Subsequent Skeletal-related Events Research Articles

Clinical, oncological, and prognostic differences of patients with subsequent skeletal-related events in bone metastases.

Advances in treatment have extended the life expectancy of patients with metastatic bone disease (MBD). Patients could experience more skeletal-related events (SREs) as a result of this progress. Those who have already experienced a SRE could encounter another local management for a subsequent SRE, which is not part of the treatment for the initial SRE. However, there is a noted gap in research on the rate and characteristics of subsequent SREs requiring further localized treatment, obligating clinicians to extrapolate from experiences with initial SREs when confronting subsequent ones. This study aimed to investigate the proportion of MBD patients developing subsequent SREs requiring local treatment, examine if there are prognostic differences at the initial treatment between those with single versus subsequent SREs, and determine if clinical, oncological, and prognostic features differ between initial and subsequent SRE treatments. This retrospective study included 3,814 adult patients who received local treatment - surgery and/or radiotherapy - for bone metastasis between 1 January 2010 and 31 December 2019. All included patients had at least one SRE requiring local treatment. A subsequent SRE was defined as a second SRE requiring local treatment. Clinical, oncological, and prognostic features were compared between single SREs and subsequent SREs using Mann-Whitney U test, Fisher's exact test, and Kaplan-Meier curve. Of the 3,814 patients with SREs, 3,159 (83%) patients had a single SRE and 655 (17%) patients developed a subsequent SRE. Patients who developed subsequent SREs generally had characteristics that favoured longer survival, such as higher BMI, higher albumin levels, fewer comorbidities, or lower neutrophil count. Once the patient got to the point of subsequent SRE, their clinical and oncological characteristics and one-year survival (28%) were not as good as those with only a single SRE (35%; p < 0.001), indicating that clinicians' experiences when treating the initial SRE are not similar when treating a subsequent SRE. This study found that 17% of patients required treatments for a second, subsequent SRE, and the current clinical guideline did not provide a specific approach to this clinical condition. We observed that referencing the initial treatment, patients in the subsequent SRE group had longer six-week, 90-day, and one-year median survival than patients in the single SRE group. Once patients develop a subsequent SRE, they have a worse one-year survival rate than those who receive treatment for a single SRE. Future research should identify prognostic factors and assess the applicability of existing survival prediction models for better management of subsequent SREs.

CORR Insights®: Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

CORR Insights®: Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

Are Current Survival Prediction Tools Useful When Treating Subsequent Skeletal-related Events From Bone Metastases?

Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India.

Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.

Randomized Double-Blind Comparative Study of First Global Denosumab Biosimilar in Oncology

Abstract Purpose The aim of this study was to compare first global biosimilar denosumab for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Methods It was a randomized, double-blind, comparative clinical study. Total of 136 patients of solid tumor were dosed (i.e., 102 subjects in study arm and 34 subjects in the reference arm) with initial double-blind period of 24 weeks (primary efficacy) followed by open-label phase till week 36. Primary endpoint was the incidence of first on-study SRE including hypercalcemia of malignancy with co-primary endpoint of median time to first on-study SRE. Secondary endpoints included mean number and time to first and subsequent on-study SREs (week 12, 24, 36), incidence/proportion of patients with first and subsequent on-study SREs (week 24, 36), change from baseline in nuclear bone scan, quality of life assessment, pharmacokinetics, pharmacodynamic, and safety. Results In biosimilar study arm, 06 (5.83%) patients suffered SRE from baseline to week 24 compared with 02 (5.71%) patients in reference arm with one (0.97%) patient showing pathological fracture in study arm and one (2.86%) patient having spinal cord compression in reference arm. There was no statistically significant difference in median time to first SRE, mean number of SRE/patient in both arms and improvement in bone repair on nuclear scan at 12, 24 and 36 weeks. Though the study arm showed better health-related quality of life (HRQoL), mean change in HRQoL was statistically not different in both the arms. Pharmacodynamics, serum bone-specific alkaline phosphatase, pharmacokinetic and safety evaluation did not show any statistical difference between arms. Conclusion There was no clinically meaningful difference in the biosimilar denosumab and reference product after detailed efficacy and safety evaluation.

Spine-specific skeletal related events and mortality in non-small cell lung cancer patients: a single-institution analysis.

The population prevalence of non-small cell lung cancer (NSCLC) continues to increase; however, data are limited regarding the incidence rate of skeletal related events (SREs) (i.e., surgery to the spinal column, radiation to the spinal column, radiofrequency ablation, kyphoplasty/vertebroplasty, spinal cord compression, or pathological vertebral body fractures) and their impact on overall mortality. In this study, the authors sought to estimate the incidence rates of SREs in NSCLC patients and to quantify their impact on overall mortality. This was a single-institution retrospective study of patients diagnosed with NSCLC between 2002 and 2014. The incidence rates for bone metastasis and subsequent SREs (per 1000 person-years) by time since lung cancer diagnosis were calculated and analyses were stratified separately for each histological type. Incidence rates for mortality at 1, 2, and 3 years from diagnosis stratified by the presence of SREs were also calculated. Kaplan-Meier survival curves were constructed to describe crude survival ratios in patients with spine metastasis and SREs and those with spine metastasis but without SREs. These curves were used to estimate the 1- and 2-year survival rates for each cohort. We identified 320 patients with incident NSCLC (median follow-up 9.5 months). The mean ± SD age was 60.65 ± 11.26 years; 94.48% of patients were smokers and 60.12% had a family history of cancer. The majority of first-time SREs were pathological vertebral body compression fractures (77.00%), followed by radiation (35%), surgery (14%), and spinal cord compression (13.04%). Mortality rates were highest in NSCLC patients with spine metastasis who had at least 1 SRE. Stratifying by histological subtype, the incidence rate of mortality in patients with SRE was highest in the large cell cohort, 7.42 per 1000 person-years (95% CI 3.09-17.84 per 1000 person-years); followed by the squamous cell cohort, 2.49 per 1000 person-years (95% CI 1.87-3.32 per 1000 person-years); and lowest in the adenocarcinoma cohort, 1.68 per 1000 person-years (95% CI 1.46-1.94 per 1000 person-years). Surgery for decompression of neural structures and stabilization of the spinal column was required in 6% of patients. SREs in NSCLC patients with bone metastasis are associated with an increased incidence rate of mortality.

Denosumab Versus Zoledronic Acid in the Prevention of Skeletal-related Events in Vulnerable Cancer Patients: A Meta-analysis of Randomized, Controlled Trials

PurposeBone metastases from solid tumors and multiple myeloma (MM) represent an important source of morbidity. The present meta-analysis was performed with the purpose of comparing the efficacy and tolerability of denosumab versus zoledronic acid (ZA) in the prevention of skeletal-related events (SREs) in patients with bone metastases secondary to solid tumors or bone lesions in multiple myeloma. MethodsWe searched PubMed, PubMed Central, EMBASE, the Cochrane Library, and ClinicalTrials.gov for relevant studies published until April 23, 2020. We included randomized, controlled trials that investigated the efficacy and tolerability of denosumab 120 mg SC versus ZA 4 mg IV, given every 4 weeks, in patients with bone lesions in multiple myeloma or bone metastases secondary to advanced solid tumors. Two reviewers independently identified studies, assessed the risk for bias, and extracted the data. Times to event outcomes were analyzed using hazard ratios (HRs) and 95% CIs. We analyzed tolerability outcomes using risk ratios (RRs) and 95% CIs, with a fixed-effects model. FindingsFour randomized, controlled trials (7379 patients) were identified as suitable for analysis. The pooled data indicated that denosumab was more favorable than ZA in delaying the time to first on-study SRE (HR = 0.86; 95% CI, 0.80–0.93; P = 0.0001) as well as the time to first and subsequent on-study SREs (HR = 0.83; 95% CI, 0.76–0.90; P < 0.0001); however, the results on overall survival and disease progression were similar between the 2 drugs. Additionally, denosumab was associated with lower risks for bone pain (risk ratio [RR] = 0.88; 95% CI, 0.80–0.97; P = 0.01), osteonecrosis of the jaw (RR = 0.75; 95% CI, 0.61–0.93; P = 0.007), and acute-phase reactions (RR = 0.47; 95% CI, 0.40–0.56; P < 0.00001). ImplicationsCompared with ZA, denosumab demonstrated efficacy in significantly delaying on-study SREs. Furthermore, it showed a better tolerability profile, despite being associated with potential yet manageable adverse events. This study was registered with PROSPERO (identifier: CRD42019126390).

Real-world outcomes of patients with metastatic breast cancer (BC) treated with osteoclast inhibitors (OIs).

e19314 Background: Patients with metastatic BC have a high incidence of bone metastasis with associated morbidity and mortality. OIs including denosumab and zoledronic acid reduce the rate of skeletal-related events (SREs). Since denosumab was approved in 2011, there have been no analyses about the comparative effectiveness and safety of denosumab versus zoledronic acid. Methods: Patients with BC treated with three or more doses of either denosumab or zoledronic acid after 2011 were identified in Stanford’s BC research database, Oncoshare. SREs were defined as a composite measure of spinal cord compression, pathologic fracture, surgery or radiation to bone. Unadjusted Cox proportional hazard models were fit to time to: first SRE, subsequent SRE, overall survival (OS) and BC-specific survival. Results: 515 patients were identified: 388 and 127 treated with denosumab and zoledronic acid per oncologist’s discretion, respectively. Groups were well balanced for age at diagnosis, race/ethnicity, tumor grade, prior chemotherapy use and median time from first OI therapy to last follow-up. More patients with triple-negative BC (TNBC) received zoledronic acid. Median follow-up time from first OI dose was 28 months. 42% of patients experienced at least one SRE and there were no differences in incidence of first or subsequent SREs between groups (Table). Median OS was 91 months with no statistically significant difference between groups. Median BC-specific survival was not reached (78% of patients survived), however, patients in the zoledronic acid group had over twice the risk of BC-specific mortality, a difference that remained significant after adjustment for TNBC status. There was no difference in adverse events including osteonecrosis of the jaw, vertebral fracture or hypocalcemia. Conclusions: In a contemporary, real-world care setting, we observed no difference in the incidence of SREs or OS between metastatic BC patients treated with denosumab or zoledronic acid. [Table: see text]

Management of bone metastasis with intravenous bisphosphonates in breast cancer: a systematic review and meta-analysis of dosing frequency

Bisphosphonates are wildly used in breast cancer patients with bone metastasis and generally administrated every 4weeks to lessen the risk of subsequent skeletal-related events. Bisphosphonates administration every 12weeks is also recommended in some guidelines. Recent clinical trials suggested that bisphosphonate treatment with reduced frequency (every 12weeks) to be non-inferior to standard therapy. The object of this analysis was to contrast the efficacy and safety of these two treatment strategies. We systematically retrieved databases such as MEDLINE, PubMed, Embase, and Cochrane library from 1947 to present for clinical trials comparing the efficacy between standard (every 4weeks) and de-escalation (every 12weeks) treatment of bisphosphates. We identified 4 articles with available data from 4 randomized clinical trials (n= 1721). Administration of bisphosphate every 12weeks was non-inferior to administration every 4weeks. There existed no significant difference in on-study skeletal-related events, renal dysfunction, and osteonecrosis of jaw. In the exploratory study, patients who received intravenous bisphosphates before enrollment experienced less on-study skeletal-related events and significant difference was observed between groups. This analysis suggested that de-escalation treatment with bisphosphates may be superior to standard treatment in terms of efficacy, safety, and economic costs. But it would be better that all the patients receive bisphosphates every 4weeks for several months before de-escalation.

Anti-osteolytic use to prevent skeletal related events in solid tumour bone metastases

Abstract Background Bone metastases from solid tumours remain a serious burden on patient morbidity leading to decreased quality of life, increased narcotic use, and higher healthcare cost. We examined the current use of anti-osteolytics including RANK-L inhibitors and Bisphosphonates with the frequency of Skeletal Related Events (SRE) in coordination with current ESMO treatment guidelines. Methods Patients with bone metastases from solid tumours in the University of Pennsylvania Hospital system (UPHS) between August 2014 and August 2019 were identified. Data regarding treatment of metastases and frequency of SREs were obtained from patient charts in EPIC EMR. This included: type of therapy, documented SRE, and documented reasoning for lack of treatment. SREs were defined as pathological fractures, spinal cord compression, radiotherapy/surgery for fracture risk, and chronic metastatic bone pain. Descriptive statistical analyses and a single two variable relative risk analysis were performed to evaluate data. Results 400 patients were identified in the UPHS to have bone metastases from solid tumours. 240 (65%) received anti-osteolytic treatment while 140 (35%) did not. The total number of SREs numbered 173 (43%). Of those receiving treatment 173 (63%) were treated with denosumab while 87 (33%) were treated with a bisphosphonate. Lack of anti-osteolytic therapy reasoning was documented in 41 cases (29%) while 99 cases (71%) had no documented reasoning. In patients who did receive treatment there was an absolute 16% reduction in SREs from 54% without treatment to 38% with (Relative risk: .540, 95% Confidence Interval: .438 to .666, P-Value: Conclusions The use of anti-osteolytic treatment after diagnosis of bone metastasis was associated with a decrease in the risk of subsequent SREs. However, at 65% use, it would appear that these drugs are being underutilized and could better be employed in accordance with current ESMO guidelines so as to optimize patient care. We suggest further study to better understand reasoning behind lack of use, timing of SREs, and associated metastatic risk in regards to primary tumor type. Legal entity responsible for the study University of Pennsylvania Hospital System - Pennsylvania Hospital. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Incidence of skeletal-related events in patients with breast or prostate cancer-induced bone metastasis or multiple myeloma: A 12-year longitudinal nationwide healthcare database study

BackgroundThis study examined the incidence of skeletal-related events (SRE) among patients with breast cancer (BC)- or prostate cancer (PC)-induced bone metastasis or multiple myeloma (MM) based on a population-based, 12-year healthcare database. MethodsPatients aged ≥18 years with bone metastasis from BC or PC or with MM between 2004 and 2015 were included. SRE was defined as pathologic fracture, spinal cord compression, radiation, or surgery to bone. Patients were followed-up from the initial diagnosis of bone metastasis (for those with BC or PC) or MM until SRE occurrence. To estimate multiple SREs, we applied a 21-day time window to ensure that subsequent SREs occurred independently from the previous event. We calculated the incidence and 95% confidence intervals (CIs), stratified according to the previous SRE history. ResultsOur cohort included 53,231 patients, including 23,811 with BC, 19,170 with PC, and 10,250 with MM. The incidence of multiple SREs in the 21-day time window was 1.03 (95% CI = 1.01–1.05) in patients with previous SRE history and 0.19 (95% CI = 0.19–0.20) in those without. The cumulative SRE incidences were 47%, 31.4%, and 38.0% in BC, PC, and MM patients. ConclusionThe incidences of multiple SREs in BC- or PC-induced bone metastasis or MM in this 12-year South Korean cohort were slightly higher than those in European countries. Our study provided real-world evidence that patients with BC- or PC-induced bone metastasis or MM are at high risk of SRE.

Abstract P1-18-02: Impact of the metastatic compartment on bone biomarkers and bone outcomes in patients (pts) with breast cancer (BC) and bone metastases (BM) in trial NCT00321464 of denosumab vs. zoledronic acid

Abstract Background: Bone is the most common site of metastatic disease in pts with BC, and BM are frequently associated with skeletal related events (SRE), as, e.g., bone pain or fracture. Bone targeted agents (BTAs; denosumab or zoledronic acid) decrease the rate of SREs. Previous exploratory studies in pts with BM showed that the site of metastatic disease (bone-only disease [BO] vs. bone + extraskeletal disease [BES]) might impact both bone remodeling (reflected in the concentration of bone biomarkers) and the risk for SREs. In this large study of pts with BC and BM, we assessed bone biomarkers after the introduction of BTAs, time to first and subsequent on-study SRE/symptomatic SRE (SSE), and bone pain score variation according to metastatic compartment (BO vs. BES). Methods: This is a retrospective analysis of the prospective, multicenter, randomized, registration clinical trial of denosumab vs. zoledronic acid in pts with BC and BM (NCT00321464). Study outcomes were variation of corrected urinary N-terminal telopeptide (uNTX) and bone alkaline phosphatase (bALP) at 3 months, time to first and subsequent SRE and SSE, and brief pain inventory (BPI) scores over time. Chi-squared test and t-test were used to compare biomarkers levels. We used the Kaplan-Meier method to describe time to event outcomes and differences were tested using the Cox proportional hazard model and Andersen–Gill model for multiple failure-time data. BPI scores were compared using mixed linear models. Results: A cohort of 2046 pts was identified, 969 (47.4%) with BO and 1077 (52.6%) with BES, all treated with either denosumab or zoledronic acid. Median follow-up was 20.1 months (interquartile range 15.9-23.8; balanced between arms). Compared to pts with BO, those with BES were more frequently hormone receptor negative (20.9 vs. 15.1%) and HER2-positive (31.0 vs. 23.4%). The number of BM was similar in both groups, but those with BES had less previous SRE (31.7 vs. 42.2%). Pts with BES were more commonly treated with chemotherapy (84.0 vs. 77.5%), but less frequently with radiotherapy (59.7 vs. 65.9%) or surgery (85.0 vs. 88.1%). Absolute levels of uNTX and bALP at baseline and at 3 months, as well as normalization rates, did not differ between groups. However, when compared to those with BO and after controlling for unbalanced clinicopathological and treatment features, pts with BES presented a lower risk of first and subsequent SREs (adjusted-hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.58 – 0.94; p=0.013) and first SSE (adjusted-HR 0.75; 95% CI 0.60 – 0.94; p=0.014). Hazard rates for SRE were higher in the first 6 months of treatment. Despite the small magnitude, pts with BO consistently showed slightly higher BPI scores (+0.2 points; p=0.014). Pts with BES had a shorter OS (HR 1.97, 95% CI 1.66 – 2.33). Conclusion: Despite the consistent reduction in uNTX and bALP in pts with BC and BO or BES disease, pts with BO disease had a higher risk for SREs and higher pain score. Hazard rates for SREs were greater in the first 6 months of treatment. Strategies of treatment de-escalation of BTAs should consider the metastatic compartment and time variation of the hazard for SRE. Citation Format: Ferreira AR, Casimiro S, Ali S, Leitzel K, Lipton A, Costa L. Impact of the metastatic compartment on bone biomarkers and bone outcomes in patients (pts) with breast cancer (BC) and bone metastases (BM) in trial NCT00321464 of denosumab vs. zoledronic acid [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 P1-18-02.

A gene expression signature-based nomogram model in prediction of breast cancer bone metastases.

Breast cancer is prone to form bone metastases and subsequent skeletal‐related events (SREs) dramatically decrease patients’ quality of life and survival. Prediction and early management of bone lesions are valuable; however, proper prognostic models are inadequate. In the current study, we reviewed a total of 572 breast cancer patients in three microarray data sets including 191 bone metastases and 381 metastases‐free. Gene set enrichment analysis (GSEA) indicated less aggressive and low‐grade features of patients with bone metastases compared with metastases‐free ones, while luminal subtypes are more prone to form bone metastases. Five bone metastases‐related genes (KRT23, REEP1, SPIB, ALDH3B2, and GLDC) were identified and subjected to construct a gene expression signature‐based nomogram (GESBN) model. The model performed well in both training and testing sets for evaluation of breast cancer bone metastases (BCBM). Clinically, the model may help in prediction of early bone metastases, prevention and management of SREs, and even help to prolong survivals for patients with BCBM. The five‐gene GESBN model showed some implications as molecular diagnostic markers and therapeutic targets. Furthermore, our study also provided a way for analysis of tumor organ‐specific metastases. To the best of our knowledge, this is the first published model focused on tumor organ‐specific metastases.

Effects on bone resorption markers of continuing pamidronate or switching to zoledronic acid in patients with high risk bone metastases from breast cancer

BackgroundSwitching patients who remain at high risk of skeletal related events (SREs) despite pamidronate to the more potent bisphosphonate zoledronate, may be an effective treatment strategy. As part of a previously reported clinic study in this setting, we evaluated whether biomarkers for bone resorption, such as Bone-Specific Alkaline Phosphatase (BSAP), bone sialoprotein (BSP), and N-terminal telopeptide (NTX) correlated with subsequent SRE risk. MethodsBreast cancer patients who remained at high risk of SREs despite at least 3 months of q.3–4 weekly pamidronate were randomized to either continue on pamidronate or to switch to zoledronate (4mg) once every 4 weeks for 12-weeks. High risk bone metastases were defined by either: occurrence of a prior SRE, bone pain, radiologic progression of bone metastases and/or serum C-terminal telopeptide (CTx) levels > 400ng/L despite pamidronate use. Serum samples were collected at baseline and weeks 1, 4, 8 and 12 (CTx and BSAP) and baseline and week 12 (NTx and BSP), and all putative biomarkers were measured by ELISA. Follow up was extended to 2 years post trial entry for risk of subsequent SREs. The Kaplan-Meier method was used to estimate time-to-event outcomes. Generalized estimating equations (GEE) were used to evaluate if laboratory values over time or the change in laboratory values from baseline were associated with having a SRE within the time frame of this study. ResultsFrom March 2012 to May 2014, 76 patients were screened, with 73 eligible for enrolment. All 73 patients were available for biochemical analysis, with 35 patients receiving pamidronate and 38 patients receiving zoledronate. The GEE analysis found that no laboratory value was associated with having a subsequent SRE. Interaction between visit and laboratory values was also investigated, but no interaction effect was statistically significant. Only increased number of lines of prior hormonal treatment was associated with subsequent SRE risk. ConclusionOur analysis failed to find any association between serum BSAP, BSP, CTx or NTx levels and subsequent SRE risk in this cohort of patients. This lack of correlation between serum biomarkers and clinical outcomes could be due to influences of prior bisphosphonate treatment or presence of extra-osseous metastases in a significant proportion of enrolled patients. As such, caution should be used in biomarker interpretation and use to direct decision making regarding SRE risk for high risk patients in this setting.

Bone targeted therapies in advanced breast cancer

Bone targeted therapies are of increasing importance, not only for bone health in the clinical course of breast cancer, but recently also in the adjuvant setting as preventative, anticancer and prognosis-improving agents. It is well established that women with advanced breast cancer receive bisphosphonates or denosumab to prevent therapy-related osteoporosis. As many as 70% of these patients suffer from bone metastases and receive bone targeted agents in order to prevent skeletal related events (SREs), which are debilitating or diminish the quality of life. A number of trials provided guidance, identifying zoledronic acid as the most efficient bisphosphonate, showing that intravenous bisphosphonate administration is superior to oral intake and illustrating the different safety profile of denosumab, which has been reported to be more beneficial than zoledronic acid in delaying the time to first and subsequent (multiple) SREs. New studies have suggested that bone targeted therapies improve rates of overall survival and contribute to preventing recurrence of breast cancer at all sites. Increased bone turnover is both a consequence and a driving factor for tumour growth, expansion, formation of bone lesions and potentially also activation of disseminated tumour cells, leading to bone relapses. We review the current knowledge of bone targeted therapies in advanced breast cancer, with a focus on new insights into their bone-preserving and antitumor activity. Current guidelines, pathology of bone metastasis, mode of action and common side effects have been summarised. We also elaborate on the use of bisphosphonates and denosumab in early breast cancer, during adjuvant therapy with aromatase inhibitors.

Use of antiresorptive therapy (ART) and skeletal-related events (SREs) in patients with bone metastases of neuroendocrine neoplasms (NEN).

4096 Background: Antiresorptive therapy (ART) with bisphosphonates or denosumab is effective in preventing skeletal-related events (SREs) in patients with bone metastases (BM). In neuroendocrine neoplasms (NEN), BM are a negative prognostic factor, however tend to be asymptomatic and SREs are considered a rare event. The role of ART in preventing SREs in NEN has not been investigated so far. Methods: Retrospective analysis of all patients with bone metastases in the NEN database of the National Center for Tumor Diseases who presented at our center between 12/2012 and 01/2017. Overall survival (OS) from diagnosis of BM as well as time to SRE (TTSRE) were calculated. In patients experiencing an SRE within 1 month after diagnosis (i.e. before efficacy of ART could be assessed), TTSRE was defined as the time to a subsequent SRE. Results: In a total of 513 patients in the database, 108 patients with BM could be identified. Median OS was not reached in a median follow-up of 15.2 months. ART was applied to 42.6 % of patients. OS with or without ART did not differ significantly (p = 0.2538). 28.7 % of patients experienced at least 1 SRE, 20.4 % after more than 1 month. Median TTSRE was 63.8 months with ART and 127.0 months without ART (p = 0.1751). TTSRE was shortened in grade 3 vs. grade 1+2 NEN (172 months vs. not reached, HR 4.058, p = 0.0032), as well as in lytic vs. non-lytic metastases (24.5 vs. not reached, HR 7.319, p &lt; 0.0001), however not significantly different in oligometastatic vs. disseminated bone disease (not reached vs. 63,8 months, HR 1.415, p = 0.4287). Application of ART did not significantly change TTSRE in either of these subgroups. Significant toxicity attributable to ART was observed in 15.2 % of ART patients. Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.

P3.02b-059 The Role of Epidermal Growth Factor Receptor in the Onset of Skeletal Related Events in Non-Small Cell Lung Cancer: Topic: EGFR Clinical

Bone metastasis is frequent in non-small cell lung cancer (NSCLC) patients, and subsequent skeletal related events (SREs) adversely deteriorate life quality and survival. Patients harboring sensitive epidermal growth factor receptor (EGFR) mutation experience a prolonged life expectancy. However, it is unclear whether survival enhancement in NSCLC patients with sensitive EGFR mutation may encounter an increase in the onset of SREs or not. Also, it is still unknown whether time to SREs is impacted by EGFR mutation status. In this study, we evaluated the impact of EGFR mutation status and other clinic-pathological variables on the incidence of SREs and on survival outcomes of SREs in stage IV NSCLC patients. We conducted a retrospective study of medical records from patients who were diagnosed stage IV NSCLC in a single institute. EGFR mutation status, and other clinical-pathological variables, bone metastasis outcomes and survival data were collected and statistically analyzed. 410 patients with evident bone metastasis were enrolled in the study. 49.0% patients were detected with sensitive EGFR mutation, and 29.0% were prophylactically administered bisphosphonate. 42.7% experienced at least one SRE, the most common type of which was palliative radiotherapy. Patient harboring sensitive EGFR mutation hold a lower incidence of SREs than patients who were detected with wild type EGFR (37.3% vs 47.8%, p=0.031), and patients who received bisphosphonate confronted a lower incidence of SRE comparing with patients who didn’t receive bisphosphonate prophylactically (36.1% vs 45.4%, p=0.087). Median time from bone metastasis to first SRE was two months longer in patients with EGFR mutation, comparing to patients with wild type EGFR, with a marginal significance (5.0m vs 3.0m, p=0.08). The administration of bisphosphonate delayed the median time to first SRE for 5 months (7.0m vs 2.0m, p=0.037). In multivariate analysis using a Cox proportion model, wild type EGFR (HR=1.559, 95% CI 1.081-2.249), multiple bone lesions (HR=1.991, 95% CI 1.217-3.258), mixed type bone lesions (HR=2.144, 95% CI 1.085-4.238) were independent risk factors of survival post first SRE, while a smoking history (HR=1.428, p=0.053) was shown marginally significant with an impaired survival post first SRE. This retrospective study shows that EGFR mutation has a propensity to impact the onset of SRE and prolong survival post first SRE in patients with stage IV NSCLC. For patients with higher risks to experience SREs, bisphosphonate is an alternative to impede the process.

Hypocalcemia in patients with metastatic bone disease treated with denosumab

Bone stands out as the most frequently affected distant site for metastatic disease, leading to significant patient morbidity, loss of autonomy, decrease in quality of life and increased societal costs. Frequent consequences of metastatic bone disease include pain, hypercalcemia, pathologic fracture, and myeloid compression, collectively referred as skeletal related events (SRE). Bone targeted agents (BTA), such as zoledronic acid (ZA) and denosumab, changed significantly this panorama by delaying time to first and subsequent SRE.

Risk Factors for Developing Skeletal-Related Events in Breast Cancer Patients With Bone Metastases Undergoing Treatment With Bone-Modifying Agents.

Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors. The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively. In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors.

Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics

BackgroundAnalyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. Patients and MethodsPatients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson–Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. ResultsCompared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79–0.84; bone metastasis location, 0.78–0.83; bone metastasis number, 0.78–0.84; visceral metastasis presence/absence, 0.80–0.82; uNTx level, 0.73–0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76–0.83; bone metastasis location, 0.78–0.84; bone metastasis number, 0.79–0.81; visceral metastasis presence/absence, 0.79–0.81; uNTx level, 0.74–0.83). Similar results were observed in subgroups across tumour types. ConclusionDenosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.