Risk Of Skeletal-related Events Research Articles

Assessment of bone turnover markers and DXA parameters to predict bone metastasis progression during zoledronate treatment: a single-center experience

Bone metastases (BM) are a serious cancer complication, potentially causing substantial morbidity. Among the clinical issues related to BM, there is the lack of specific tools for early diagnosis and prognosis. We explored whether combining bone turnover markers (BTM) with dual-energy X-ray absorptiometry (DXA) assessment could identify early BM progression and risk of skeletal-related events (SREs) during zoledronate treatment. Before the initiation of zoledronate (T0) and after six months of treatment (T1), serum levels of five BTM were measured, and patients (N = 47) underwent DXA evaluation. Standard radiological imaging was performed to assess bone tumor response to medical anti-cancer treatment. High tumor burden in bone correlated with higher serum CTX (p = 0.007) and NTX (p = 0.005) at baseline. Low concentrations of OPG at T0 predicted BM progression with a sensitivity and specificity of 63% and 77%, respectively, when a cutoff of 5.2 pmol/l was used; such a predictive meaning was stronger in patients with lytic BM (sensitivity: 88%, specificity: 80%; p = 0.0006). As for the risk of SREs, we observed an association between low baseline OC (p = 0.04) and OPG (p = 0.08) and the onset of any-time SREs, whereas an increase in OPG over time was associated with reduced risk of on-study events (p = 0.03). Moreover, a statistically significant correlation emerged between low baseline lumbar T-score and femur BMD and on-study SREs (p < 0.001 in both instances). These findings suggest that addition of DXA to BTM dosage could help stratifying the risk of SREs at the time of BM diagnosis but does not enhance our capability of detecting bone progression, during zoledronate treatment.

Bone Metastases in Patients with Pancreatic NETs: Prevalence and Prognosis.

The clinical relevance of bone metastases (BM) in advanced pancreatic neuroendocrine tumors (PanNETs) is poorly described. We analyzed 314 consecutive PanNET patients treated at the European Neuroendocrine Tumour Society (ENETS) Center Essen between 2009 and 2021 in terms of the occurrence and clinical and prognostic impact of BM using hybrid imaging with 68Ga-DOTATOC PET/CT. According to UICC staging, 171/314 (54.5%) patients had stage IV PanNETs. BM was diagnosed in 62/171 (36.3%) patients. Initially, 35% of BMs were visible by pathological tracer uptake only. Skeletal-related events (SREs) were detected in 11 of the 62 patients (17.7%). Patients with antiresorptive therapy had a significantly lower rate of SRE (2/36, 5.6%) than individuals without bone-specific therapy (9/26, 34.6%) (odds ratio 9.0, p=0.0054, Fisher's exact test). The median overall survival (OS) was 82 months (53.6-110.4, 95% CI) in the stage IV PanNET cohort. The median OS was significantly lower for patients with BM (63 months; 49.9-76.0, 95% CI) than for patients with distant metastases other than BM (116 months; 87.6-144.3, 95% CI) (p=0.016, log-rank test). BM occurs in more than one-third of advanced PanNETs and is associated with an unfavorable prognosis. One in five patients experiences a persistent quality-of-life-lowering SRE. Antiresorptive therapy is associated with a more favorable risk of SREs and should be offered to all patients with BM in PanNETs.

Impact of Bone Modifying Agent Initiation Time, Frequency, and Duration on Skeletal-Related Events in Patients with Multiple Myeloma

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values &amp;gt;0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors

BackgroundBone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. MethodsData from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike’s information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. ResultsOf 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9–12.8) versus (vs) 6.8 m (95% CI 4.0–9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4–14.2) vs 3.5 m (95% CI 2.9–4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6–4.4) vs 1.8 m (95% CI 1.6–2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1–30.7) vs 3.5 m (95% CI 2.9–4.1) p = 0.002]. ConclusionsIn the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

Retrospective analysis of the relationship between time to anti-resorptive therapy and incidence of skeletal related events in patients with multiple myeloma.

8048 Background: Patients with multiple myeloma (MM) often have bone disease at diagnosis and are at risk of developing skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that for patients with lytic bone lesions at diagnosis, the use of anti-resorptive agents lead to a lower incidence of SREs. However, it is common for initiation of anti-resorptive therapy to be delayed. Recent studies have demonstrated that anti-resorptive therapy is underutilized in patients with MM. However, the effect of time to initiation of anti-resorptive agent after diagnosis of MM on SREs has not been well studied. Herein, we conducted a multi-center retrospective analysis to determine if time to anti-resorptive agent has an adverse impact on the risk of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify patients with newly diagnosed MM between July 1st, 2016 and June 30th, 2019 at two large academic centers. Patients previously treated or patients not treated with anti-resorptive therapy were excluded. The study’s primary endpoint was hazard ratio of developing a SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, gender, age, International Staging System (ISS) stage at diagnosis, and prior SRE present at diagnosis was analyzed by using a multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: 759 patients were included in the study (Thomas Jefferson University: n = 232; The Ohio State University: n = 527). Median age at diagnosis is 60.2 years (IQR: 12.4 years). 57% of patients were male. 77.9% and 20.3% of patients identified as white and black respectively. 210 patients (27.7%) were noted to have osteopenia, 45 (5.9%) had osteoporosis, 229 (30.2%) were vitamin D deficient, and 319 (42%) were obese at diagnosis. A skeletal related event was present at diagnosis in 338 (45.1%) of patients. 180 (34%) patients received anti-resorptive agents within 31 days. A delay in initiating anti-resorptive agents of greater than 31 days from diagnosis had an increased risk for SRE with a hazard ratio 1.654 (1.054~2.598; p-value: 0.029). Conclusions: This large multicenter retrospective study demonstrated that time to anti-resorptive therapy MM patients has a significant impact on the risk of SRE. Given many of the challenges in starting anti-resorptive therapy in a timely manner, this study emphasizes the need for inter-professional, multi-disciplinary collaborations to streamline the workflow and start therapy within the first month of diagnosis. Ongoing efforts are underway to develop quality improvement processes to achieve this goal.

Bone health practices in metastatic prostate cancer (mPCA).

e17119 Background: Patients (pts) with mPCA and bone metastases (BM) are at risk for skeletal-related events (SREs), which include pathologic fracture, bone irradiation or surgery, spinal cord compression, and hypercalcemia. This study examined the evaluation, prevention, and treatment of osteopenia/-porosis (OP/P) and BM in pts with mPCA at the UCCC and affiliated sites. Methods: Pts diagnosed with mPCA and BM between 2011-2021 and treated with ADT were included. Demographic, clinical, treatment, and outcomes data were retrospectively collected. The primary endpoint was time from mPCA diagnosis to first SRE. Secondary endpoints included rates of DEXA scans, rates of vitamin D and calcium supplementation, and bone agent toxicity. The log-rank test was conducted to compare the primary endpoint by use of a bone strengthening agent. The Kruskal Wallis non-parametric test was used for continuous variables and Fisher’s exact test for categorical variables. Results: Of the 369 pts with mPCA, 247 (66.9%) were treated with a bone agent. Median age at metastatic diagnosis (mDx) was 69.6 years. Pts were predominately white (315, 85.4%) with hormone-sensitive mPCA (mHSPC) (327, 88.6%) at mDx. There were no significant differences in race, ethnicity, PSA, Gleason score, or time on ADT between patients who did and did not receive a bone agent. 222 pts (60.2%) were former or current smokers, 5 (1.4%) had pre-existing low testosterone ( &lt; 150 ng/dL), 8 (2.2%) had prolonged glucocorticoid use (equivalent &gt; 10 mg prednisone for 30 days), and 17 (4.6%) had known OP/P prior to mDx. 130 pts (35.3%) had a DEXA scan (27 pre-ADT, 103 post-ADT). 325 pts (88.1%) and 286 pts (77.5%) were recommended vitamin D and calcium supplementation, respectively. Bone agent use and toxicity are presented in table 1. 110 of 247 pts (44.5%) treated with a bone agent were started in the mHSPC setting without OP/P. Time from mPCA diagnosis to first SRE was a median of 32.8 months (IQR 13.5 to 66.8) for pts who received a bone agent vs. 28.2 months (IQR 8.7 to 59.1) who did not (Chi-squared = 7.089, p = 0.008). Among SREs, 102 pts (27.6%) had a pathologic fracture, 1 (0.3%) severe hypercalcemia &gt; 14 mg/dL, 23 (6.2%) bone surgery, 142 (38.5%) bone irradiation, and 4 (1.1%) spinal cord compression. Conclusions: Bone agent use was associated with an expected improvement in time to first SRE. Pts with mPCA had high rates of vitamin D and calcium supplementation for OP/P prevention. Denosumab was the most used bone agent in concordance with guidelines for mPCA. DEXA scan rates were low, and nearly half of patients received a bone agent prior to castrate resistance. [Table: see text]

Clinical factors associated with prescribing patterns of bone modifying agents in men with metastatic castration-resistant prostate cancer.

e18878 Background: Bone metastases occur in up to 90% of men with metastatic prostate cancer and cause skeletal-related events (SREs) such as fracture and spinal cord compression. Although bone modifying agents (BMAs) have been shown to decrease the risk of SREs in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are not widely used in this patient population. In this retrospective study, we report the prescribing patterns of BMAs and predictors of BMA use in a large national cohort. Methods: We used the VA corporate data warehouse to identify patients with mCRPC who were treated with first-line mCRPC therapy (abiraterone, enzalutamide, docetaxel, or ketoconazole) between 2010 and 2017. BMA prescribing frequency and patterns were analyzed. Multivariable regression analysis was used to evaluate clinical and disease-specific factors associated with BMA use which are presented as adjusted odds ratios (OR) with 95% confidence intervals (CI). Results: In the final cohort of 4,079 patients, the median age at mCRPC diagnosis was 73 years (IQR 66-81). 29% of patients in the cohort were Black. Diagnosis codes identified bone metastases at mCRPC diagnosis in 48% of the cohort (ICD-9 and 10 coding for sites of metastases are known to underestimate the actual incidence of metastases). Only 48% of patients received a BMA following initiation of treatment for mCRPC, 47% of which had already received a BMA 6 months prior to mCRPC diagnosis. For those who were new BMA starts, the median time to BMA administration from mCRPC treatment was 3.4 months (IQR 1.2-8.8). Factors associated with BMA use were having an ICD-9 or 10 diagnosis code for bone metastases at time of mCRPC treatment (OR 1.28, 95% CI 1.10-1.48), concurrent corticosteroid use (OR 1.90, 95% CI 1.53-2.38), and docetaxel use as first-line mCRPC therapy (OR 1.78, 95% CI 1.45-2.18). Factors associated with decreased BMA use were Charlson comorbidity index score of ≥ 2 (OR 0.75, 95% CI 0.62-0.90), advancing age (OR 0.86 per 10 years, 95% CI 0.79-0.94), and decreased eGFR (eGFR 30-59, OR 0.81, 95% CI 0.68-0.96; eGFR 0-29, OR 0.23, 95% CI 0.14-0.37). Having a diagnosis code for a SRE before mCRPC diagnosis (e.g., bone fracture and cord compression) did not impact BMA use, but the incidence of those events was low. Conclusions: Less than half of this VA cohort received a BMA after starting therapy for mCRPC. Key factors associated with BMA use were corticosteroid use and first-line docetaxel use, which likely represented more aggressive disease. Notably, patients who were older and had more comorbid conditions were less likely to receive a BMA despite being highest risk for frailty and SREs. Future quality improvement efforts aimed at increasing BMA use may address the needs of the geriatric mCRPC patient population.

Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312)

BackgroundZoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. MethodsWe conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. ResultsBetween November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. ConclusionsAn eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Management of bone metastasis in prostate cancer.

Progression of bone metastases is the primary cause of death in prostate cancer, and skeletal-related events (SREs), including pathologic fractures, spinal cord compression, radiation, or surgery to bone can impair patients' quality of life. Over the past decade, the development of cytotoxic agents, androgen-receptor-axis-targeted therapies (ARATs), and radioligand therapies has prolonged overall survival of prostate cancer patients with bone metastases and reduced the risk of SREs. The use of bone-modifying agents has also contributed to the reduced risk of SREs. Initial use of a cytotoxic agent, docetaxel, or an ARAT agent with androgen deprivation therapy (ADT) is the current approach to metastatic castration-sensitive prostate cancer. However, there is no consensus on the optimal medication for upfront use in combination with ADT, or on specific patient selection. Recently, next-generation imaging modalities, such as whole-body magnetic resonance imaging and prostate-specific membrane antigen-positron emission tomography have been utilized to detect bone metastases at an early stage. In addition, metastasis-directed therapy, such as stereotactic body radiation therapy, has been attempted. In the future, patients with bone metastatic prostate cancer will be divided into subgroups and their treatment options will be tailored to their specific characteristics.

Assessment of Bone Health Awareness and Education in Breast Cancer Patients with Bone Metastasis in the USA

Bone metastases are common in advanced breast cancer (BC) patients and increase the risk for skeletal-related events (SREs), which present a significant health and economic burden. Bone targeting agents (BTAs) can improve health-related quality of life by delaying or preventing SREs; nevertheless, a significant portion of eligible BC patients are not receiving this therapy. A bone health education needs assessment survey was conducted to examine cancer-related bone health awareness and to identify opportunities to improve bone health education. Direct-to-patient outreach was used to recruit adult BC patients in the USA self-reporting a diagnosis of bone metastasis within the past 3 years. Of the 200 patients, 59% experienced at least one SRE prior to survey participation (44% radiation to bone, 29% bone fracture, 17% spinal cord compression, 15% surgery to bone), and 83% were currently receiving a BTA. Awareness of general cancer bone health, protection strategies against SREs, and screening tests were low to moderate. Patients currently not receiving a BTA were least knowledgeable about cancer bone health, with only 40% aware of BTAs as a protective strategy, and only 26% were very or extremely satisfied with the information received from healthcare providers. Sixty-two percent of patients wanted to receive information by more than one mode of communication. Notable gaps in bone health education were observed in bone metastatic BC patients at risk for SREs, suggesting the need for earlier and more effective communication and education strategies to promote appropriate BTA use and better health outcomes.

Skeletal-Related Events After Surgery With or Without Radiotherapy for Bone Metastases to Weight-Bearing Bones.

Introduction In patients with metastatic disease involving weight-bearing bones, postoperative radiotherapy (PORT) is commonly administered following surgical stabilization of an impending or confirmed pathologic fracture to reduce the risk of a seeded local recurrence. The goalwas to re-evaluate the beneficial effect of PORT in a modern cohort of patientsand determine any potential clinical predictors of skeletal-related events (SREs) which were defined as a pathologic fracture or the necessity for radiation or surgery to the affected bone. Methods Consecutive patients undergoing surgical stabilization of metastatic disease to weight-bearing bones of the extremities between 2012 and 2019 were reviewed. Patient, disease, and treatment factors were abstracted. The cumulative incidenceof SREs was determined using competing risks methodology; overall survival (OS) was estimated using the Kaplan-Meier method. Results A total of 82 patients were identified, 74% of whom had undergone intramedullary nail fixation and 26% internal fixation or replacement. The femur was the most commonly involved bone (94%).A majority (78%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1-2. Bone-strengthening agents were given to 38% and PORT to 54%. The median PORT dose was 30 Gy in 10 fractions and the median percent coverage of surgical hardware was 100% (range, 25-100). SREs occurred in 10 of 82 patients. There were no differences between no RT and RT groups for the two-year cumulative incidence of SREs (8.2% vs 11.5%, p=0.59) or two-year cumulative incidence of local failure (10.8% vs4.6%, p=0.53). The only identified predictors of SREs were the use of bone-strengthening agents (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.05-1.06, p=0.06) and malnutrition (HR 3.69, 95% CI 0.91-14.93, p=0.07). For patients treated with PORT, a biologically effective dose or percent coverage of surgical hardware was not associated with SREs. Conclusion In this series, the addition of PORT following surgery for metastatic disease involving weight-bearing bones does not significantly affect the rate of SREs. The use of bone-strengthening agents appears protective, and malnourished patients appear particularly at high risk for future SRE.

Skeletal-related events after abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer: A population-based study using the SEER-Medicare linked dataset.

Skeletal-related events (SREs) from bone metastases disease carry significant morbidity in men with metastatic castration resistant prostate cancer (mCRPC). The differential risk of SREs among patients receiving abiraterone acetate (AA) or enzalutamide (ENZ) is unknown. To compare the risk of SREs among men with mCRPC receiving AA or ENZ, a retrospective cohort study using the SEER-Medicare Linked Database was conducted. Men with prostate cancer aged ≥65 years at first AA or ENZ prescription (index date) from 2011 to 2015 were identified. Patients were followed until the earliest occurrence of SRE, death, Medicare disenrollment, or December 31, 2016. The primary outcome was a composite endpoint of SRE (pathologic fracture, spinal cord compression, or surgery or radiation to bone) after the index date. Multivariable logistic regressions including key demographic and clinical covariates with death as a competing risk were conducted. Overall, 5,856 patients were identified (4,207 received AA and 1,649 received ENZ). Median age was 76.5 years (IQR 71.4-82.3), 4,557 (77.8%) were White, 1,112 (19.2%) had recent chemotherapy, and 2,730 (46.6%) had recent zoledronic acid or denosumab. Eight-hundred and thirty-seven (14.3%) patients had ≥1 SRE after index date. In multivariable analyses, there was no difference in SRE risk based on AA and ENZ (HR=0.99 for ENZ, 95%CI 0.84-1.16, P=0.890). Denosumab was associated with lower SRE risk (HR=0.75, 95%CI 0.64-0.88, P=0.001). In this large cohort of men with mCRPC, there was no difference in risk of SRE between AA and ENZ. Decision-making should be informed by prior therapies, comorbidities, toxicity profiles, and patient preferences. Denosumab has evidence of benefit in preventing SREs in this real-world population.

Bone Disease in Multiple Myeloma: Biologic and Clinical Implications.

Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with associated osteolytic lesions is a hallmark of MM and develops in the majority of MM patients. Approximately half of patients with bone disease will experience skeletal-related events (SREs), such as spinal cord compression and pathologic fractures, which increase the risk of mortality by 20–40%. At the cellular level, bone disease results from a tumor-cell-driven imbalance between osteoclast bone resorption and osteoblast bone formation, thereby creating a favorable cellular environment for bone resorption. The use of osteoclast inhibitory therapies with bisphosphonates, such as zoledronic acid and the RANKL inhibitor denosumab, have been shown to delay and lower the risk of SREs, as well as the need for surgery or radiation therapy to treat severe bone complications. This review outlines our current understanding of the molecular underpinnings of bone disease, available therapeutic options, and highlights recent advances in the management of MM-related bone disease.

The effects of bone targeted therapy in patients with greater than two years survival with metastatic breast cancer and bone metastasis.

e13076 Background: Administration of bone targeted therapy such as zoledronic acid (ZA) or of denosumab (D) decrease the risk of skeletal related events (SRE) such as radiation to the bone, pathological bone fractures, and spinal cord compression in patients with a diagnosis of metastatic breast cancer (MBC) and bone metastasis. As these patients continue to live longer it is unknown what are the impacts from long-term administration of ZA or D among those who live longer than 2 years. Methods: This was a retrospective analysis of patients with MBC and bone metastasis who lived for more than 2 years since diagnosis and received treatment at MD Anderson Cancer Center for MBC in addition to ZA and/or D between 2015 and 2021. Patient demographics, date of diagnosis, tumor characteristics, bone targeted agent treatment plans and SRE were extracted from the institutional database and electronic health records. We defined 3 patterns of receipt of bone targeted therapy: Pattern A: ZA every 3-4 weeks; Pattern B: D every 4-6 weeks; Pattern C; D every 4-6 weeks for a period followed by every 3 months. The association between these patterns and SRE was assessed using Fisher’s exact test. Results: We included 178 patients: Pattern A with 49 patients, Pattern B with 85 patients, and Pattern C with 44 patients. The proportion of patients who suffered a SRE in Patterns A, B, and C were 22.4% (11/49), 20% (17/85), and 21.4% (10/44). There was no statistical difference in the proportion of SRE between these three groups (p = 0.92). Conclusions: We did not observe a difference in the rate of SRE between the three different patterns of bone targeted therapy administration in patients with MBC and bone metastasis. Other treatment patterns will be considered in future analysis.[Table: see text]

Real-world associations between bone-targeted agents and palliative bone radiotherapy in prostate cancer decedents: A province-wide population study.

e17043 Background: Palliative bone radiation is the predominant skeletal-related event (SRE) reported in advanced prostate cancer. Bone targeted agents (BTA), such as denosumab and zoledronic acid, are shown to both prevent and delay SREs including bone radiation. This study evaluated real-world use of BTA in a large provincial database in relation to palliative bone radiotherapy prior to prostate-cancer related death. Methods: Linked, province-wide administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98646), who received continuous androgen deprivation therapy (n = 29453), died between 2013-2018 (n = 4184), and qualified for Ontario Drug Benefits (OBD; 65 years or older, n = 3788). Patients receiving novel life prolonging therapy (LPT) for metastatic castration-resistant prostate cancer (mCRPC; abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223) were selected, and use of BTA (denosumab, zoledronic acid) was identified. Demographic, health, and treatment characteristics were collected over a 2-year observation window looking back from the date of death. Multivariable analyses were conducted to identify factors important in use of palliative bone radiation. Results: 1769 patients received LPT for mCRPC, including abiraterone (n = 1094, 62%), docetaxel (n = 881, 60%), enzalutamide (n = 480, 27%), radium-223 (n = 250, 14%) and cabazitaxel (n = 108, 6%). Amongst patients receiving LPT, 57% received BTA and 60% received palliative radiation to bone. Factors associated with palliative bone radiation were receipt of BTA (OR 1.46; 95% confidence interval [CI] 1.13-1.91), metastatic disease at diagnosis (OR 1.48; CI: 1.11-1.97), radiation oncologist involvement (OR 103.11; CI: 47.03-226.25), whereas patients with fewer chronic diseases (OR 0.73; CI: 0.54-0.98) and who had prior prostatectomy (OR 0.54; CI: 0.36-0.84) were less likely to receive radiation. This relationship was maintained for both zoledronic acid (OR 1.68; CI: 1.09-2.58) and denosumab (OR 1.35, CI: 1.03-1.77). No specific LPT was associated with use of palliative bone radiation. Conclusions: Despite clinicians prescribing BTAs to prevent SREs, in this cohort, radiotherapy to bone was more likely in patients receiving BTAs. This suggests that clinicians are prescribing BTAs to patients at greater risk of SREs, but that patients dying of prostate cancer continue to have significant bone-related morbidity despite contemporary prostate cancer treatment. An analysis of primary (before bone radiotherapy) versus secondary (after bone radiotherapy) BTA prescriptions will be presented, as well as timing of BTA initiation in relation to death.

Long-term safety and efficacy of bisphosphonate therapy in advanced lung cancer with bone metastasis.

Aim: This retrospective, observational study evaluated the long-term (>12months) safety and effectiveness of bisphosphonate. Methods: Data collected for 359 patients included quantity and proportion of adverse events (AEs) and skeletal-related events (SREs), and times to first AE and first SRE. Results: Patients in the ≤24-month group experienced significantly fewer AEs compared with the >24-month treatment group (p=0.008), and treatment for >24 months was a potential risk factor for AEs (p=0.05). Neither the proportion nor the risk of SRE was significantly associated with therapy duration (p=0.525 and 0.084, respectively). Conclusion: Bisphosphonate treatment beyond 2 years may increase the risk of AEs, but may prolong SRE-free survival early after 24months, compared with medication administered for ≤24months.

Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach

BackgroundClinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. PurposeWe aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. MethodsUsing the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. ResultsA total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19–89) years with a median duration of denosumab treatment of 253 (range, 88–2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. ConclusionThis analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient’s need to continue denosumab treatment and improve patient outcomes.

Abstract P1-20-02: A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer

Abstract Background: The anti-RANKL monoclonal antibody denosumab has been demonstrated to be superior to the bisphosphonate zoledronate in preventing skeletal-related events (SREs) among patients with incident bone metastases (BMs) from solid tumors (STs), including breast cancer. Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥2 years. However, the denosumab treatment duration is often &amp;lt;1 year in the US. We applied a supervised machine learning approach using real-world data to estimate patient-level SRE risk following cessation of denosumab and determine risk factors associated with increased SRE risk. The method selected prior SREs, shorter denosumab treatment duration, and higher number of clinic visits as the top-ranked risk factors among a diverse group of patients with BMs from STs (Stopeck et al., ASCO 2021). Here, we report the top-ranked risk factors for the subgroup of patients with BMs from breast cancer. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BMs from a primary ST between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients must have received ≥2 consecutive 120 mg denosumab doses on every 4-week (±14 days) schedule and had a minimum follow-up ≥1 year after the last denosumab dose or an SRE occurrence between days 84 and 365 following denosumab cessation. An SRE risk prediction model was developed using extreme gradient boosting and evaluated on an independent test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential risk factors for SREs. After denosumab cessation, the impact and relative importance of these factors were extracted from the model using Shapley Additive Explanations (SHAP). In addition, findings from univariate analyses on risk factors with high importance from the breast cancer model were reported. Results: Of 1414 patients who met the inclusion criteria, 563 (40%) had BMs from breast cancer. Following denosumab cessation, 167 (30%) patients in the breast cancer subgroup experienced ≥1 SRE. The breast cancer model performance was meaningful, as evidenced by the area under the receiver operating characteristic (AUROC) score of 73%. SHAP resulted in several significant factors that predicted an increased SRE risk for the subgroup following denosumab cessation, including denosumab treatment duration of ≤8 months, prior SREs, and an average of &amp;gt;2 clinic visits per month (Table). Univariate analyses showed a positive correlation between increased SRE risk and prior SREs, while they revealed an inverse relationship between increased SRE risk and longer durations of denosumab. Conclusion: Shorter denosumab treatment duration, prior SREs, and higher number of clinic visits are top-ranked risk factors associated with SREs after discontinuation of denosumab treatment in patients with BMs from STs, including breast cancer. A machine learning approach to SRE risk factor identification may help clinicians assess the risks of discontinuing denosumab treatment and improve clinical outcomes for patients with BMs from breast cancer. SHAP Risk Factors That Increase SRE Risk 3-12 Months After Denosumab Cessation in Patients With BMsDenosumab therapy decisions: denosumab duration ≤8 months, time to denosumab initiation ≤2 months after BM diagnosisPrior SREs: ≥2 cumulative number of SREs since baseline up to cessationa, SRE occurrence (from denosumab initiation to cessation)Comorbidities: patients with anxietyVisits: &amp;gt;2 average number of visits per month (hospitalization, emergency room, and other visits [excluding nonphysician interaction]), ≥1 hospitalization, ≥1 emergency room visitaBaseline was defined as 180 days before the date of initial BM diagnosis. BM, bone metastasis; SHAP, Shapley Additive Explanations; SRE, skeletal-related event Citation Format: Alison Stopeck, Celestia Higano, David Henry, Basia Bachmann, Marko Rehn, Dionna Jacobson, Benoit Cadieux, Hossam Saad. A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-20-02.

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy

Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.