A distinct inflammatory marker pattern in patients with aromatase inhibitor (AI)-induced musculoskeletal symptoms.
Authors: Henry NL , Charles P , Pshezhetskiy D , Nguyen A , Ahern R , Waxman J , Storniolo A , Hayes DF , Flockhart DA , Stearns V , Stebbing J 
Published: December 2010

Abstract
Abstract #1129
Background. AI-associated musculoskeletal symptoms (AIMSS) have been reported in up to 50% of treated patients. Inflammatory processes can occur in cancer patients, and inflammatory mediators including interleukins, interferons, MMPs and immunoregulatory molecules have been associated with estrogen signaling. Ceramide and sphingosine-1-phosphate (S1P) are lipid mediators with roles in inflammation. We hypothesized that AIMSS may develop in the context of increased circulating inflammatory markers.&#x2028; Methods. Cases (n=24) were selected from 150 early stage ER-positive breast cancer patients who were enrolled on a prospective multicenter randomized trial of exemestane or letrozole. Changes in pain and function during therapy were assessed prospectively, and those patients whose symptoms exceeded a predefined threshold were referred for detailed rheumatologic evaluation. Controls (n=30), who did not develop AIMSS that exceeded the threshold, were matched for age, ethnicity, and prior chemotherapy. Serum samples collected at baseline and 1 and 6 mo following AI initiation were assayed in a blinded manner. The majority of inflammatory molecules were quantified in serum using an addressable laser bead multiplex assay (BMD, Paris) on a Luminex S100 analyzer (Austin, TX). Ceramide and S1P were alkaline chloroform/methanol-extracted from serum, 32P-labeled, and quantified using autoradiography. Statistical comparisons between cases and controls for each factor were performed using the non-parametric Mann-Whitney test or by log transforming the data and using unpaired two-tailed t tests.&#x2028; Results. The mean serum concentrations for the majority of assayed factors (IFNγ, IL1Rα, IL2/4/5/7/10/15/17, IL2R, IL12p40, IP10, MIP1α, MIG, bFGF, HGF, GCSF, and GMCSF) were significantly lower at baseline in cases compared to controls (p&lt;0.05 for each factor); no differences in changes relative to baseline were evident at 1 and 6 mo of AI therapy. Baseline serum concentrations of RANTES, a chemokine, were higher for cases than controls (p=0.04); no differences relative to baseline were noted during therapy. At the 6 mo timepoint, serum concentrations of S1P were higher in cases and lower in controls (p=0.01); no differences were found at baseline or 1 month. No associations were found between serum concentrations of EGF, IL6, IL13, MCP1, MMP3/9/13, or ceramide and the development of AIMSS at any timepoint.&#x2028; Conclusions. Subjects who develop AIMSS appear to have an underlying anergic cytokine phenotype at baseline. During AI therapy, patients with AIMSS develop higher levels of S1P, a potential inflammatory mediator known to induce COX2 and NFκB. These hypothesis-generating results suggest a potential mechanism underlying the development of AIMSS, distinct from other rheumatologic conditions.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1129.