Jones, C. F.

Abstract Introduction: Breast cancer most commonly metastasizes to the bones, with bone pain and other skeletal related events (SREs) having a limiting effect on quality of life. Bisphosphonates are widely used in breast cancer patients to reduce SREs and bone loss, particularly in those with bone metastases or receiving endocrine therapy. We aim to study the real world comparative data between two widely used bisphosphonates in clinical practice, zoledronic acid and pamidronate, along with evaluation of their toxicity profiles. Methods: A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, and encompassing data from 105 global healthcare organizations. Female patients aged 18 and above with breast cancer metastatic to the bone were identified and then stratified into two groups based on treatment with zoledronic acid or pamidronate. The two groups were then propensity-matched based on age, sex, race, and comorbidities. We followed these patients for 5 years to assess outcomes, including mortality, osteoporotic fracture, hypercalcemia, pathological fracture, fall, and osteonecrosis. Results: We identified 7887 patients in the zoledronic acid cohort and 635 patients in the pamidronate cohort. After propensity matching, each cohort consisted of 625 patients with similar baseline characteristics. The average age was 66.4 years in zoledronic acid cohort and 69.1 in the pamidronate cohort. In the zoledronic acid cohort, the ethnicity distribution was 74.68 % White, 11.55% African American, and 6.36% Hispanic. In contrast, the pamidronate group had an ethnicity distribution of 63.04% White, 20.64% African American, and 8.16% Hispanic. Our analysis found that within 5 years, patients with breast cancer metastatic to the bone who received zoledronic acid had a significantly lower risk of mortality (Hazard Ratio [HR] 0.593, 95% CI: 0.509-0.691, p-value <0.001), osteoporotic fracture (Risk difference: -5.28%, 95% CI: -7.65 to -2.90), p-value < 0.001), hypercalcemia [HR: 0.262, 95% CI: 0.212 - 0.323, p-value = 0.001), pathological fracture (Risk difference: -6.88%, 95% CI: -10.69 to -3.07), p-value < 0.001). However, the zoledronic acid group had higher risk of falls [Risk difference: 3.52%, 95% CI: 0.518 to 6.522), p-value = 0.021). There was no statistically significant difference in the occurrence of osteonecrosis between the two cohorts. Conclusion: Our study revealed that patients with breast cancer with metastatic disease to the bone who received zoledronic acid had significantly lower rates of mortality, osteoporotic fracture, hypercalcemia, and pathological fracture compared to those receiving pamidronate. Additional longitudinal cohort studies are imperative to explore the outcomes between these agents and inform clinical practice guidelines. Citation Format: Y. Arya, A. Syal, C. Jones, H. Mahadevia, N. Batra, A. Uriepero-Palma. Real-world outcomes comparing zoledronic acid and pamidronate in patients with metastatic breast cancer with bone metastases: A propensity score matched analysis from a global federated health research network [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-06-02.

Abstract Introduction: Patients with metastatic breast cancer frequently develop bone metastases and experience other skeletal-related events (SREs). These complications substantially impair quality of life and may negatively influence clinical outcomes. In this context, bisphosphonates and denosumab are the most commonly utilized therapeutic agents. We aim to study the real-world comparative data between bisphosphonates and denosumab in breast cancer patients with bony metastases along with evaluation of their toxicity profiles. Methods: A retrospective cohort study was conducted using the US Collaborative Network, TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Female patients aged 18 and above with breast cancer metastatic to the bone were identified and then stratified into two groups based on treatment with zoledronic acid or pamidronate. The two groups were then propensity-matched based on age, sex, race, and comorbidities. We followed these patients for 5 years to assess outcomes, including mortality, osteoporotic fracture, hypercalcemia, pathological fracture, fall, and osteonecrosis. Results: We identified 7887 patients in the zoledronic acid cohort and 635 patients in the pamidronate cohort. After propensity matching, each cohort consisted of 625 patients with similar baseline characteristics. The average age was 66.4 years in the zoledronic acid cohort and 68.5 in the denosumab cohort. In the zoledronic acid cohort, the ethnicity distribution was 74.68 % White, 6.36% Hispanic, and 11.55% African American. In comparison, the denosumab group had an ethnicity distribution of 74.49% White, 10.31% African American, and 5.68% Hispanic. Our analysis found that within 5 years, patients with breast cancer metastatic to the bone who received zoledronic acid had a significantly lower risk of mortality (Risk difference: -3.49%, 95% Confidence Interval [CI]: -5.063 to -1.916), p-value <0.001) compared to denosumab. However, patients in the zoledronic acid arm were noted to have a higher risk of osteoporotic fracture (Risk difference: 0.817%, 95% CI: 0.232 to 1.402), p-value = 0.006), hypercalcemia [Hazard Ratio [HR]: 1.524, 95% CI: 1.407 to 1.65, p-value <0.001), and pathological fracture (HR: 1.501, 95% CI: 1.349 to 1.671), p-value =0.03). There was no significant difference in the occurrence of falls and osteonecrosis between the two subgroups. Conclusion: Our study revealed that patients with breast cancer with metastatic disease to the bone who received zoledronic acid had significantly lower rates of mortality but higher occurrence of osteoporotic fracture, hypercalcemia, and pathological fracture compared to those receiving denosumab. Additional longitudinal cohort studies are imperative to explore the outcomes between these agents and inform clinical practice guidelines in these patients. Citation Format: A. Syal, Y. Arya, C. Jones, H. Mahadevia, N. Batra, A. Uriepero Palma. Real-world outcomes comparing zoledronic acid and denosumab in patients with metastatic breast cancer and bone metastases: A propensity score matched analysis from a global federated health research network [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-17.

Abstract Introduction: Endocrine therapy (ET) is central to treating hormone receptor-positive breast cancer (BC), but its side effects impact adherence and quality of life, especially in patients with metabolic dysfunction. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer cardiometabolic benefits, potentially improving inflammation, glycemic control, and physical well-being. However, data on SGLT-2 use in BC patients is scarce. This study is the first to evaluate the real-world effects of SGLT-2 inhibitors on all-cause mortality and ET tolerability in BC patients. Methodology: We conducted a real-world analysis using the TrinetX database, which includes data from 184 million patients in 156 healthcare organizations, to identify BC patients on ET (letrozole, anastrozole, exemestane, tamoxifen) who received SGLT-2 inhibitors vs. those who did not. Patients were grouped by age (≤50 and ≥51 years as a surrogate for menopausal status. Primary outcome: all-cause mortality from the start of the index event, defined as the first day meeting BC diagnosis and ET use, with or without SGLT-2. Secondary endpoint: ET tolerability. Propensity score matching completed by TriNetX adjusted for confounders. Multivariate analysis yielded odds ratios and risk differences with 95% CI. Results: Among 1,136 BC patients ≤50 years, 568 were assigned to each group (SGLT-2 vs non-SGLT-2). For patients ≥51 years (n=28,600), each group included 14,300. Demographics across cohorts were comparable. No mortality benefit was seen in premenopausal patients. In postmenopausal women, SGLT-2 use reduced all-cause mortality—647/13,676 events (SGLT-2) vs 953/13,517 (non-SGLT-2) [OR: 0.655 (0.591-0.726)]. In premenopausal patients, SGLT-2 reduced endometrial cancer risk [RD: -0.018 (-0.029, -0.007)] but increased diarrhea risk [OR: 2.305 (1.078, 4.930)]. No significant differences were found in hot flashes, PE, DVT, depression, osteoporosis, joint pain, fatigue, nausea/vomiting, abdominal pain, or dizziness. Among postmenopausal patients, SGLT-2 reduced PE [OR: 0.757 (0.605-0.948)] and osteoporosis [OR: 0.877 (0.784-0.981)], but increased risks of depression [OR: 1.153 (1.007-1.319)], nausea/vomiting [OR: 1.120 (1.001-1.253)], diarrhea [OR: 1.193 (1.058-1.345)], and dizziness [OR: 1.234 (1.103-1.380)]. No significant differences were found for hot flashes, DVT, EC, joint pain, fatigue, or abdominal pain. Conclusion: This analysis reveals novel evidence supporting the cardiometabolic potential of SGLT-2 inhibitors in hormone receptor-positive BC, particularly postmenopausal populations. These agents were linked to lower all-cause mortality and improved tolerance of specific ET-related effects. However, certain adverse risks require caution. Future prospective studies are essential to validate their role and safety in oncologic care. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Evaluating all-cause mortality and endocrine therapy tolerability with sodium glucose cotransporter-2 inhibitors in hormone receptor-positive breast cancer: A real-world analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-05-28.

Abstract Introduction: Endocrine therapy (ET) improves survival in hormone receptor-positive breast cancer (BC) but has side effects that may affect compliance. GLP-1 receptor agonists (GLP-1 RA), used for diabetes and obesity, possess anti-inflammatory properties and may reduce cancer incidence. Their impact on all-cause mortality and ET tolerability remains underexplored. This real-world analysis is the first of its kind to examine the effects of GLP-1 RA on these outcomes. Methods: We used de-identified data across 130 million patients and 108 health systems from the TriNetX database to identify obese women (BMI ≥30) with BC receiving ET. Patients were grouped by GLP-1 RA exposure into age cohorts (≤50 and ≥51 years, as a surrogate for menopause). The primary endpoint was all-cause mortality; the secondary endpoint was ET tolerability. The index event was the first day meeting all criteria: BC and obesity diagnoses, and initiation of ET ± GLP-1 RA. Patients with outcomes before the study window were excluded. Propensity score matching performed by TriNetX adjusted for demographics, diabetes, comorbidities, cancer stage, and prior chemotherapy. Multivariate logistic regression assessed associations (risk ratios [RR], 95% CIs). Results: After matching, 2,574 patients were assigned to the age ≤50 group: Cohort A (GLP-1 RA exposure, n=1,287) and Cohort B (non-exposure, n=1,287). 13,012 patients were in the age ≥51 group: Cohort C (GLP-1 RA exposure, n=6,506) and Cohort D (non-exposure, n=6,506). In the ≤50 group, the mean age at index event was 42.3 ± 5.2, 99.5% female, 68.9% White, 16.9% Black, and a mean BMI of 37 in Cohort A, with similar demographics and BMI in Cohort B. In the ≥51 group, there was a mean age at index event of 61.8 ± 7.7, 99% female, 71.7% White, 17.4% Black, and a mean BMI of 37 in Cohort C with similar demographics and BMI in Cohort D. GLP-1 RA use significantly reduced all-cause mortality in all cohorts. In the age ≤50 group, there were 29/1,242 events in Cohort A and 71/1,258 in Cohort B [RR 0.414 (0.271-0.633)]. In the age ≥51 group, there were 240/6,287 events in Cohort C and 400/6,285 in Cohort D [RR 0.600 (0.513-0.701)]. GLP-1 RA use worsened ET side effects. In the age ≤50 group, GLP-1RA increased the risk of hot flashes [RR: 1.473 (1.235-1.756)], venous thromboembolism (VTE) [RR: 1.439 (1.090-1.902)], nausea/vomiting [RR: 1.460 (1.242-1.717)], abdominal pain [RR: 1.353 (1.184-1.545)], diarrhea [RR: 1.319 (1.096-1.589)], joint pain [RR: 1.382 (1.243-1.536)], and depression [RR:1.634 (1.382-1.932)]. No significant risk was found in endometrial cancer (EC) and osteoporosis. In the age ≥ 51 group, GLP-1 RA use increased hot flashes [RR: 0.1.239 (1.091-1.407)], [RR:0.591 (0.482-0.724)], nausea/vomiting [RR: 1.429 (1.324-1.542)], abdominal pain [RR: 1.310 (1.227—1.399)], diarrhea [RR: 1.446 (1.328-1.575)], joint pain [RR: 1.334 (1.270-1.400)], osteoporosis [RR: 1.110 (1.026-1.201)], and depression [RR: 1.536 (1.413-1.670)]. No significant differences were noted in VTE and EC risk. Conclusion: This real-world analysis demonstrates that GLP-1RA use is associated with a significant reduction in all-cause mortality among obese BC patients undergoing ET. However, GLP-1 RA exposure appears to exacerbate several ET-related adverse effects. Future prospective studies are needed to determine these associations as they may warrant clinical consideration. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Real-world Analysis on the Impact of GLP-1 Receptor Agonists on All-cause Mortality and Endocrine Therapy-Tolerability in Obese Breast Cancer Patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD8-06.