Abstract PS3-08-19: Evaluation of stable calcium isotope ratios in women undergoing neoadjuvant chemotherapy (NACT) with and without denosumab (GeparX)

Abstract Background: Blood and bone Ca isotope compositions are in isotopic equilibrium. During equilibrium between bone material absorption and resorption the blood Ca isotope composition remains stable. However, when bone resorption is persistently greater than bone absorption, as seen in osteoporosis, the blood Ca isotope ratio decreases. This indicates a net shift of calcium from the bone into the blood. The calcium isotope marker (CIM) is a novel biomarker that sensitively detects changes in bone calcium balance in humans. For the first time, this study aims to evaluate the effects of neoadjuvant chemotherapy (NACT), with and without denosumab (Dmab), on bone calcium balance in postmenopausal women with early breast cancer enrolled in the GeparX trial (NCT02682693). Methods: This analysis was conducted on a predefined cohort of the patients (pts) enrolled in the GeparX trial (Blohmer, JAMA Oncol. 2022), specifically including postmenopausal pts with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer who received NACT with weekly nab-paclitaxel followed by epirubicin/cyclophosphamide. Patients included in this cohort were randomized to receive Dmab or not in addition to NACT. Eligible pts had two serum samples available: one prior to treatment and one after completion of NACT. In total, 20 pts included in this study were treated in the NACT + Dmab arm and 29 received NACT alone. Paired serum samples (collected before therapy and before surgery) were analyzed for CIM ratios. Results: A total of 98 serum samples were tested for CIM serum levels and valid measurements were obtained for all. Pre-treatment mean CIM values were comparable in both cohorts (mean±SD -0.87±0.16 ‰ vs. -0.94±0.19 ‰; p=0.115; without vs. with Dmab, respectively), indicating a net loss of calcium; however, the difference was not statistically significant. In pts treated with NACT alone, a significant decrease in CIM-serum levels to -1.02±0.17 ‰ was detected signifying bone calcium loss (p<0.001) and osteoporotic situation. In contrast, pts treated in the Dmab arm had a significant increase in CIM-serum levels reaching a mean of -0.61±0.18 ‰ (p<0.001), indicating a net accumulation of calcium and new bone formation. No relationship between CIM levels and pathologic complete response was observed. Pre-treatment levels of CIM showed a mild positive correlation with age (slope = 10.9; R2 = 0.10) and body mass index (BMI) (slope = 4.3; R2 = 0.04). Post-treatment, the CIM levels showed a reverse trend with a mild negative correlation for age (slope = -5.4; R2 =0.06) and no correlation with BMI (slope = 0.11; R2 = 0). Within the post-treatment cohort, however, age and BMI showed contrasting weak correlations with CIM levels in relation to treatment with Dmab: there was a negative correlation with age for pts who did not receive Dmab (slope = -5.54; R2 = 0.03), and a positive correlation with age for pts who did (slope = 13.03; R2 = 0.12); there was no correlation with BMI for pts who did not receive Dmab (slope = -0.02; R2 = 0), and a positive correlation with BMI for pts who did (slope =9.82; R2 = 0.19). Hence, Dmab was associated with improved bone mineralization post-treatment, particularly in older pts and those with higher BMI. Conclusion: Analyses of CIM serum levels provide critical insights into the extent of bone mineral loss induced by NACT in postmenopausal pts with HR+/HER2− breast cancer. Concurrent administration of Dmab appears to mitigate this effect by promoting bone mineralization. CIM serum levels may serve as a valuable, easily measurable biomarker for monitoring bone mineral balance in patients undergoing chemotherapy for breast cancer, enabling early intervention in case of bone mass loss and preventing osteoporosis. Citation Format: M. T. van Mackelenbergh, T. Link, C. Doering, T. Karn, S. Rachakonda, M. Thill, C. Denkert, B. Heinrich, V. Müller, P. Krabisch, F. Marmé, C. Salat, A. Noske, V. Nekljudova, B. Felder, J. Blohmer, S. Loibl, A. Eisenhauer. Evaluation of stable calcium isotope ratios in women undergoing neoadjuvant chemotherapy (NACT) with and without denosumab (GeparX) [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 PS3-08-19.