Single nucleotide polymorphisms (SNPs) and circulating endothelial cells (CECs) as outcome predictors in patients (pts) with recurrent glioblastoma (rGBM) treated with bevacizumab (BEV) and sorafenib (SOR).

Abstract

2019 Background: There is a lack of biomarkers to predict outcome or monitor antiangiogenetic therapies. We investigated whether SNPs or CECs could predict treatment efficacy/toxicity in rGBM pts treated with BEV/SOR. Methods: Blood was obtained for SNP and CEC analyses from rGBM pts enrolled in the Phase II trial N0776 (Galanis et al., ASCO. 2010). VEGF, VEGFR2, and HIF-1alpha SNPs were analyzed by Taqman or direct sequencing. Blood for CECs was collected at baseline, cycle 1 day 3, prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and at the time pt went off study. CECs were enumerated by flow cytometry. Unequal variance two-sample and paired t-tests were performed to compare values between pt outcome groups and serial measurements within a pt, respectively. Results: All 53 eligible pts had DNA available for SNP analyses. Significant differences (Chi-square or Fisher’s exact, p<0.05) were observed between genotypes and either progression free survival at 6 months (PFS6) (VEGF rs1005230, rs1570360, rs699947, rs833061, VEGFR2 rs2071559) or grade 3+ adverse events (AEs) fatigue (VEGF rs10434, rs1005230, rs699947, rs833061) or hypertension (rs1005230, rs699947, rs833061). After correcting for multiple comparisons (method of Benjamini & Hochberg), none of the p-values remained significant (p>0.05). CEC analysis was performed on 49 of 53 pts. Median baseline CECs (bCEC) were 83.3 (mean: 136; range: 6.5-594) cells/mL; there was no correlation between bCEC values and PFS6 (p=0.19). Absolute differences between bCECs and other time points were not significant; yet, the CEC log2-fold change (FC) from bCECs decreased during treatment and reached significance at cycles 2, 7, 9, and 11 (0.03, 0.047, 0.005, and 0.005, respectively). Differences in log2-FC from bCECs to off study CECs (≤ 14 days) for pts off study for progression was higher compared to pts off study for other reasons (p=0.02, t-test). Conclusions: Based upon this 53 pt cohort, further biomarker studies examining the utility of SNPs for predicting PFS and AEs and use of CEC monitoring for predicting pt progression in rGBM pts treated with BEV appear warranted.