Abstract P1-18-02: Impact of the metastatic compartment on bone biomarkers and bone outcomes in patients (pts) with breast cancer (BC) and bone metastases (BM) in trial NCT00321464 of denosumab vs. zoledronic acid
Authors: Ferreira AR , Casimiro S , Ali S , Leitzel K , Lipton A , Costa L 
Published: May 2019

Abstract
Background: Bone is the most common site of metastatic disease in pts with BC, and BM are frequently associated with skeletal related events (SRE), as, e.g., bone pain or fracture. Bone targeted agents (BTAs; denosumab or zoledronic acid) decrease the rate of SREs. Previous exploratory studies in pts with BM showed that the site of metastatic disease (bone-only disease [BO] vs. bone + extraskeletal disease [BES]) might impact both bone remodeling (reflected in the concentration of bone biomarkers) and the risk for SREs. In this large study of pts with BC and BM, we assessed bone biomarkers after the introduction of BTAs, time to first and subsequent on-study SRE/symptomatic SRE (SSE), and bone pain score variation according to metastatic compartment (BO vs. BES).
Methods: This is a retrospective analysis of the prospective, multicenter, randomized, registration clinical trial of denosumab vs. zoledronic acid in pts with BC and BM (NCT00321464). Study outcomes were variation of corrected urinary N-terminal telopeptide (uNTX) and bone alkaline phosphatase (bALP) at 3 months, time to first and subsequent SRE and SSE, and brief pain inventory (BPI) scores over time. Chi-squared test and t-test were used to compare biomarkers levels. We used the Kaplan-Meier method to describe time to event outcomes and differences were tested using the Cox proportional hazard model and Andersen–Gill model for multiple failure-time data. BPI scores were compared using mixed linear models.
Results: A cohort of 2046 pts was identified, 969 (47.4%) with BO and 1077 (52.6%) with BES, all treated with either denosumab or zoledronic acid. Median follow-up was 20.1 months (interquartile range 15.9-23.8; balanced between arms). Compared to pts with BO, those with BES were more frequently hormone receptor negative (20.9 vs. 15.1%) and HER2-positive (31.0 vs. 23.4%). The number of BM was similar in both groups, but those with BES had less previous SRE (31.7 vs. 42.2%). Pts with BES were more commonly treated with chemotherapy (84.0 vs. 77.5%), but less frequently with radiotherapy (59.7 vs. 65.9%) or surgery (85.0 vs. 88.1%). Absolute levels of uNTX and bALP at baseline and at 3 months, as well as normalization rates, did not differ between groups. However, when compared to those with BO and after controlling for unbalanced clinicopathological and treatment features, pts with BES presented a lower risk of first and subsequent SREs (adjusted-hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.58 – 0.94; p=0.013) and first SSE (adjusted-HR 0.75; 95% CI 0.60 – 0.94; p=0.014). Hazard rates for SRE were higher in the first 6 months of treatment. Despite the small magnitude, pts with BO consistently showed slightly higher BPI scores (+0.2 points; p=0.014). Pts with BES had a shorter OS (HR 1.97, 95% CI 1.66 – 2.33).
Conclusion: Despite the consistent reduction in uNTX and bALP in pts with BC and BO or BES disease, pts with BO disease had a higher risk for SREs and higher pain score. Hazard rates for SREs were greater in the first 6 months of treatment. Strategies of treatment de-escalation of BTAs should consider the metastatic compartment and time variation of the hazard for SRE.
Citation Format: Ferreira AR, Casimiro S, Ali S, Leitzel K, Lipton A, Costa L. Impact of the metastatic compartment on bone biomarkers and bone outcomes in patients (pts) with breast cancer (BC) and bone metastases (BM) in trial NCT00321464 of denosumab vs. zoledronic acid [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-02.