Skeletal Events Research Articles

Physician-reported barriers and facilitators to thyroid hormone deprescribing in older adults.

Thyroid hormone is one of the most commonly prescribed medications in the United States. Misuse of and overtreatment with thyroid hormone is common in older adults and can lead to cardiovascular and skeletal adverse events. Even though deprescribing can reduce inappropriate care, no studies have yet explored specific barriers and facilitators to guide thyroid hormone deprescribing in older adults (defined as discontinuation of thyroid hormone when initiated without an appropriate indication or dose reduction in those overtreated). We conducted semi-structured interviews with 19 endocrinologists, geriatricians, and primary care physicians who prescribe thyroid hormone. Interviews were completed between July 2020 and December 2021 via two-way video conferencing. We used both an inductive and deductive content analysis guided by the Theoretical Domains Framework to evaluate transcribed and coded participant responses. Thematic analysis characterized themes related to barriers and facilitators to thyroid hormone deprescribing practices in older adults. The most commonly reported barriers to thyroid hormone deprescribing were related to patient-level factors, followed by physician- and system-level factors. Patient factors included patients' perceived need for thyroid hormone use and patient anxiety/concerns about potential side effects related to thyroid hormone dose reduction, patient lack of knowledge, and misinformation regarding deprescribing. Physician- and system-level barriers included clinic visit time constraints, physician inertia, physician lack of knowledge about deprescribing, perceived lack of sufficient patient follow-up, and electronic health record limitations. The most prominent physician-reported facilitators to thyroid hormone deprescribing were effective physician-to-patient communication, and positive physician-patient relationship, including patients' trust in their treating physician. Barriers and facilitators to thyroid hormone deprescribing in older adults were reported at multiple levels including patient-, physician-, and system-level factors. Interventions to improve thyroid hormone deprescribing in older adults should aim to improve patient education and expectations, increase multidisciplinary physician awareness, and overcome physician inertia.

6539 Hungry Bone Syndrome & Osteoblastic Metastasis In The Setting Of Prostate Cancer : A Rare Cause Of Hypocalcemia

Abstract Disclosure: B. Sharma: None. M. Khan: None. A. Rao: None. P. Guido: None. Background: Hungry bone syndrome (HBS) is due to excessive calcium and phosphorus sequestration in the bone, manifesting as hypocalcemia and hypophosphatemia.It is most commonly seen as a postoperative complication of parathyroidectomy.Advanced prostate cancer with osseous metastasis has been previously described as is a rare cause of HBS. Clinical Case: A 65 year old male was admitted to the hospital with acute congestive heart failure and severe hypocalcemia.He exhibited symptoms of muscle spasms and perioral paraesthesias. Physical exam was positive for Trousseau's sign.Initial tests were consistent with severe hypocalcemia (corrected non-ionized calcium 6.8 [8.8-10.2] mg/dL), low ionized calcium (0.58 [1.10-1.30] mmol/L). Three weeks prior to admission, corrected non-ionized calcium was 9.8 mg/mL. Other labs showed normal magnesium, normal phosphorus, elevated alkaline phosphatase (1044 [45-117] U/L), low Vitamin D (12 [>30] ng/mL ), elevated iPTH (567 [19-88] pg/mL) and low PTH-rp (9 [11-20] pg/mL]. His electrocardiogram showed regular rate and rhythm with Qtc prolongation (497 ms).He had a significant oncological history of prostate cancer and multiple myeloma in remission.He was previously treated with zoledronic acid, discontinued 1 year prior to admission, for reducing skeletal complications while being treated for multiple myeloma. He had a recent workup with medical oncology for recurrence of prostate cancer due to elevated Prostate-specific antigen (380 [<4.00] ng/mL).Computed tomography imaging showed diffuse osteoblastic metastatic disease in the axial skeleton, pelvis and proximal femur. During hospital admission hypocalcemia was persistent, likely also due to concurrent furosemide use, necessitating the administration of intravenous calcium infusion and use of cholecalciferol and calcitriol.He was discharged on calcium carbonate 4500 mg twice a day, cholecalciferol 50 000 units weekly for 12 weeks and calcitriol 2 mcg twice a day. Conclusion: Hypocalcemia in the setting of prostate cancer is most commonly due to the use of bisphosphonates or Receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitors. Hypocalcemia in this case was due to sequestration of calcium in the bone by osteoblastic metastasis. This case illustrates the importance of recognising osteoblastic metastasis as a differential in protracted and severe hypocalcemia in malignancy.High doses of calcium, vitamin D, and calcitriol replacement are often needed as the hypocalcemia is usually severe and refractory with some cases requiring prolonged IV calcium infusion.Treatment of the underlying cancer and bone metastases with chemotherapy has been shown to improve hypocalcemia and reduce the requirement of calcium and vitamin D supplementation.There is limited data to suggest if bisphosphonates can be safely used in these cases for prevention of skeletal related events. Presentation: 6/1/2024

Biomarkers of bone metabolism in [223Ra] RaCl2 therapy - association with extent of disease and prediction of overall survival

BackgroundThe alpha-emitting radionuclide therapy [223Ra]RaCl2 (Radium-223) improves overall survival (OS) and time to symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence suggests that the effect of Radium-223 is partly exerted through an impact on the surrounding bone matrix. We hypothesized that bone metabolism markers (BMM) could provide predictive information regarding response to Radium-223. Accordingly, the aim of this study was to investigate changes in BMM during Radium-223 therapy and evaluate association with clinical outcome.MethodsProspective study of BMM in patients with mCRPC receiving Radium-223. Blood samples were collected before each administration of Radium-223 and the following BMM were quantified; bone-specific alkaline phosphatase (BALP), osteocalcin, procollagen type I N-propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), receptor-activated nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Clinical outcomes were scintigraphic progression during/after therapy, change in bone scan index (BSI), occurrence of SSE, and OS.ResultsA total of 55 mCRPC patients were included. There was a significant linear association between skeletal extent of disease and CTX-MMP, PINP, BALP, and osteocalcin. No significant association between dynamics in BSI and BMM were detected. Median OS for the cohort was 14 months (95% CI: 10.7–16.8). Baseline levels of Log2-CTX-MMP (HR = 2.15 (95%CI: 1.1–4.1)) and Log2-BALP (HR = 1.59 (95%CI: 1.1–2.1)) were associated with OS. Patients with increasing CTX-MMP during therapy had significantly shorter OS (Median OS = 4 mo. (95%CI: 2.3–5.7)) than patients with stable or decreasing CTX-MMP (Median OS = 12 mo. (95%CI: 10.1–13.9), P < 0.001).ConclusionBMM are significantly associated with scintigraphic extent of skeletal disease and OS in patients with mCRPC. Particularly, the bone resorption marker CTX-MMP is a promising surrogate marker for prediction of outcome in patients receiving Radium-223 therapy and could potentially improve selection of patients for therapy and assessment of response.Trial registrationClinicaltrials.gov, NCT03247010. Registered 10th of August 2017, https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1.

Bone-seeking tumor cells alter bone material quality parameters on the nanoscale in mice

Bone metastases related to breast and prostate cancer present with multiple challenges and skeletal related events like fragility fractures impair the quality of life of the patients significantly. To determine local alterations in bone material quality with bone metastasis, we subjected murine tibial specimens, generated after intratibial injections of either RM-1 prostate cancer cells or EO771 breast cancer cells into male and female mice respectively, to high-resolution imaging modalities. Small and wide-angle X-ray scattering showed unaltered mineral characteristics in the more osteosclerotic prostate cancer model, while the quantification of calcium weight percentage via backscattered electron microscopy determined minor differences along the perilacunar bone matrix. Further analyses of mineral and collagen characteristics were performed using Raman spectroscopy and focused ion beam electron microscopy. Our study indicates that alterations in nanochannel properties occur due to the presence of bone seeking tumor cells with more prevalent nanopores in the perilacunar matrix.

1599P Symptomatic skeletal events, health-related quality of life and pain in a phase III study of [177Lu]Lu-PSMA-617 in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer: Third interim analysis of PSMAfore

1599P Symptomatic skeletal events, health-related quality of life and pain in a phase III study of [177Lu]Lu-PSMA-617 in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer: Third interim analysis of PSMAfore

Role of osteoclast inhibitors in prostate cancer bone metastasis; a narrative review.

To study the role of Osteoclast inhibitors in advanced prostate cancer metastasis treatment and their efficacy in reducing skeletal related events. A comprehensive search was done using search terms as "osteoclast inhibitors" "Bisphosphonates" "Zoledronic acid" " pamidronate" " Alendronate" "Denosumab" " Prostate cancer metastasis" in pubmed and Google scholar. Relevant articles were screened and collected . The collected articles were used to frame the review and data showing use of Osteoclast inhibitors In prostate cancer bone metastasis was collected. Prostate cancer metastasizes most commonly to the skeleton thus leading to significant morbidity ranging from pain, pathological fractures to spinal cord compression and are the primary cause of patient disability and reduced quality of life.Initially, radiation therapy and radiopharmaceuticals were the mainstay of treatment however the role of Bisphosphonates and denosumab has become an integral part of therapy to manage metastatic prostate cancer. These agents significantly decrease skeletal related events and enhance patients quality of life. Emerging therapies like Radium-223 have also shown promise in reducing skeletal related events and also improving survival rates in patients with bone metastasis. Other treatment options which are being used are systemic agents like Docetaxel, cabazitaxel, hormonal therapies like abiraterone and enzalutamide. Immunotherapy with sipuleucel-T has demonstrated a reduction in mortality among prostate cancer patients with metastasis, highlighting the need for further research in this area. Ongoing studies are investigating novel agents that target both tumor cells and the bone microenvironment. Osteoclast inhibitors are effective in reducing skeletal related events in advanced bone metastasis and improve the quality of life of patients.

Are bone targeted agents still useful in times of immunotherapy? The SAKK 80/19 BTA pilot study

BackgroundPatients with bone metastases from solid tumors often have additional treatment with bone targeted agents (BTAs) to avoid symptomatic skeletal events (SSEs) such as clinically significant pathological fracture leading toradiation therapy or surgery to the bone, spinal cord compression, or hypercalcemia. The absolute value of BTA treatment in the era of immunotherapy (IO) is unknown. MethodsPatients with bone metastases treated with immunotherapy within the Alpine Tumor Immunology Registry were compared based on whether they received an additional BTA such as denosumab or zoledronic acid. The primary endpoint was time to first SSE. Continuous data were summarized as median and range, categorical data using frequency counts and percentages. Kaplan-Meier estimates were used to describe and visualize the effect of categorical variables. ResultsOne hundred and ninety-seven patients with bone metastases and treatment with immunotherapy such as nivolumab (48 %), pembrolizumab (40 %), atezolizumab (12 %), ipilimumab (9 %) and other immunotherapy (5 %) were included. The most frequent tumor types were lung cancer (50 %), malignant melanoma (11 %), renal cell cancer (10 %) and bladder cancer (9 %), respectively. One hundred and twenty-two patients (62 %) received a BTA treatment (91 % denosumab). The median treatment duration of a BTA was 178 days (min: 1 day, max: 2010 days). Out of the 197 patients, 47 (24 %) experienced at least one SSE, 100 (51 %) had bone pain. Ten of the 122 patients (8 %) receiving a BTA developed osteonecrosis of the jaw (ONJ). The percentage of patients without an SSE at fixed time points was higher if treated with a BTA (e.g., at 6 months, 92 % [95 % CI: 84 % - 96 %] versus 88 % [95 % CI: 77 % - 94 %]), but no significant difference in time to first SSE (HR 0.69; 95 % CI 0.34–1.39, log-rank p = 0.29) or time to first bone pain (HR: 0.85; 95 % CI: 0.51–1.43, p = 0.54) between these two groups could be detected. There were differences in OS between patients treated with a BTA and patients not treated with a BTA (HR: 1.46; 95 % CI: 1.01–2.10, p = 0.043). ConclusionNo significant difference in time to first SSE or bone pain was observed between patients who have received a BTA or not when treated with immunotherapy. Based on these retrospective results the indication of BTAs to reduce SSEs in cancer patients under treatment with immunotherapy needs further evaluation.

A Prospective Randomised Comparative Study to Evaluate the Effect of Single Dose (6.25Gy Vs 8Gy) Palliative Radiotherapy with Zoledronic Acid in Patients with Painful Bone Metastases

Background: To assess the effectiveness of a single fraction dose of radiotherapy (6.25Gy versus 8 Gy) with zoledronic acid in cancer patients with painful bone metastases in treating pain; quality of life; duration of pain response and incidence of skeletal related events (SREs). Material and methods: A total of 80 patients with bone metastases presented in the department of Radiation Oncology, S.M.S hospital were randomly assigned to: Group A, received single dose of 6.25Gy with Zoledronic acid 4mg and Group B, received single dose of 8Gy with Zoledronic acid 4mg. The main variable was pain which was assessed with 11 point Numeric pain Rating Score (NRS). Results: There were total 80 patients, 40 in each group, with mean age 54.6 years and 54.5 years in group A and B respectively. Most frequent primary malignant sites were lung (36.2%), breast (28.7%), and prostate (8.7%). At 4 weeks post radiotherapy, complete response was 25% in group A, 27.5% in group B and overall response was 82.5% in group A, 85% in group B. At 2 months post radiotherapy complete response was observed in 25% of patients in group A, while 30% in group B and overall response in 85 % in group A and 87.5% in group B. Quality of life improved in both groups. Mean duration of pain relief was 13.5 weeks vs. 14.5 weeks respectively in group A and group B. Conclusion: There was improvement in pain relief and quality of life post radiotherapy in both the groups. On comparison between 2 groups, the overall pain relief was insignificant between the two dose schedules. So a lower dose 6.25Gy is almost as effective as 8 Gy single fractions for treatment of painful bone metastases.

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications.Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset.In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled.SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0–246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309–0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410–0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877–0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396–0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405–0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274–0.718]; P = .001) were associated with a reduced risk of death.SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

Real-world evaluation of access-driven Canadian treatment sequences in progressive prostate cancer (REACTIVATE).

The results of the phase 3 ALSYMPCA trial showed that Radium-223 (Ra-223) improves overall survival (OS) and delays onset of first symptomatic skeletal event vs. placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of the REACTIVATE study was to inform the optimal placement of Ra-233 in the treatment sequence by evaluating clinical outcomes and healthcare resource utilization using real-world data from multiple Canadian provinces. This retrospective cohort study analyzed patient outcomes according to Ra-223 placement using administrative databases of four Canadian provinces, encompassing 4301 patients with mCRPC who received at least two lines of life-prolonging therapy (LPT) for mCRPC. Outcomes included OS, event-free survival (EFS), and healthcare resource utilization. Each province was analyzed separately. OS, measured from the start of second-line LPT, differed between provinces: those in Ontario receiving second-line Ra-223 had a longer OS vs. those receiving it in third-line or later (hazard ratio [HR ] 0.79, 95% confidence interval [CI] 0.66-0.95). There was no difference between lines of therapy in patients in British Columbia (HR 1.165, 95% CI, 0.894-1.518, p=0.2576), and OS was numerically worse but not statistically significant in patients receiving Ra-223 in second-line in Quebec (HR 1.44, 95% CI, 0.93-2.24). Other outcomes also varied across provinces, with second-line use of Ra-223 being associated with longer EFS and reduced healthcare utilization vs. third-line use in Ontario but not in Quebec. Significant heterogeneity exists in the management and outcomes of mCRPC between provinces, particularly regarding the placement of Ra-223 in the treatment sequence.

Bone metastases and skeletal related events in patients with gastrointestinal neuroendocrine tumors.

Bone metastases and skeletal related events in patients with gastrointestinal neuroendocrine tumors.

What Affects Healing Rates in Patients Treated for Medication-Related Osteonecrosis of the Jaw? The Role of Operative Therapy and Other Clinical Factors

BackgroundIn the therapy of medication-related osteonecrosis of the jaw (MRONJ), the healing rate, effectiveness of operative therapy, and factors associated with healing remain unclear. PurposeThis study aimed to estimate MRONJ therapy healing rates and identify associated prognostic factors. Study design, setting, sampleA 25-center prospective cohort study was conducted on 291 patients with MRONJ treated with a common therapeutic protocol during 2013–2016. Patients unable to continue examinations or treatment were excluded. Predictor variableThe primary predictor variable was MRONJ therapy grouped into two categories: operative and nonoperative. Secondarily, the prognostic factors categorized as demographic, medical, clinical, and perioperative were evaluated. Main outcome variablesThe primary outcome variable was treatment duration, defined as the time (in months) between the initiation of therapy and when the site was healed or the date of the final visit or loss to follow-up. CovariatesNot applicable. AnalysesDescriptive statistics and 3-year cumulative healing rates were calculated. The association between clinical factors and time to healing were analyzed using bivariate and multivariate analyses and propensity score analysis. P < .05 was considered significant. ResultsWe analyzed data from 291 subjects with 76 (26.1%) and 215 (73.9%) subjects in the operative and nonoperative therapy groups, respectively. The healing rates for operative and nonoperative therapies were 95.8% and 70.7%, respectively (hazard ratio [HR] = 1.6, 95% confidence interval [CI] = 1.1–2.2, P-value [P] < .01). The healing rates in patients for whom anti-resorptive agent (ARA) treatment was discontinued and continued were 87.2% and 37.4%, respectively (HR = 1.8, 95% CI = 1.1–3.0, P = .02). In a multiple regression analysis using ARA indication, the therapy method showed a significant association in the MRONJ malignancy group (HR = 2.75, 95% CI = 1.46–5.17, P < .01). Conclusions and RelevanceOperative therapy and ARA discontinuation were associated with better healing rates in MRONJ therapy. However, the choice of therapy for MRONJ should be based on a comprehensive consideration of the patient’s condition. ARA discontinuation should be considered an adjunctive measure because of the possibility of adverse events such as fragility fractures and skeletal related events.

Preventing skeletal related events with radiation therapy in cancer patients with bone metastases

Preventing skeletal related events with radiation therapy in cancer patients with bone metastases

Real-world data of efficacy and safety of denosumab on patients with breast cancer with bone metastasis: Results from Chinese clinical experience.

e13103 Background: Bone is the most common metastasis site in advanced metastatic breast cancer disease. Denosumab is advocated by various guidelines with high-quality of evidence for the treatment of breast cancer patients with bone metastases (BM) to delay or reduce the occurrence of skeletal related events (SRE). Data for bone lesion repair after treatment on image is still needed in real world. This retrospective study aims to evaluate the efficacy of denosumab on breast cancer with BM by MD Anderson (MDA) criteria which is specific to BM and its safety in real world. Methods: Data of patients age ≥18 years diagnosed with advanced breast cancer with BM and treated with denosumab from June 1st 2020 to Dec 31st 2022 were retrospectively analyzed. The primary endpoint was the objective response rate (ORR) for bone lesions by MDA criteria in evaluable patients. Secondary endpoints include disease control rate (DCR) for bone lesions, risk of SRE occurrence and safety in total population. Subgroup analysis investigated the impact of the time of denosumab treatment initiation post-diagnosis of BM as well as the duration of treatment with denosumab on efficacy. Comparative analysis was performed using Chi-squared test and a p value of &lt;0.05 was considered statistically significant. Results: Atotal of 185 patients were enrolled with median age of 52.45 (SD: 12.02) years. The median follow-up time was 25.2 months. 49 out of the 130 evaluable patients achieved partial response, resulting in an ORR of 37.69% (95% CI: 0.29-0.47), and a DCR of 90% (95% CI: 0.84-0.95). 16 out of 185 (8.65%) patients developed SRE after denosumab treatment with the median time to the first occurrence of SRE not reached. The ORR and DCR for bone lesions of starting denosumab after diagnosis of BM in ≤3 months vs. &gt;3 months were 31.54% vs. 6.15% (p&lt;0.001) and 68.46% vs. 21.54% (p&lt;0.001), respectively. The ORR and DCR for bone lesions of the duration of denosumab treatment &lt;6 months vs. ≥6 months were 4.62% vs. 33.08% (p&lt;0.001) and 37.69% vs. 76.92% (p&lt;0.001), respectively. Renal function impairment decreased from 33 patients before treatment to 8 patients post-treatment, while hypocalcemia increased from 1.62% to 11.35%. Osteonecrosis of the jaw occurred in one patient (1/185,0.54%) post-treatment. Conclusions: Denosumab was found to be effective and safe for breast cancer patients with BM in this large retrospective study. Early initiation and longer duration of denosumab treatment may generate better clinical outcomes for bone lesions by MDA criteria.

The Effect of Thyrotropin Suppression on Survival Outcomes in Patients with Differentiated Thyroid Cancer: A Systematic Review and Meta-Analysis.

Background: Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. Methods: We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (≥18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Results: Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; I2 = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; I2 = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; I2 = 0%). Significant study heterogeneity was noted for primary outcomes. Conclusion: TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings. Registration: PROSPERO #252396.

Abstract PO4-07-11: FDG-PET is superior to bone scintigraphy for the detection of bone metastases in breast cancer patients

Abstract Background: Bone is the commonest site for metastases in breast cancer patients, with up to 44% of patients having bone as their sole site of metastatic disease. Patients are at increased risk of morbidity from skeletal related events (SRE) from bone metastases due to pathological fractures and spinal cord compression. Early diagnosis is crucial so that bone modifying agents can be used to prevent SREs and other agents such as CDK4/6 inhibitors can be considered. Bone scintigraphy is the most widely performed first investigation for patients at high risk or symptomatic from bone metastases. Methods: We performed a meta-analysis comparing FDG-PET and bone scintigraphy using PubMed, Science Direct, and Embase for the literature search. 1009 patients were included in the study. Data for 2 × 2 contigency tables was selected and QUADAS-2 was used for quality assessment. Diagnostic accuracy was performed using Graph pad Prism 9.5.1 and R studio 2022. Pooled sensitivity and specificity of FDG-PET/CT was 96.6% (95% CI=91.5%-98.7%) and 96.8% (95% CI=82.1%-99.5%) respectively. Respective results for BS were 88.3% (95% CI=79.8%-93.5%) and 81.3% (95% CI=63.1%-91.7%). Sensitivity and specificity of FDG-PET/CT was significantly higher than BS (P=0.0063, P= 0.0068, respectively). The diagnostic odds ratio and area under ROC curve were significantly higher for FDG-PET/CT than BS (654.36 vs 35.24, and 0.980 vs 0.877, respectively). Conclusion: FDG-PET is superior to bone scinitigaphy for the detection of bone metastases in breast cancer.The benefits of replacing BS with FDG-PET/CT are evident. However othere technologies such as DW-MRI should be considered. Large multicentre prospective trials with strict FDG-PET/CT imaging protocols compared to DW-MRI both for disease detection and monitoring of response are required to strengthen the evidence in this field, to help inform imaging guidelines and best practices in the future. Newer technologies such as [18F]estradiol (FES)-PET and [18F]GE-226 for HER2 expression also warrant further investigation in ER positive and HER2 positive breast cancer. Citation Format: Laura Kenny, Maisher Tin-U. FDG-PET is superior to bone scintigraphy for the detection of bone metastases in breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-07-11.

Abstract PO1-02-13: Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA)

Abstract Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA) Background: There is accumulating evidence that the RANK/RANKL signaling pathway plays a pivotal role in breast tumorigenesis, particularly in the development of BRCA1-mutated tumors. Targeting the RANK pathway has been shown to attenuate breast cancer (BC) proliferation in vitro and in vivo. Studies using bone modifying agents as adjuvant therapy showed reduced rates of bone metastases and improved BC survival, as well as prevention of treatment-induced skeletal events. The GeparX clinical trial assessed the use of denosumab in patients with primary BC as an adjunct to neoadjuvant chemotherapy for its ability to enhance pathological complete response (pCR) rate and improve outcome. The trial randomized 780 patients twice to a total of 4 treatment groups (to receive or not receive denosumab; to receive nab-paclitaxel 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles, both followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 every 2 weeks/every 3 weeks according to the investigator´s choice). Carboplatin was given in triple-negative breast cancer (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in human epidermal growth factor-2-positive (HER2+) BC. Overall, the pCR (ypT0 ypN0) rate was 41% with denosumab vs 43% without; nab-paclitaxel at a dosage of 125 mg/m2 weekly resulted in a significantly higher pCR rate of 45% vs 39% with a dosage of 125 mg/m2 days 1 and 8 every 3 weeks. Research question: Does the germline mutation status of BRCA1/2 and other BC predisposition genes affect treatment outcome in the GeparX study? Methods: Genetic germline analyses assessing pathogenic variants in BRCA1/2 and 16 other BC predisposition genes were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany; 767 patients were included in this secondary investigation (308 TNBC, 306 HER2-/hormone receptor positive [HR+], 153 HER2+). Findings: Germline BRCA1/2 mutations were present in 91/767 patients (11.9%), with a higher mutation prevalence in TNBC (50/308, 16.2%) and HER2-/HR+ BC (37/306, 12.1%), and a low mutation prevalence in HER2+ BC (4/153, 2.6%). Overall, the pCR rate (ypT0 ypN0) was elevated in BRCA1/2 mutation carriers vs non-carriers (49.5% vs 41.1%, respectively; overall: OR 1.40, 95% CI 0.90-2.17; TNBC: OR 1.24, 95% CI 0.67-2.32; HER2-/HR+: OR 1.83, 95% CI 0.86-3.88). Highest pCR rates were observed in TNBC in BRCA1/2 mutation carriers vs non-carriers (60% vs. 54.7%, respectively). Highest pCR rate differences were observed HER2-/HR+ BC in BRCA1/2 mutation carriers vs non-carriers (32.4% vs. 20.8%, respectively). Regarding treatment arms, both BRCA1/2 mutation carriers and non-carriers benefitted most from nab-paclitaxel at a dosage of 125 mg/m2 weekly vs 125 mg/m2 days 1 and 8 every 3 weeks (BRCA1/2 mutation carriers: 55.3% vs 43.2%, respectively; OR 1.63, 95% CI 0.71-3.73; non-carriers: 43.7% vs 38.6%, respectively; OR 1.24, 95% CI 0.91-1.68). No beneficial effect was observed for denosumab vs no denosumab (51.1% vs 47.8% for BRCA1/2 mutation carriers, respectively; OR 1.14, 95% CI 0.50-2.60; 40.3% vs 41.9% for non-carriers, respectively; OR 0.94, 95% CI 0.69-1.27). Of the 617 BRCA1/2-negative patients, 59 patients carried mutations in other BC predisposition genes which did not predict therapy response compared to patients without any mutation. Conclusions: Irrespective of the treatment arm, higher pCR rates were observed in BRCA1/2 mutations carriers vs non-carriers. Both BRCA1/2 mutation carriers and non-carriers benefitted most from weekly nab-paclitaxel. No pronounced effect was observed for denosumab in either group. Key words: GeparX, denosumab, BRCA1/2 germline mutations, therapy response Funding: GeparX was financially supported by Amgen and BMS (Celgene). Citation Format: Rita K. Schmutzler, Theresa Link, Eric Hahnen, Mattea Reinisch, Jan Hauke, Marianne Just, Michael Untch, Corinna Ernst, Oliver Stötzer, Peter A. Fasching, Mohamad Kayali, Pauline Wimberger, Andreas Schneeweiss, Sandra Schmidt, Sabine Seiler, Christian Jackisch, Marc Thill, Kerstin Rhiem, Carsten Denkert, Valentina Nekljudova, Johannes Holtschmidt, Jens-Uwe Blohmer, Sibylle Loibl. Germline mutation status of BRCA1/2 and other breast cancer predisposition genes as predictive and prognostic biomarker: Results of the GeparX study (GeparX-BRCA) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-13.

KNOWLEDGE PRODUCTS TO HELP EXERCISE PROFESSIONALS IMPLEMENT EXERCISE RECOMMENDATIONS FOR PEOPLE WITH BONE METASTASES: CO-DESIGN OF A HEALTH INFORMATION FORM

INTRODUCTION People with bone metastases have historically been advised to limit exercise due to risk of skeletal adverse events, such as bone fracture. Published recommendations by the International Bone Metastases Exercise Working Group (IBMEWG) emphasize regular exercise may benefit people with bone metastases; however, there are barriers to adopting these guidelines into clinical practice. For example, exercise professionals (EPs) report challenges obtaining necessary medical information about bone metastases to develop/design safe exercise programs. To address this, a Health Information Form (HIF) was developed using an experience-based co-design approach with three knowledge user (KU) groups: patient/family partners (PFPs), oncology healthcare providers (HCPs), and EPs. The aim of this study was to gather feedback from an international audience on the usability of the HIF. METHODS An online survey was advertised widely to KU groups using a social media toolkit and targeted email invitations to professional organizations. Questions included demographic information, usability of the HIF, and suggestions for dissemination. Analysis of survey responses was descriptive. RESULTS 69 respondents from North America (71%), Europe (20%), and Australasia (9%) provided feedback on the HIF. Most were EPs (54%) or PFPs (36%), and half (54%) had some awareness of the IBMEWG exercise recommendations. 81% of respondents found the purpose of the HIF easy to understand and 77% rated the content as excellent or very good. The design was rated as excellent or very good by 62% with feedback such as “… covers a lot of areas in a way that is brief and effective”. 14 respondents suggested information that could be added to the HIF (e.g., fracture risk factors, recent surgeries). CONCLUSION Overall, the HIF was well received by an international audience. The feedback provided by respondents will be utilized to enhance both the design and content of the form.

Acute Hypoxia Following Disuse Atrophy in Aged Mice Enhances Cellular Remodeling and Whole-body Strength During Early Recovery

Age-related impairments in muscle recovery following disuse atrophy are associated with altered macrophage metabolism and blunted inflammatory function. HIF-1α is a key regulator of macrophage metabolism and inflammatory function. Therefore, we investigated the effects of acute hypoxia on muscle recovery following disuse in aging. We hypothesized that transient hypoxic exposure following disuse in aged mice would enhance macrophage metabolism and inflammatory status, resulting in improved muscle cellular remodeling and recovery. Accordingly, old (~20 months) and young adult male mice (~4 months) were exposed to acute (24 hours) normobaric hypoxia (8% O2) immediately following 14-days hindlimb unloading. We characterized muscle phenotype and function during early recovery (4- and 7-days) with and without hypoxia exposure. We found that acute hypoxia stimulated the expression of inflammatory (TNF-α, VEGF p&lt;0.01) and glycolytic transcripts (PFK-1 p&lt;0.05), LDH, PDH p=0.08) downstream of HIF-1α in aged skeletal muscle under basal conditions. Following disuse atrophy, transient hypoxic exposure enhanced macrophage inflammatory function, indicated by increased phagocytosis capacity (p&lt;0.01), and promoted early skeletal muscle cellular remodeling events, including enhanced muscle satellite cell content (p&lt;0.05). Furthermore, these effects facilitated the recovery of whole-body strength in aged mice indicated by a return to baseline values (p&gt;0.05). The results of this investigation suggest that hypoxic exposure following disuse atrophy promoted inflammatory macrophage function, muscle cellular remodeling, and enhanced early recovery in aged mice. These findings elucidate the potential benefits of hypoxia in manipulating macrophage function to ameliorate age-related deficits in muscle recovery following disuse atrophy. This research was supported by R01AG076075 (MJD) and the National Institutes of Health Ruth L. Kirschstein National Research Service Award 5T32DK091317 from the National Institute of Diabetes and Digestive and Kidney Diseases. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Current state of theranostics in metastatic castrate-resistant prostate cancer.

Prostate cancer remains one of the leading causes of cancer-related death in the world. There have been significant advances in chemotherapy, hormonal therapy and targeted therapy options for patients with castrate-resistant disease. However, these systemic treatments are often associated with unwanted toxicities. Targeted therapy with radiopharmaceuticals has become of key interest to limit systemic toxicity and provides a more precision oncology approach to treatment. Strontium-89, Samarium-153 EDTMP and Radium-223 have been trialled with mixed results. Strontium-89 and Samarium-153 EDTMP have shown benefits in palliating metastatic bone pain but with no impact on survival outcomes. Early therapeutic radiopharmaceuticals targeting PSMA that were developed were beta-emitting agents, but recently alpha-emitting agents are being investigated as potentially superior options. Radium-223 is the first alpha-particle emitter therapeutic agent approved by the FDA, with phase III trial evidence showing benefits in overall survival and delay in symptomatic skeletal events for patients. Recently, 177-Lutetium-PSMA-617 has demonstrated significant survival advantages in pre-treated metastatic castrate-resistant cancer patients in a number of phase II and III studies. Furthermore, 225-Actinium-PSMA-617 also showed promise even in patients pre-treated with 177-Lutetium-PSMA-617. Hence, there has been an explosion of radiopharmaceutical treatment options for patients with prostate cancer. This review explores past and current theranostic capacities in the radiopharmaceutical treatment of metastatic castrate-resistant prostate cancer.