of the standard therapy in managing painful lesions in patients with multiple myeloma, breast cancer and prostatic cancer. Nevertheless, further studies are needed with bisphosphonates in the adjuvant setting before bone metastases appear. Could new and more potent bisphosphonates such as zoledronate further reduce bone metastases morbidity?     

Zoledronic acid: multiplicity of use across the cancer continuum

Zoledronic acid (ZOL) has proven efficacy for reducing the risk of skeletal-related events in patients with bone metastases from a broad range of solid tumors and bone lesions from multiple myeloma. In a head-to-head trial in patients with breast cancer, ZOL demonstrated efficacy at least comparable with, and some benefits beyond those of, pamidronate. Several studies have also demonstrated additional benefits from ZOL, including preventing bone loss, and potential anticancer activity. Adding ZOL to anticancer therapy improved disease-free and overall survival in clinical trials in women receiving adjuvant endocrine therapy for breast cancer and in patients with newly diagnosed multiple myeloma. Thus, recent advances suggest that, in addition to its established role in reducing skeletal morbidity, ZOL might also help preserve bone health in patients with early stage breast cancer. The potential role of ZOL as an anticancer therapy in this setting is the focus of intense investigation and awaits insights from ongoing clinical trials.     

Zoledronic acid: multiplicity of use across the cancer continuum

Zoledronic acid (ZOL) has proven efficacy for reducing the risk of skeletal-related events in patients with bone metastases from a broad range of solid tumors and bone lesions from multiple myeloma. In a head-to-head trial in patients with breast cancer, ZOL demonstrated efficacy at least comparable with, and some benefits beyond those of, pamidronate. Several studies have also demonstrated additional benefits from ZOL, including preventing bone loss, and potential anticancer activity. Adding ZOL to anticancer therapy improved disease-free and overall survival in clinical trials in women receiving adjuvant endocrine therapy for breast cancer and in patients with newly diagnosed multiple myeloma. Thus, recent advances suggest that, in addition to its established role in reducing skeletal morbidity, ZOL might also help preserve bone health in patients with early stage breast cancer. The potential role of ZOL as an anticancer therapy in this setting is the focus of intense investigation and awaits insights from ongoing clinical trials.     

Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases

Bisphosphonates are important treatments for bone metastases. Considerations for optimizing the clinical benefits of bisphosphonates include efficacy, compliance, and safety. Several bisphosphonates are approved for clinical use; however, few have demonstrated broad efficacy in the oncology setting and been compared directly in clinical trials. Among patients with bone metastases from breast cancer, the efficacy of approved bisphosphonates was evaluated in a Cochrane review, showing a reduction in the risk of skeletal-related events (SREs) ranging from 8% to 41% compared with placebo. Between-trial comparisons are confounded by inconsistencies in trial design, SRE definition, and endpoint selection. Zoledronic acid has demonstrated clinical benefits beyond those of pamidronate in a head-to-head trial that included patients with breast cancer or multiple myeloma. Compliance and adherence also have effects on treatment efficacy. In a comparison study, the adherence rates with oral bisphosphonates were found to be significantly lower compared with those of intravenous bisphosphonates. The safety profiles of oral and intravenous bisphosphonates differ. Oral bisphosphonates are associated with gastrointestinal side effects, whereas intravenous bisphosphonates have dose- and infusion rate-dependent effects on renal function. Osteonecrosis of the jaw is an uncommon but serious event in patients receiving monthly intravenous bisphosphonates or denosumab. The incidence of this event can be reduced with careful oral hygiene. A positive benefit-risk ratio for bisphosphonates has been established, and ongoing clinical trials will determine whether individualized therapy is possible.     

Aromatase inhibitors in the treatment and prevention of breast cancer.

PURPOSE: The purpose of this article is to provide an overview of the current clinical status and possible future applications of aromatase inhibitors in breast cancer. METHODS: A review of the literature on the third-generation aromatase inhibitors was conducted. Some data that have been presented but not published are included. In addition, the designs of ongoing trials with aromatase inhibitors are outlined and the implications of possible results discussed. RESULTS: All of the third-generation oral aromatase inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and exemestane (steroidal, type I)--have now been tested in phase III trials as second-line treatment of postmenopausal hormone-dependent breast cancer. They have shown clear superiority compared with the conventional therapies and are therefore considered established second-line hormonal agents. Currently, they are being tested as first-line therapy in the metastatic, adjuvant, and neoadjuvant settings. Preliminary results suggest that the inhibitors might displace tamoxifen as first-line treatment, but further studies are needed to determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal breast cancer and in combination with chemotherapy and other anticancer treatments are areas of future exploration. The ongoing adjuvant trials will provide important data on the long-term safety of aromatase inhibitors, which will help to determine their suitability for use as chemopreventives in healthy women at risk of developing breast cancer.