Abstract only 4125 Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether serum 2HG levels in IDHm ICC pts may 1) serve as a surrogate biomarker for IDH status, 2) correlate with tumor burden, and 3) correlate with circulating proangiogenic biomarkers. Methods: Blood samples from 33 ICC pts 11 IDHm, 22 IDH wild-type (IDHwt) of different AJCC stages from MGH and 39 surgically resected ICC patients (7 IDHm, 32 IDHwt) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry. Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA. Results: In the MGH cohort, median serum 2HG levels were significantly elevated in IDHm (478 ng/ml interquartile range 174–643) versus IDHwt ICC pts (118ng/ml 68–160)(p<0.001). Similarly, in the HKU cohort, the pre-resection median serum 2HG levels were significantly elevated in IDHm (343ng/ml 192–596) versus IDHwt ICC pts (56ng/ml 42–81) (p<0.0001). The area under ROC curve for prediction of an IDH mutation using 2HG was 93%; with a threshold of 2HG≥170ng/ml, the sensitivity was 83% and specificity was 90%. IDH2 mutations were more frequent in the HKU cohort (3/7, 43%) compared with the MGH cohort (0/11, 0%) (p<0.05), but 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. 2HG levels correlated directly with tumor burden (Spearman’s rho=0.89; p<0.05) in the HKU cohort. Median plasma levels of PlGF—a growth factor from the VEGF-family—were higher in IDHm (35pg/ml 33–40) versus IDHwt ICC pts (median 26pg/ml 24–34) from the HKU cohort (p<0.05). No other associations were seen between proangiogenic biomarkers and IDH status. Conclusions: IDHm ICC pts had significantly higher serum 2HG levels compared to IDHwt ICC pts. High serum 2HG correlated with increased tumor burden. Pre-resection circulating PlGF levels were higher in IDHm ICC versus IDHwt pts. These data support further exploration of circulating 2HG as potential surrogate and response biomarker in IDHm ICC.