Adjuvant Bisphosphonates Research Articles

Therapeutic Bone-Modifying Agents in the Nonmetastatic Breast Cancer Setting: The Controversy and a Value Assessment.

Clinical trials and meta-analyses investigating bisphosphonates as an adjuvant breast cancer therapy have shown a consistent trend, with postmenopausal women and women receiving ovarian suppression with gonadotropin-releasing hormone therapy gaining improved breast cancer outcomes with the use of adjuvant bisphosphonate therapy. The interpretation of these data is controversial, because the primary endpoints of the majority of adjuvant bisphosphonate studies have been negative. Pros and cons as well as the value of adjuvant bisphosphonate therapy are discussed here.

Management of Bone Health in Breast Cancer Patients Established on Aromatase Inhibitors

Purpose: (1) To audit compliance with national guidelines of screening, diagnosis and treatment of osteoporosis or osteopenia in breast cancer patients on aromatase inhibitors at the West Middlesex University Hospital (WMUH). (2) To model the effect of the introduction of adjuvant bisphosphonates at WMUH.

Adjuvant Bisphosphonates for Patients with Breast Cancer

Sponsoring Organizations: Cancer Care Ontario and the American Society of Clinical OncologyTarget Audience: Oncologists, women's health

Traitements anti-résorptifs pour le traitement et la prévention des métastases osseuses

Bone-targeted treatments play an important role in the management of malignant tumor osteolysis. Bisphosphonates and denosumab have demonstrated their efficacity for delaying the time to skeletal-related event (SRE) in patients with bone metastases. In large randomized trials, denosumab was more effective than zoledronic acid in preventing skeletal morbidity in patients with breast or prostate cancer with bone metastases, and non-inferiority was shown in the trial with other solid tumors. Questions concerning the duration of the treatment, the optimal dosing interval remain. The interest of these treatments as adjuvant therapy before the occurrence of bone metastases is currently being evaluated; recent data with adjuvant bisphosphonate treatment in breast cancer could change clinical practice, especially in postmenopausal women with breast cancer at high risk of recurrence.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline.

Purpose To make recommendations regarding the use of bisphosphonates and other bone-modifying agents as adjuvant therapy for patients with breast cancer. Methods Cancer Care Ontario and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature. Results Adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with nonmetastatic breast cancer. In this guideline, postmenopausal includes patients with natural menopause or that induced by ovarian suppression or ablation. Absolute benefit is greater in patients who are at higher risk of recurrence, and almost all trials were conducted in patients who also received systemic therapy. Most studies evaluated zoledronic acid or clodronate, and data are extremely limited for other bisphosphonates. While denosumab was found to reduce fractures, long-term survival data are still required. Recommendations It is recommended that, if available, zoledronic acid (4 mg intravenously every 6 months) or clodronate (1,600 mg/d orally) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. Further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. Data for adjuvant denosumab look promising but are currently insufficient to make any recommendation. Use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline. Recommendations are not meant to restrict such use of bone-modifying agents in these situations. Additional information at www.asco.org/breast-cancer-adjuvant-bisphosphonates-guideline , www.asco.org/guidelineswiki , https://www.cancercareontario.ca/guidelines-advice/types-of-cancer/breast .

Bone Modifier Use as Adjuvant Therapy for Early Breast Cancer

Many studies have examined the effects of adjuvant bisphosphonates on long-term breast cancer outcomes. However, results have been inconsistent. Here, we review the evidence for their role in early breast cancer. In a recent meta-analysis, no significant decreases in recurrence or breast cancer mortality were observed in the overall population. In postmenopausal women, statistically significant, but modest, reductions in distant recurrence were observed, driven by decreased bone recurrence. This translated to decreased breast cancer mortality. While most individual studies were not performed exclusively in postmenopausal patients and were not adequately powered to detect subgroup effects based on menopausal status, observed effects were highly consistent. Adjuvant bisphosphonates in postmenopausal women should be considered in individual cases of high-risk patients, where the absolute benefit justifies associated risks. There is no evidence supporting their routine use in premenopausal women except in selected patients receiving ovarian function suppression.

Abstract S6-02: The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer. First results of the TEAM IIB trial (BOOG 2006-04)

Abstract Background: Results of clinical trials concerning adjuvant bisphosphonates for the prevention of (bone) metastases in patients with early breast cancer are conflicting. A recent large meta-analysis, however, suggests that bisphosphonates reduce the incidence of (bone) metastases and improve skeletal-related events in early breast cancer patients. Subgroup analyses show that postmenopausal women seem to benefit the most. In this subgroup a modest overall survival benefit was observed with the addition of adjuvant bisphosphonates to standard adjuvant systemic therapy (EBCTCG, Lancet, 2015). TEAM IIB, a randomized phase III study (ISRCTN17633610), prospectively investigates the value of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Methods: Postmenopausal women with stage I-III breast cancer and an indication for adjuvant hormonal treatment were randomized to receive at least 5 years of hormonal therapy (tamoxifen followed by at least 2-3 years exemestane, or in case of high risk at least 5 years of exemestane) with or without ibandronate 50mg orally, once daily for three years. Primary endpoint was disease-free survival (DFS). Secondary endpoints included time to and rate of bone metastases, other sites of recurrence, overall survival and safety. The study was amended because of slower than anticipated accrual and the sample size calculations were amended accordingly in June 2009. To detect a hazard ratio (HR) of 0.615 with a 2-sided alpha of 0.05 and a power of 0.8, 139 DFS-events were required in the intention-to-treat population. Results: Between February 2007 and May 2014, 1116 patients were enrolled in 37 hospitals in the Netherlands of whom 40% had positive axillary lymph nodes and 56% of all patients received (neo)adjuvant chemotherapy (>95% anthracyclines, 69% taxanes). Baseline characteristics were well balanced. At September 9, 2016, 143 DFS events had been reported. Median follow-up was 4.6 years and 80 patients were still on ibandronate treatment. Adherence to 3 years ibandronate was 67%, 21 patients randomized to receive ibandronate never started. 19 patients, of whom 9 in the control group were excluded because of major ineligibility. In the ibandronate treated group 3-year DFS was 94.4% versus 90.8% in the control group (HR 0.84; 95% confidence interval [CI] 0.60-1.17). In total, 48 patients in the ibandronate versus 45 in the control group died, of whom 18 (37,5%) versus 28 (62,2%) of breast cancer. 3 years after randomization 1.6% of ibandronate treated patients developed bone metastases versus 4.6% in patients who were treated with adjuvant hormonal therapy only (HR 0.76; [CI] 0.43-1.32). 14 (29,2%) versus 9 (20%) of patients died because of secondary malignancies respectively. There was no significant difference in creatinine clearance during the first three years after randomization. 36 Serious adverse events (SAEs) were reported in the ibandronate group versus 51 in the control group. Of patients randomized to ibandronate 4 developed osteonecrosis, but without residual complaints. Conclusion: So far, at a median follow-up of 4.6 years there is no statistically significant benefit from adding ibandronate to adjuvant hormonal treatment in postmenopausal women with hormone-receptor positive early breast cancer. However, since hazard rates are in favor of ibandronate longer follow-up is warranted before final conclusions can be drawn. Citation Format: Vliek SB, Meershoek-Klein Kranenbarg E, van Rossum AGJ, Tanis BC, Putter H, van der Velden AWG, Hendriks MP, van Bochove A, van Riet Y, van Leeuwen-Stok AE, Tjan-Heijnen VCG, Kroep JR, Nortier JWR, van de Velde CJH, Linn SC. The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer. First results of the TEAM IIB trial (BOOG 2006-04) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-02.

Abstract P1-09-01: Impact of MAF gene amplification on disease recurrence and effects of adjuvant zoledronic acid in early breast cancer

Abstract Background: Meta-analysis of clinical trials has shown that adjuvant bisphosphonates reduce bone metastases and improve survival in postmenopausal (PM) pts1. However, we are unable to select pts most likely to benefit. To address this, the recently identified early breast cancer bone relapse biomarker, 16q23(MAF) gain (MAF+)2, was tested retrospectively in the large prospectively randomized AZURE trial3 of standard adjuvant therapy +/- zoledronic acid (ZOL) to determine the prognostic value of MAF and its potential to predict the effects of ZOL on disease outcomes. Materials and methods: All analyses were performed with ethics approval and consent. The biomarker analysis was completed on TMAs from primary tumors. Quadruplicate cores of breast tumor tissue were arrayed across replicate TMAs. MAF+ was detected using a validated (MAF/D16Z3) FISH test (Inbiomotion SL, Barcelona, Spain). A central laboratory (Targos, Kassel, Germany) validated the assay for analytic and diagnostic performance, established acceptance criteria, included appropriate quality controls for each assay, and performed the analyses in a blinded fashion. A copy number cut-off ≥2.5 was preset for MAF+. Invasive disease free (IDFS), overall (OS) survival and time to bone metastases multivariate analyses were performed in control and ZOL pts separately. Subsequently, interactions between MAF+ and effects of ZOL on disease outcomes by menopausal status were evaluated. Results: 1769 of the 3360 AZURE pts donated primary tumor samples. Median follow-up was 84 months. 865 pts (49%) had 2 FISH evaluable cores and were included in the analysis of which 184 (21%) had MAF+ tumors. Tumors that were MAF+ were more likely to be of higher grade, ER-ve and Her2+. In control pts, MAF was not prognostic for IDFS or OS although there were differences in IDFS by menopause (HR for MAF-/MAF+ in PM=0.47 [95%CI 0.25-0.88]; HR in non-PM=1.58 [0.82-3.03], test for interaction (TFI) by menopause P=0.007). In ZOL pts, MAF was prognostic for IDFS (HR=0.52 [0.36-0.75] and OS (HR=0.48 [0.31-0.75]). There were insufficient bone events (19 MAF+, 73 MAF-) in this sample set to reliably assess the impact of MAF+ on relapse in bone. In pts with MAF- tumors, ZOL was associated with improved IDFS (HR=0.74 [0.56-0.98]) and OS (HR=0.78 [0.55-1.10]). However, the effects of ZOL in MAF+ were profoundly influenced by menopausal status with possibly better outcomes in PM women (HR for IDFS=0.74 [0.35-1.58]) but clearly worse IDFS and OS outcomes in ZOL treated MAF+ pts who were non-PM (HR for IDFS 2.46 [1.23-4.92], TFI by treatment P=0.002 and HR for OS=2.27 [1.04-4.93], TFI by treatment P=0.032). The interactions between disease outcomes, ZOL use and menopause were driven largely by an association between MAF+ and an increased risk of extra-skeletal recurrence with the use of ZOL in women who were not PM. Conclusions: Absence of MAF amplification is associated with improved disease outcomes with adjuvant ZOL. However, the use of adjuvant ZOL in women with MAF+ tumors who are not PM at the start of treatment is associated with extraskeletal spread and worse DFS and OS. 1EBCTCG Lancet 2015;386:1353–1361; 2Pavlovic M et al JNCI 2015;107(12):djv256; 3Coleman RE et al Lancet Oncol 2014;15:997-1006. Citation Format: Coleman R, Hall A, Bell R, Cameron D, Marshall H, Jean-Mairet J, Tercero J, Rojo F, Albanell J, Gomis R. Impact of MAF gene amplification on disease recurrence and effects of adjuvant zoledronic acid in early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-01.

Abstract P2-09-12: A single-blind, randomized, placebo-controlled phase II study to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: Final results of the single-center BONADIUV trial

Abstract Background. Several randomized trials demonstrated aromatase inhibitors (AI) superiority in terms of disease-free survival compared to tamoxifen treatment for postmenopausal hormone receptor-positive breast cancer (BC) patients. Anyway AI toxicity profile due to estrogen suppression is a concern. Pivotal trials demonstrated a significant bone mineral density (BMD) loss due to AI, with a consistent risk of fractures, thus impacting on patients' quality of life. Bisphosphonates represent an effective treatment in postmenopausal osteoporosis fractures prevention. Several studies demonstrated that upfront bisphosphonates therapy prevents bone loss in postmenopausal women receiving adjuvant AI for early-stage BC. However an adequate patients selection for adjuvant bisphosphonates treatment during AI endocrine therapy is still a challenge. We present the final results of the BONADIUV trial, a single-blind, randomized, placebo-controlled phase 2 study designed to evaluate the impact of ibandronate treatment on BMD in osteopenic women taking AI. Methods. Between January 2011 and May 2014, 561 patients underwent a baseline BMD assessment before starting AI as planned adjuvant treatment. Overall 171 osteopenic patients (lumbar spine [LS] and/or trochanter -1< T-score <-2.5), were randomized in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). All patients receive oral supplementation of calcium and vitamin D3. Study duration was 2 years. Exclusion criteria were: premenopausal status at time of randomization; comorbidities with increased risk of osteoporosis; body mass index <18; chronic use of steroids; previous use of bisphosphonates; psychiatric disorders. Primary endpoint was the mean BMD difference between the two arms at a 2-year follow up. ClinicalTrials.gov identifier: NCT02616744. A total of 72 patients per arm of treatment were needed to obtain an 85% statistical power in order to detect a 2% BMD mean difference between the two arms. Considering a 10% dropout, at least 158 patients were required. Results. A total of 171 patients were randomized in the study. Overall 27 patients (15.8%) withdrew the protocol (17 ibandronate vs 10 placebo arm): the final analysis was performed on 144 patients (72 patients per arm). P-value from Wilcoxon test showed no significant difference between arms at baseline both for LS (p=0.94) and trochanter (p=0.83). At 2-year, osteopenic patients treated with ibandronate gained +18.7% and +15.5% at the LS and trochanter BMD, respectively. Patients treated with placebo lost -13.3% at the LS, and gained +2.9% at the trochanter. Trochanter p-value from covariance analysis showed a mean BMD change significantly in favor of ibandronate arm at 1-year (p=0.012), and borderline at 2-year (p=0.087). Concerning LS, the mean BMD change was significantly in favor of ibandronate arm both at 1-year (p=0.002) and 2-year (p<0.0001). Conclusions. Final results of our study showed that treatment with ibandronate, as compared to placebo, improved BMD change in osteopenic women treated with adjuvant AI, and consistently protected patients' bone loss. Citation Format: Livi L, Saieva C, Desideri I, Scotti V, De Luca Cardillo C, Carta G, Cecchini S, Orzalesi L, Sanchez LJ, Casella D, Bernini M, Nori J, Bianchi S, De Feo ML, Meattini I. A single-blind, randomized, placebo-controlled phase II study to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: Final results of the single-center BONADIUV trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-12.

Therapeutic Bone-Modifying Agents in the Nonmetastatic Breast Cancer Setting: The Controversy and a Value Assessment

Clinical trials and meta-analyses investigating bisphosphonates as an adjuvant breast cancer therapy have shown a consistent trend, with postmenopausal women and women receiving ovarian suppression with gonadotropin-releasing hormone therapy gaining improved breast cancer outcomes with the use of adjuvant bisphosphonate therapy. The interpretation of these data is controversial, because the primary endpoints of the majority of adjuvant bisphosphonate studies have been negative. Pros and cons as well as the value of adjuvant bisphosphonate therapy are discussed here.

Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo.

Bisphosphonates are standard treatments for bone metastases. When given in the adjuvant setting, they reduce breast cancer mortality and recurrence in bone but only among post-menopausal patients. Optimal drug use would require biomarker-based patient selection. Such biomarkers are not yet in clinical use. Based on the similarities in inflammatory responses to bisphosphonates and Toll-like receptor (TLR) agonists, we hypothesized that TLR9 expression may affect bisphosphonate responses in cells. We compared bisphosphonate effects in breast cancer cell lines with low or high TLR9 expression. We discovered that cells with decreased TLR9 expression are significantly more sensitive to the growth-inhibitory effects of bisphosphonates in vitro and in vivo. Furthermore, cancer growth-promoting effects seen with some bisphosphonates in some control shRNA cells were not detected in TLR9 shRNA cells. These differences were not associated with inhibition of Rap1A prenylation or p38 phosphorylation, which are known markers for bisphosphonate activity. However, TLR9 shRNA cells exhibited increased sensitivity to ApppI, a metabolite that accumulates in cells after bisphosphonate treatment. We conclude that decreased TLR9-expression sensitizes breast cancer cells to the growth inhibitory effects of bisphosphonates. Our results suggest that TLR9 should be studied as a potential biomarker for adjuvant bisphosphonate sensitivity among breast cancer patients.

38th Annual San Antonio Breast Cancer Symposium. Resumen de las aportaciones más relevantes

We summarise the most interesting and clinically relevant works presented at the 38th Annual San Antonio Breast Cancer Symposium (December 2015). In the field of translational research, the main contributions were made in clonal dynamics and tumour heterogeneity, as well as in the possibility of studying emerging resistance mutations with liquid biopsy and next-generation sequencing, as shown by data from the BELLE-2 and BOLERO-2 trials. From the clinical point of view, the final analysis of BCIRG-006 trial and the intermediate analysis of the ExteNET trial will probably change the adjuvant treatment of HER2 breast cancer patients. The results of the ABCSG-18 trial with adjuvant denosumab in luminal breast cancer are consistent with previous data from trials of adjuvant bisphosphonate therapy. In triple-negative breast cancer, interesting data were reported supporting the addition of carboplatin and nab-paclitaxel to neoadjuvant chemotherapy regimens. The CREATE-X trial is the first study showing a survival benefit (larger in triple negative disease) of adjuvant chemotherapy with capecitabine in those patients without pathologic complete response after neoadjuvant chemotherapy. Finally, other problems addressed during the meeting were treatment de-escalation in some patient subgroups, the controversies surrounding and integration of nodal irradiation and axillary surgery, and early clinical results with immune therapy.

Editorial comment on ‘Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials’

In this issue of the European Journal of Cancer, Kroep et al. present their meta-analysis of randomised trials of adding zoledronic acid (ZOL) to neoadjuvant therapy in breast cancer [1]. In their well written paper, they have pooled the individual patient data of 750 patients from four randomised clinical trials. For some, the overall result may be disappointing: In essence, the addition of ZOL overall did not increase complete pathological remission (pCR), which is viewed as the surrogate parameter of choice in the neoadjuvant treatment of breast cancer. Interestingly, however the addition of the bisphosphonate nearly doubled pCR rates in the subgroup of postmenopausal patients, a striking parallelism to the differential menopausal effect of adjuvant bisphosphonate therapy [2]. While it may be considered unlikely that neoadjuvant ZOL will become part of routine clinical practice, this paper raises interesting scientific questions: What is the mechanism of action? And why is there an activity signal in postmenopausal patients only? In any case, the long and winding road of bone-targeted therapy in breast cancer with respect to outcome benefit is enriched with another interesting facet.

Abstract S2-02: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial

Abstract Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve disease-free and overall survival outcomes in postmenopausal (natural or induced) BC patients (EBCTCG meta-analysis, Lancet 2015). The aim of ABCSG-18 was to investigate the effects of adjuvant anti-RANK-ligand Denosumab on bone health and disease outcomes in postmenopausal patients with early hormone receptor+ (HR+) BC receiving AI treatment. Patients and Methods: 3,425 postmenopausal patients with HR+ BC receiving AI were recruited in 58 trial sites into this prospective, randomized, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to either Denosumab 60mg or placebo q6mo s.c. Bone end point results showed that adjuvant denosumab significantly reduced clinical fractures (primary endpoint, HR=0.5, p<0.0001), improved bone mineral density, and reduced vertebral fractures without relevant toxicity (Gnant et al., Lancet 2015). Disease-free survival (DFS) is a secondary endpoint. Following an IDMC recommendation based on the results of a protocol-specified interim analysis, a DFS analysis took place in September 2015, before a patients' choice unblinding option will be provided to trial patients in the year 2016. Additional disease outcome related end points (BMFS, OS) will be analysed during further study follow up. Results: With a median follow-up of 4 years, 370 DFS events were recorded. 203 DFS events occurred in the placebo group, and 167 in the Denosumab group (HR 0.816, p=0.051). Subgroup analyses indicate that the Denosumab benefit (overall absolute 2.1% at 5 years) may be particularly driven by tumors larger than 2cm (HR=0.66, p=0.016), ductal breast cancer histology type (HR=0.79, p=0.048), and tumors with both ER and PR positive (HR=0.75, p=0.013). Summary and conclusion: Adjuvant Denosumab 60mg q6mo s.c. improves disease-free survival of HR+ breast cancer patients receiving aromatase inhibitors. Numerically, this benefit of adjuvant Denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. Bases on these results and the previously reported dramatic reduction of fractures, adjuvant Denosumab should be offered to all postmenopausal HR+ breast cancer patients on AI. Citation Format: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-02.

Characterizing and quantifying the effects of breast cancer therapy using mathematical modeling.

We designed a mathematical model to describe and quantify the mechanisms and dynamics of tumor growth, cell-kill and resistance as they affect durations of benefit after cancer treatment. Our aim was to explore how treatment efficacy may be related to primary tumor characteristics, with the potential to guide future trial design and appropriate selection of therapy. Assuming a log-normal distribution of both resistant disease and tumor doubling times generates disease-free survival (DFS) or invasive DFS curves with specific shapes. Using a multivariate mathematical model, both treatment and tumor characteristics are related to quantified resistant disease and tumor regrowth rates by allowing different mean values for the influence of different treatments or clinical subtypes on these two log-normal distributions. Application of the model to the CALGB 9741 adjuvant breast cancer trial showed that dose-dense therapy was estimated to achieve an extra 3/4 log of cell-kill compared to standard therapy, but only in patients with more rapidly growing ER-negative tumors. Application of the model to the AZURE trial of adjuvant bisphosphonate treatment suggested that the 5-year duration of zoledronic acid was adequate for ER-negative tumors, but may not be so for ER-positive cases, with increased recurrences after ceasing the intervention. Mathematical models can identify different effects of treatment by subgroup and may aid in treatment design, trial analysis, and appropriate selection of therapy. They may provide a more appropriate and insightful tool than the conventional Cox model for the statistical analysis of response durations.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-016-3684-4) contains supplementary material, which is available to authorized users.

Singapore Cancer Network (SCAN) Guidelines for Bisphosphonate Use in the Adjuvant Breast Cancer Setting

The SCAN breast cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines regarding the optimal time-point for initiation of bisphosphonates when using adjuvant aromatase inhibitors (AIs) and provide a consensus for their role in modifying clinical breast cancer outcomes. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. Six international guidelines were evaluated-those developed by the National Cancer Comprehensive Network (2015), the European Society of Medical Oncology (2014), the National Institute for Clinical Evidence (2012), the Scottish Intercollegiate Guidelines Network (2013), the British Columbia Cancer Agency (2013) and the treatment algorithm based on the National Osteoporosis Foundation guidelines (2006). Recommendations on the use of bisphosphonates in postmenopausal women initiating adjuvant AIs in breast cancer to preserve bone health and the use of adjuvant bisphosphonates to improve breast cancer outcomes were developed. These adapted guidelines form the SCAN Guidelines on the use of adjuvant bisphosphonates to influence breast cancer outcomes and maintenance of bone health when on AIs.

Adjuvant Bisphosphonates and Breast Cancer Survival.

Randomized trials have studied bisphosphonates in the adjuvant setting of early breast cancer to investigate their ability to prevent treatment-induced bone loss. Trial results have also suggested their potential to prevent disease recurrence and metastases. These trials are summarized in this review. A recent patient-level meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) finds convincing evidence that adjuvant antiresorptive treatments provide persistent benefits to breast cancer patients in low-estrogen situations and should be considered an important part of the treatment algorithm.

Targeting bone microenvironment: Clinical implications

Bone-targeting agents such as bisphosphonates are well established for the prevention and treatment of osteoporosis and the prevention of skeletal related events associated with bone metastases from solid tumours including breast cancer [1]. In the early breast cancer seeting, treatment-induced bone loss is a major clinical problem, leading to substantial morbidity and subsequent health care cost [2]. There are multiple reasons for bone loss in breast cancer patients, including existing risk factors (smoking, family history, low body weight), but endocrine therapy (particularly ovarian function suppression in premenopausal women and aromatase inhibitors in postmenopausal women) presents the most important burden on bone health in these patients [3]. In addition to lifestyle recommendations, anti-resorptive drugs have been demonstrated to prevent and treat cancer-treatment induced bone loss [4]. With respect of cancer-therapy induced bone loss (CTIBL), several trials have demonstrated the usefulness of adjuvant bisphosphonates for the prevention and treatment of CTIBL both in premenopausal [5] and postmenopausal women [6,7]. As a result, anti-resorptive therapy is part of current guidelines for the treatment of breast cancer patients [8]. Current clinical guidelines recommend the use of bisphosphonates in breast cancer patients on endocrine therapy if their fracture risk (assessed by DXA and or tools such as the FRAX score) is presumably increased [9]. While bisphosphonates have been studied in randomized trials in the adjuvant setting of early breast cancer to investigate their ability to either prevent cancer treatment induced bone loss, there are also indications in these trials about their potential to prevent disease recurrence and metastases [10]. The exact mechanism of this anti-cancer activity in the adjuvant setting remains unknown, and several potential ways of action have been proposed. In addition to preclinically established direct anti-tumour properties of bisphosphonates, a putative impact on the bonemicroenvironment

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). We received data on 18,766 women (18,206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02). Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Cancer Research UK, Medical Research Council.

Phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: SWOG/Alliance/ECOG-ACRIN/NCIC Clinical Trials Group/NRG Oncology study S0307.

503 Background: Randomized trials and a recent meta-analysis suggest that adjuvant bisphosphonates can decrease recurrence and death, primarily in a postmenopausal population. SWOG S0307 compares e...