Abstract P2-05-12: Effects of de-escalated bisphosphonate therapy on bone turnover or metastasis markers and their correlation with risk of skeletal related events – A biomarker analysis in conjunction with the REFORM study.
Authors: Addison CL , Zhao H , Mazzarello S , Mallick R , Amir E , Tannock I , Clemons M 
Published: August 2014

Abstract
Background: Despite variability in an individual's risk of skeletal related events (SREs) from bone metastases (BM), all patients are treated using a similar dose and schedule (q3-4 wk) of IV bisphosphonate (BP). The REFORM trial (Amir et al., Am J Clin Oncol, in press) was a pilot randomised study evaluating the efficacy of de-escalated (q12 wk) versus standard (q3-4 wk) pamidronate in maintaining C-telopeptide (CTx) levels in the low risk range (&lt;600ng/L) in patients with BM from breast cancer. Here we report a biomarker substudy, where additional biomarkers of bone turnover and BM behaviour were measured and correlated with SRE risk.
Methods: Eligible patients with BM, who had received ≥ 3 months of q3-4 wk IV BP and no systemic treatment change within 4 wks of study entry were enrolled. Serum & urine obtained at baseline and at 12 wks were assessed for urinary N-telopeptide (uNTx), serum procollagen type I amino-terminal propeptide (P1NP), transforming growth factor (TGF)-β, activinA and bone sialoprotein (BSP) by ELISA. Levels were correlated with number of SREs using linear regression analysis. Changes in biomarkers from baseline to 12 wks were used to calculate odds ratios for coming off study (due to either elevated CTx or SRE) or having an SRE alone using logistic regression analysis.
Results: REFORM randomized 19 patients to each treatment arm, and found that the SRE rate at 1 year in both arms was the same (n = 2). Although the mean level of the standard bone turnover marker CTx decreased slightly from baseline to wk 12 in the q3-4 wk group (240±50ng/L to 206±46ng/L), and slightly increased in the q12 wk treated group (263±65ng/L to 313±71ng/L), these changes were not statistically significant (p = 0.8). Mean activinA levels were slightly increased in both treatment arms from baseline to wk 12 (730±93pg/ml to 875±148pg/ml in q3-4 wk group vs 445±35pg/ml to 582±61pg/ml in q12 wk group) but did not quite reach statistical significance (p = 0.1). Levels of TGF-β from baseline to 12 wks in both groups was similar (22±1.6ng/ml to 22±2.3ng/ml for q3-4 wk vs 23±2.2ng/ml to 24±2.4ng/ml for q12 wk group, p = 0.8). Although the number of SREs was small, mean CTx levels at wk 12 were statistically different between patients who experienced SREs vs those that did not (615±72ng/L, n=4 vs 190±26ng/L, n=19, p &lt; 0.0001). Although it did not reach statistical significance, mean activinA levels at wk 12 were also higher in patients who had SREs than those that did not (1069±358pg/ml, n=3 vs 681±83pg/ml, n=18, p = 0.12). Results of NTx, BSP and P1NP and correlations with more mature clinical data will also be presented.
Conclusions: In patients with BM from breast cancer with low levels of bone resorption markers, CTx predicted and activinA trended to predict SRE risk. However the non-significant trends in increasing CTx in de-escalated BP treatment, together with the observation that activinA levels are similar regardless of dosing regimen, suggest that analysis of conventional and experimental biomarkers of SRE risk requires further examination in other larger patient cohorts comparing de-escalated therapy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-12.