Effects of de-escalated bisphosphonate therapy on bone turnover biomarkers in breast cancer patients with bone metastases.

Christina L Addison,Gregory R Pond,Sasha Mazzarello,Eitan Amir,Mark Clemons,Lisa Vandermeer,Huijun Zhao,Robyn Goldstein

doi:10.1186/2193-1801-3-577

Christina L Addison, Gregory R Pond + Show 6 more

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https://doi.org/10.1186/2193-1801-3-577

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Abstract

While de-escalation of bisphosphonates from 4 to 12-weekly dosing has been shown to be clinically non-inferior to standard dosing, there is evidence the de-escalation is associated with increased bone turnover biomarkers. Here we evaluated the effect of de-escalated dosing on a panel of biomarkers and determined their association with incidence of skeletal related events (SREs) in breast cancer patients with ‘low risk’ bone metastases. As part of a pilot randomized trial, women with baseline C-telopeptide levels <600 ng/L after >3 months of 3–4 weekly pamidronate were randomized to continue pamidronate every 4 weeks or de-escalation to 12-weekly treatment. Serum was analysed for bone biomarkers (C-telopeptide, N-telopeptide, bone-specific alkaline phosphatase, transforming growth factor-β, procollagen type 1 N-propeptide, activinA and bone sialoprotein) using ELISA. The associations between changes in biomarkers, pain scores and SREs were assessed by univariable logistic regression. Numerical increases in all biomarkers were observed between baseline and 12 weeks but were of higher magnitude in the de-escalated arm. Pain scores in the de-escalated treatment arm showed a greater magnitude of pain reduction from baseline to 12 weeks. Neither baseline levels nor changes in biomarkers from baseline to 12 weeks on treatment were associated with on study SREs. Baseline pain as measured by the FACT-BP was associated with increased risk of SRE. In conclusion, biomarkers of bone activity do not appear to predict for SREs in ‘low risk’ cohorts. However, baseline bone pain appears to be associated with SRE occurrence, a finding which warrants evaluation in larger cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-577) contains supplementary material, which is available to authorized users.

Highlights

Bone is the most common site of metastasis in breast cancer (Coleman & Rubens 1987) and skeletal metastases are associated with skeletal related events (SREs) such as; surgery/radiation to bone, pathological fractures, spinal cord compression and hypercalcemia
With availability of longer follow-up data we explore a series of bone biomarkers including CTx (Lipton et al 2008; Lipton et al 2011; Coleman et al 2005), urinary (u)NTx (Rosen et al 1994; Gorai et al 1997; Clemens et al 1997), bone-specific alkaline phosphatase (BSAP), transforming growth factor (TGF)-β (Baselga et al 2008; Desruisseau et al 2006), procollagen type 1 amino terminal peptide (P1NP) (Garnero et al 2000a; Chevrel et al 2007), activinA (Reis et al 2002), bone sialoprotein (BSP) (Diel et al 1999) and pain scores (Harris et al 2007; Broom et al 2009) and their association with the incidence of SREs in the REFORM trial
Patients allocated to the de-escalated treatment group who remained with telopeptide levels below 600 ng/L continued to receive treatment according to protocoldefined frequency, while patients whose telopeptide levels rose above 600 ng/L remained on study, but thereafter received treatment every 3–4 weeks

Summary

Introduction

Bone is the most common site of metastasis in breast cancer (Coleman & Rubens 1987) and skeletal metastases are associated with skeletal related events (SREs) such as; surgery/radiation to bone, pathological fractures, spinal cord compression and hypercalcemia. Given the long terminal half life of these agents, and the fact that patients may be treated with them for years, their dosing frequency has come into question (Kimmel 2007), leading to a number of trials looking at de-escalated therapy To date both single arm (Addison et al 2014) and randomized trials (Amadori et al 2013; Hortobagyi et al 2014; Amir et al 2013) have confirmed that de-escalated treatment is feasible and at least over the short term is not associated with a greater risk of SREs. It is noteworthy that cumulative exposure to these drugs is associated with significant toxicities (Mariotti 2008), which could be reduced with use of deescalated treatment strategies. These findings raise questions around the long term safety of deescalation of bone targeted therapy

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