Adjuvant Use Of Bisphosphonates Research Articles

A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer.

While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling.We evaluated a single zoledronate infusion in a prospective randomised trial. Postmenopausalpatientswith EBC were randomised to receive a single infusion of zoledronate (4mg IV) or 6-monthly treatment for 3years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS). 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104).After 3years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group).While the frequency of APRs decreased over 3years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronateearlyin the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3year follow up, there were no differences between arms for RFS, BMFS or OS. A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing.

Metastasis prevention with bone-targeted agents: a complex interaction between the microenvironment and tumour biology.

The use of bone-targeted treatments has transformed the clinical care of many patients with metastatic breast cancer. In addition, due to the profound effects of bisphosphonates and denosumab on bone physiology and the bone microenvironment, the potential of bone-targeted agents to modify the process of metastasis has been studied extensively. Many adjuvant trials with bisphosphonates in early breast cancer have been performed. Variable outcomes in terms of disease recurrence have been reported, with any treatment benefits apparently influenced by the age and menopausal status of the patients. Results show that in breast cancer the use of adjuvant bisphosphonates reduce bone metastases and breast-cancer deaths in postmenopausal women. These effects are in addition to the benefits associated with the use of standard adjuvant endocrine, cytotoxic and targeted treatments with prevention of one in six breast-cancer deaths at 10years. Biomarkers that can predict patient benefit from the use of bone-targeted treatments in the adjuvant setting are being evaluated. Currently, tumour expression of the transcription factor, MAF, seems to be the most promising biomarker; benefits from adjuvant bisphosphonates are seen in the 80% of patients with normal levels of expression irrespective of menopausal status and age, while over expression is associated with a poor prognosis and a higher rate of visceral metastases. Adjuvant bisphosphonates are now part of standard clinical guidelines for postmenopausalwomen with early breast cancer at intermediate to high risk of recurrence. MAF testing of primary tumours may improve patient selection for treatment.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update.

To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline. An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations. Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients' risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer.Additional information can be found at www.asco.org/breast-cancer-guideline.

Adjuvant bisphosphonate use in patients with early stage breast cancer: a physician survey.

PurposeDespite the increasing use of adjuvant bone-modifying agents (BMAs) such as zoledronate and clodronate in the treatment of patients with early stage breast cancer (EBC), little is known about real world practice patterns. A physician survey was performed to address this deficit and determine interest in clinical trials of alternative strategies for BMA administration.MethodsCanadian oncologists treating patients with EBC were surveyed via an anonymized online survey. The survey collected information on: physician demographics, knowledge and interpretation of adjuvant bisphosphonate guidelines, and real world prescribing practices. Questions also determined thoughts around the design of future adjuvant BMA trials.ResultsOf 127 surveyed physicians, 53 eligible invitees responded (response rate 42%). The majority of physicians are offering high-risk postmenopausal patients adjuvant BMAs. The most common BMA regimen was adjuvant zoledronate (45/53, 85%) every 6 months for 3 years. Concerns around toxicities and repeated visits to the cancer centre were perceived as the greatest barriers to adjuvant bisphosphonate use. Respondents were interested in future trials of de-escalation of BMAs comparing a single infusion of zoledronate vs. 6-monthly zoledronate for 3 years. The most favoured primary endpoints for such a trial included disease recurrence and fragility fracture rates.ConclusionQuestions around optimal use of adjuvant bisphosphonates in patients with EBC still exist. There is interest among physicians in performing trials of de-escalation of these agents. The results of this survey will assist in designing pragmatic clinical trials to address this question.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10549-021-06147-1.

Adjuvant bisphosphonate use in patients with early stage breast cancer: Patient perspectives on treatment acceptability and potential de-escalation

BackgroundDespite the increasing use of adjuvant bisphosphonates for early stage breast cancer (EBC), little is known about the patient experience with such treatments. A patient survey was performed to identify current prescribing practices, perceptions around the role of treatment, the impact of treatment on patients’ quality of life, and future trial designs. MethodsEBC patients who had either completed or were currently receiving adjuvant bisphosphonates were sent an anonymized survey. The survey collected information on patient and disease characteristics, bisphosphonate scheduling, compliance, and tolerance. Questions also assessed patient interest in trials of de-escalated bisphosphonate therapy. ResultsA total of 255 patients were contacted, with 164 eligible respondents (eligible response rate 164/255, 64.3%). Median patient age was 52 years (range 28 to 82 years). The majority (111/163, 68.1%) were postmenopausal at the time of diagnosis, 23.3% (38/163) were premenopausal, and 7.4% (12/163) were perimenopausal. Most patients (78%) had received chemotherapy. Zoledronate was the most commonly used bisphosphonate (92%), with the majority receiving treatment every 6 months for 3 years (73%). While 66% (107/161) of respondents had experienced side effects with treatment, most had, or expected to, complete treatment (154/163, 94%). Provided there was no detriment in breast cancer outcomes, there was strong interest in future studies of de-escalating adjuvant bisphosphonate therapy. ConclusionWhile most patients tolerate their treatment, there is interest in performing trials of de-escalation of these agents.

Bisphosphonates and breast cancer - From cautious palliation to saving lives.

Bone metastases are common in breast cancer and may cause considerable morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Alongside developments in the multidisciplinary management for patients with metastatic breast cancer, the use of bisphosphonates, and more recently denosumab, has transformed the course of advanced breast cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Additionally, because the bone marrow microenvironment is so intimately involved in the metastatic processes required for cancer dissemination, the use of adjuvant bisphosphonates has been studied extensively over the past 25years in many randomised trials. We now have clear evidence that bisphosphonates significantly reduce both metastasis to bone and mortality in postmenopausal women with early breast cancer. Efficacy seems similar across different biological subgroups of postmenopausal breast cancer with the use of either a nitrogen-containing bisphosphonate such as intravenous zoledronate or daily oral ibandronate as well as the non-nitrogen containing agent, daily oral clodronate. In this overview of evolving role of bisphosphonates in breast cancer, focussing particularly on pamidronate and zoledronate, the long winding development road from the 1970s through to the present day is described and some of the serendipitous findings, "lucky breaks" and regulatory decisions along the way outlined.

Usage and factors associated with adjuvant bisphosphonate therapy among postmenopausal women diagnosed with early-stage breast cancer.

e12532 Background: Early Breast Cancer Trialist Collaborative Group meta-analysis suggested significant reduction in bone metastasis and breast cancer mortality among post-menopausal women diagnosed with early breast cancer when treated with an adjuvant bisphosphonate. Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline published in 2017, recommends the use of an adjuvant bisphosphonate in postmenopausal women who are candidates for adjuvant systemic therapy. Our goal was to evaluate trends and factors associated with adjuvant bisphosphonate usage since the guideline’s publication. Methods: This study is a retrospective review of postmenopausal women treated for early breast at the London Regional Cancer Program from 2017-2018. Univariate and a multivariable logistic regression models were used to investigate factors potentially associated with adjuvant bisphosphonate use including age, stage, grade, estrogen receptor, progesterone receptor, HER2 receptor status and previous use of adjuvant chemotherapy. The percentage of patients offered, receiving and declining therapy was also recorded and the time interval from surgery to start of bisphosphonate therapy (< 6 months, 6-12 months or >12 months). Results: We identified 286 postmenopausal breast cancer patients, of whom 75 (28%) received adjuvant bisphosphonate therapy. In our multivariable model, cancer stage [odds ratio (OR) stage II vs. I=2.26, 95% confidence interval (CI) 1.08-4.74) and OR Stage III vs. I=4.94, 95% CI 1.84-13.17] and previous use of adjuvant chemotherapy (OR=2.76, 95%CI 1.37-5.55) were significantly associated with adjuvant bisphosphonate use. Among 133 patients who received adjuvant systemic chemotherapy, 51% were offered adjuvant bisphosphonate and of these 81% patients accepted therapy. Among a total of 75 patients receiving adjuvant bisphosphonate therapy 19% initiated therapy within 6 months of surgery, 48% within 6-12 months of surgery, and 33% after 12 months following surgery. Conclusions: Stage and previous use of chemotherapy were significantly associated with adjuvant bisphosphonate therapy. Our study observes the potential underutilization of adjuvant bisphosphonate therapy and possible need to start treatment earlier in some patients. Further education and awareness of the clinical practice guidelines regarding adjuvant bisphosphonate therapy may be warranted and additional population-based study investigating treatment patterns and real-world effectiveness.

Real-world data on adjuvant bisphosphonate use in a breast cancer center in Mexico.

e12544 Background: Results from the Early Breast Cancer Trials Collaborative Group (EBCTCG) meta-analysis published in 2015 showed a significant reduction in risk of distant recurrence, bone recurrence and a 10-year breast cancer mortality reduction1. Moreover, Cancer Care Ontario and ASCO issued a guideline regarding the use of adjuvant bisphosphonates (AB) in breast cancer postmenopausal patients2. While these data are compelling, we have no information to support the implementation of this recommendation at Hospital San José’s Breast Cancer Center (HSJBCC). Methods: A retrospective analysis was performed to evaluate our compliance to the current recommendations for AB administration from 2015 through 2019. Inclusion criteria were based on the ASCO guidelines and comprised invasive breast cancer, postmenopausal status and early or locally advanced stage. Furthermore, in AB-treated patients we assessed the percentage of baseline calcium and creatinine measurement, prior dental evaluation, and concurrent calcium and vitamin-D supplementation during AB use. Results: A total of 106 patients met the inclusion criteria. Within the 4-year timeframe, AB was prescribed to 28/106 (26%) patients. Stratifying by year, we observed an increase of AB use rate from 4% in 2015 to 32% in 2019. Moreover, we observed a 93% baseline calcium and creatinine measurement, a 60% prior dental evaluation, and a 43% concurrent calcium and vitamin-D supplementation in the AB-treated population. Conclusions: HSJBCC recommendation for AB use is less than expected in the evaluated eligible patients in the 4-year timeframe. Despite an increase in our compliance to current ASCO guidelines it is not yet the standard of care at HSJBCC. Based on these results, we are currently planning a quality improvement initiative to undertake our low percentage of AB usage. [Table: see text]

Adjuvant bisphosphonate therapy in early-stage breast cancer-Treating the soil to kill the seed.

Bisphosphonates alter the tumor microenvironment, possibly preventing cancer cell growth in the bone. Analyses of data from numerous clinical trials and a large individual patient-level data meta-analysis have suggested an anti-tumor effect for bisphosphonates in patients with early-stage breast cancer who are postmenopausal. The absolute benefit from the use of bisphosphonates on breast cancer-related mortality reduction mirrors that seen with the use of anthracycline-based chemotherapy versus a first-generation chemotherapy regimen (CMF). In this review, we discuss the evidence base for the use of adjuvant bisphosphonates in early-stage breast cancer and provide recommendations for clinical use.

Clinical practice patterns on the use of adjuvant bisphosphonate for early breast cancer: A Canadian perspective.

e12002 Background: Adjuvant bisphosphonates (ABPs) in menopausal women with early breast cancer (EBC) decrease the risk of BC relapse and modestly improve overall survival (OS). In the era of personalized medicine, a one size fits all approach is not ideal–it is important to identify the subgroup of patients who may not derive a clinically meaningful benefit to avoid over treatment, unnecessary toxicity, and optimize resource utilization. Objectives: To better characterize how Canadian medical oncologists (MOs) use ABPs and whether practice patterns are concordant with the CCO/ASCO guideline. Methods: A brief survey was circulated by e-mail to 618 Canadian MOs between Nov 2017 - May 2018. Questions were designed to gather data on demographics, patient selection, choice of bisphosphonate, schedule/duration of treatment and barriers to use. No incentive was provided. Results: Sixty-eight MOs from 8 Canadian provinces completed the survey (response rate 11.0%). Most practiced in Ontario (65.7%) and just over half (51.5%) were community oncologists. MOs offered ABPs to 52.2% of menopausal women with EBC. Use was higher in the community compared to the academic setting (p=0.049). Most used zoledronic acid (85.3%) every 6 months (95.6%) for 3 years (69.1%) and started treatment within 3 months of completing adjuvant chemotherapy/radiation (67.7%). Factors associated with use of ABPs were: high Oncotype Dx score (89.1%), high tumor grade (72.1%), triple negative disease (63.6%), osteoporosis (87.7%)/osteopenia (83.9%) and use of aromatase Inhibitor (75.0%). The most common factor precluding use of ABPs was presence of comorbidities (89.7%). About 1/3rd indicated they would offer ABPs to women with stage I HR positive/Her2 negative EBC. Conclusions: Canadian MOs have added intravenous ABPs to their armamentarium of therapies in keeping with the spirit of the recent guideline. High-risk disease features and low bone density appear to be influencing the decision-making process. Further work aimed at identifying those patients who are unlikely to benefit from treatment is needed.

Abstract P2-06-23: New biomarkers for adjuvant bisphosphonate use in triple-negative breast cancer

Abstract We first showed that triple-negative breast cancer (TNBC) patients with low Toll-like receptor 9 (TLR9) expression have significantly worse prognosis than patients with high TLR9 expression. TLR9 is an innate immunity DNA receptor which is also expressed in several cancers, including TNBC. Later, we showed that low-TLR9 cells and tumors are more sensitive to amino-bisphosphonates, especially to zoledronate. Bisphosphonates (BP) inhibit osteoclasts and thereby effectively prevent bone fractures in osteoporosis and in cancer-induced bone disease. BPs also have direct anticancer effects. Interestingly, adjuvant BP use is associated with significantly improved progression-free and overall survival, but only among post-menopausal breast cancer patients. The molecular mechanisms behind this observation is unclear. CD73 is a 70 kDa glycophosphatidylinositol-anchored cell protein, which converts adenosine monophosphate to adenosine and organic phosphate. High CD73 expression has been shown to have cancer cell invasion-promoting properties. On the other hand, CD73 is associated with poor prognosis in TNBC. Interestingly, TLR9 and CD73 have been shown to have inverse relationship in T cells and during colonic inflammation. Currently, we study the relationship of CD73 and TLR9 in vitroand in vivo upon BP treatment. Our preliminary results show that TLR9 and CD73 have an inverse relationship also in TNBC cells. We use both nitrogen-containing (zoledronate and alendronate) and pyrophosphate-like (clodronate) BPs together with doxorubicin to study TNBC cell responses. We have seen that zoledronate and alendronate, but not clodronate, inhibited 4T1 murine triple-negative mammary tumor cell proliferation in a dose-dependent manner. Also, high concentrations of zoledronate and alendronate significantly inhibited 4T1 cell migration. Additionally, CD73 shRNA cells are more sensitive to zoledronate and alendronate, showing morphological changes and disruption in actin organization. Our results suggest that CD73 expression may affect treatment responses to BPs in TNBC. Further, low-CD73 tumors could benefit more of BP therapy, compared with high-CD73 tumors. Citation Format: Sandholm JA, Petruk N, Selander KS, Tuomela JM. New biomarkers for adjuvant bisphosphonate use in triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-23.

Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer.

Bone health and breast cancer are two connected subjects, because breast cancer patients have a higher prevalence of osteopenia/osteoporosis and reduced bone health parameters than healthy woman of the same age. Therefore, the positive effect of adjuvant bisphosphonate therapy plays an important role in breast cancer treatment. Several randomized trials have studied bisphosphonates in the adjuvant setting in postmenopausal woman and demonstrated their potential to prevent treatment-induced bone loss. The prevention of fractures and the subsequent preservation of patients' quality of life are important arguments for the use of adjuvant bisphosphonates in postmenopausal breast cancer patients. In addition, trials of adjuvant bone-targeted agents showed a reduction of recurrences in and outside bone and an improved outcome in patients treated with bisphosphonates.

The implementation of a regional adjuvant zoledronate service (AZS) for early breast cancer: A review of the first 10 months

Background: In 2015 the results of a large meta-analysis on the use of adjuvant bisphosphonates in early breast cancer (EBC) were practice changing. The data showed that in postmenopausal women bisphosphonates resulted in an absolute improvement in breast cancer mortality.

The implementation of a regional adjuvant zoledronate service (AZS) for early breast cancer: A review of the first 10 months

Background: In 2015 the results of a large meta-analysis on the use of adjuvant bisphosphonates in early breast cancer (EBC) were practice changing. The data showed that in postmenopausal women bisphosphonates resulted in an absolute improvement in breast cancer mortality.

Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial

Adjuvant use of bisphosphonates can reduce the incidence of bone metastases in early breast cancer. Recurrence and survival seem to be improved only in postmenopausal patients, but the underlying mechanisms remain unclear. We investigated whether MAF amplification (a biomarker for bone metastasis) in primary tumours could predict the treatment outcomes of adjuvant zoledronic acid. The study population included patients enrolled in the international, open-label, randomised, controlled, phase 3 AZURE trial at eligible UK sites who had stage II or III breast cancer and who gave consent for use of their primary tumour samples. Patients were randomly assigned (1:1) to receive standard adjuvant systemic therapy alone (control group) or with zoledronic acid every 3-4 weeks for six doses, then every 3-6 months until the end of 5 years. Minimisation took into account the number of involved axillary lymph nodes, clinical tumour stage, oestrogen-receptor status, type and timing of systemic therapy, menopausal status, statin use, and treating centre. The primary endpoint was disease-free survival; the secondary endpoint, invasive-disease-free survival, was the primary disease endpoint for the analysis in this report. MAF amplification was assessed by fluorescence in-situ hybridisation of two cores of breast tumour tissue in a microarray, done in a central laboratory by technicians unaware of treatment assignment. We used multivariate analyses to assess disease outcomes by intention to treat. We also assessed interactions between MAF-positive status and menopausal status on efficacy of zoledronic acid. The AZURE trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN79831382. 1739 AZURE patients contributed primary tumour samples, of whom 865 (50%) had two assessable cores (445 in the control groups and 420 in the zoledronic acid group). 184 (21%) tumours were MAF positive (85 in the control groups and 99 in the zoledronic acid group) and the remaining tumours were MAF negative. At a median follow-up of 84·6 months (IQR 72·0-95·8), MAF status was not prognostic for invasive-disease-free survival in the control group (MAF-positive vs MAF-negative: hazard ratio [HR] 0·92, 95% CI 0·59-1·41), but was in the zoledronic acid group (0·52, 0·36-0·75). In patients with MAF-negative tumours, zoledronic acid was associated with higher invasive-disease-free survival than was control treatment (HR 0·74, 95% CI 0·56-0·98), but not in patients who had MAF-positive tumours. Additionally, among 121 patients not postmenopausal at randomisation with MAF-positive tumours, zoledronic acid was associated with lower invasive-disease-free survival (HR 2·47, 95% CI 1·23-4·97) and overall survival (2·27, 95% CI 1·04-4·93) than control treatment. MAF status can predict likelihood of benefit from adjuvant zoledronic acid and merits further investigation as a potential companion diagnostic. Novartis Global and Inbiomotion.

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 .

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.

Bisphosphonates in the adjuvant treatment of young women with breast cancer: the estrogen rich is a poor candidate!

During the last 2 decades the role of bisphosphonates (BPs) to reduce skeletal-related events from bone metastases in breast cancer has been well defined. Several preclinical studies have strongly suggested that BPs may also provide an anti-cancer effect in early breast cancer. Indeed, the use of adjuvant BPs represents a unique approach that attempts at eradicating occult tumor micro-metastases residing in the bone marrow via targeting the bone microenvironment to render it less favorable for cancer cell growth. Although, this concept has been tested clinically for more than 15 years, no final consensus has been reached as for the routine use of BPs in the adjuvant phase of breast cancer, owing to conflicting results of randomized studies. Nevertheless, accumulating evidence from recent trials has indicated a therapeutic benefit of adjuvant BPs-particularly zoledronic acid-in women with established menopause, with no or perhaps detrimental effects in premenopausal women. Indeed, this hypothesis has opened a new chapter on the role of estrogen-poor microenvironment as a potential pre-requisite for the anti-tumor effects of BPs in the adjuvant phase of breast cancer. In this review, we will emphasize the biological rational of using BPs to target bone microenvironment in patients with early breast cancer and we will explore mechanistic differences; related to bisphosphonates effects in premenopausal versus postmenopausal women and how the endocrine environment would influence the anticancer potential of these compounds.

Bisphosphonates and their Role in Therapy for Breast Cancer - Results from the PATH Biobank.

Introduction: Bisphosphonates are well known above all for their use in the treatment of osteoporosis. They also play an important role as accompanying therapy for advanced tumour diseases with extensive spread into the skeletal system. Their adjuvant use in the treatment of breast cancer without bony metastases is currently a subject of controversial discussion. The objective of the present evaluation is to describe the use of bisphosphonates in the therapy for breast cancer. We will show how frequently bisphosphonates are used, which bisphosphonates are preferred and what specific features patients under bisphosphonate therapy exhibit. Methods and Materials: The pseudonymous data set from the biobank of the German PATH foundation was used for the evaluation. From the total collective, 2492 patients were selected after consideration of the inclusion and exclusion criteria. The selected patient collective was divided into twogroups (with and without bisphosphonate therapy) and the two groups compared with one another with the help of descriptive statistics. Results: 17.5 % of the 2492 patients had prescriptions for a bisphosphonate as part of their therapy. The most frequently administered bisphosphonate was zoledronate. Pathological (induced by tumour therapy) osteoporosis was the most frequently stated indication among the bisphosphonate patients, followed by consumption starting prior to the breast cancer therapy and treatment of bony metastases. Patients under bisphosphonate and antihormonal therapy frequently received an aromatase inhibitor as the active principle in the antihormonal therapy whereas patients under antihormonal therapy but without bisphosphonates more frequently received tamoxifen as active principle. Ten of the 2492 patients reported receiving bisphosphonate therapy as prophylaxis for bony metastases without a documented and approved indication. Use of bisphosphonates in the course of the GAIN, ICE, SUCCESS or, respectively, NATAN trials was reported by 29 of the 2492 patients. Conclusions: In the PATH collective, bisphosphonates were employed above all for the treatment of (tumour therapy-induced) osteoporosis and bony metastases. Off-label use and participation in clinical trials played only a minor role in this patient collective. Against the background of the uncertain data status for the adjuvant use of bisphosphonates, the development (and use) of standardised, validated questionnaires to record the indications for and frequency of use of bisphosphonate therapy is recommended.

Treatment Recommendations for the Use of Bone-Targeted Agents in 2011—Report from the 6th Annual Bone and the Oncologist New Updates Meeting

The 6th annual Bone and the Oncologist New Updates conference was held in Ottawa, Ontario, April 14–15, 2011. This meeting traditionally focuses on innovative research into the mechanisms and consequences of treatment-induced and metastatic bone disease. This year, the multidisciplinary audience was polled to produce “treatment recommendations for the use of bone-targeted agents.” In addition, the meeting report itself outlines some of the key topics presented on adjuvant bisphosphonate use and the role of bone-targeted agents in the settings of meta-static and cancer-therapy-induced bone loss.