Brivanib‐induced changes in the circulating metabolome associated with hypertension
hypertension, CRC, HT
HYPERTENSION
To determine how brivanib‐induced hypertension affects the circulating metabolome, changes in plasma metabolomic features were compared from baseline to 12 weeks after treatment initiation in patients with Grade 2 or worse hypertension and in patients without hypertension. GC–MS detected 386 common features in all samples, of which 94 were named metabolites and included in the downstream analysis. A preliminary PCA of 14 patients with hypertension and 56 patients without hypertension did not demonstrate any intrinsic pattern distinguishing the two groups, but two outliers were identified (outside of the 95% ellipse), which were excluded from further analysis (Figure Changes in circulating metabolites are identifiable at 12 weeks after chemotherapy initiation. (A) PCA scatter plot depicting changes in plasma metabolites as a function of hypertension development. B. Supervised (OPLS‐DA) scores scatter plot based on a model distinguishing changes in the circulating metabolome that accompany treatment‐induced development of hypertension. C. Coefficient column plot describing directionality of changes of individual metabolites in association with chemotherapy‐induced hypertension. Metabolite correlations with the model are determined by Centered and Scaled (CS) coefficients. D. Loadings column plot depicting behavior of individual metabolites in the cetuximab control arm and the brivanib‐induced hypertension.Metabolite changes from baseline to Week 12 post‐drug initiation, in patients who received brivanib and cetuximab. Metabolites listed comprised the multiparametric model that described the pattern of changes associated with treatment‐related hypertension. Abbreviation: HT, hypertension.Changes in circulating metabolites associated with brivanib induced hypertension. A. Coefficient column plot describing the behavior of the biomarker in the two treatment arms. The pattern of metabolite changes observed in the brivanib arm were absent or opposite in directionality in the control arm. B. Venn diagram depicting the number of metabolites shared between each sub group of patients.A similar approach was taken at earlier time periods (Weeks 1 and 4) to determine whether systemic metabolomic changes appear at earlier time points (Figure Biomarker‐defined hypertension vs. no hypertension, based on S‐scores. A. ROC curves for validation of metabolomic biomarker of hypertension at Weeks 1 and 4, in the independent validation cohort. B. Kaplan–Meier curves comparing progression‐free survival (PFS) in discovery patients with metabolomic biomarkers of treatment‐induced hypertension and no hypertension. C. Kaplan–Meier curves comparing overall survival (OS) in patients with metabolomic biomarkers of treatment‐induced hypertension and no hypertension. D. Validation ROC curve measuring performance of the metabolomic biomarker for hypertension/no hypertension in the validation cohort, Week 12.To further assess the identified hypertension biomarker, we evaluated its association with PFS and OS (Figure Internal validation of the metabolomic signature of hypertension for CRC was performed in an independent cohort consisting of patients from the same clinical trial (