OS05.6 Final risk model for Temozolomide (TMZ)-Myelotoxicity in patients with Glioblastoma treated on NRG Oncology’s RTOG 0825
Year: 2017
Type: conference-abstract
Abstract: BACKGROUND: Myelotoxicity is a rare but serious side effect of TMZ. In RTOG0825, 16% and 23% of patients experienced grade 3 or higher myelotoxicity during chemoradiation or adjuvant phase, respectively. Our goal was to evaluate risk and validate prediction of myelotoxicity in patients treated with TMZ +/- bevacizumab (BEV). METHODS: Clinical characteristics (including age, height, weight, gender, race/ethnicity, concurrent medications, baseline laboratory studies, performance status, and tumor characteristics) as well as severe TMZ-related myelotoxicity (CTCAE version 3.0 for grade 3 and higher leukopenia, neutropenia and/or thrombocytopenia) were extracted from the RTOG 0825 database. First, a risk prediction model of myelotoxicity was built including only clinical factors; second, that model was extended using the single nucleotide polymorphisms (SNPs) identified by a genome-wide association study (GWAS). We also conducted a joint effects analysis to test the hypothesized dose-response relationship between genotype and myelotoxicity, by summing the number of at-risk alleles of the top SNPs identified from the main effect analysis. Results: There were 134 cases and 457 controls. Receiving BEV with TMZ increased myelotoxicity risk 80% (odds ratio OR=1.82; 95% confidence interval [CI], 1.02–3.27; adjusted p= 0.04). Females were approximately 4.5 times more likely to develop toxicity (OR=4.45; 95% CI, 2.45–8.08; adjusted p <0.0001). Taking anticonvulsants trended toward increased risk but was not statistically significant (OR=1.64; 95%CI 0.85–3.18; adjusted p=0.14). The SNP association study (367 patients tested) revealed 15 SNPs significant at 10–7 genome-wide level; the five top SNPs remained after removing those in LD (D’ ≥ 0.99). Four SNPs were in the MGMT gene on chromosome 10 and the fifth in gene ANKS1B on chromosome 12. Carrying one risk (minor) allele of the top 5 SNPs was associated with 64% increased risk of myelotoxicity (OR=1.64; 95% CI, 1.43–1.89; adjusted p <0.0001). The AUC of the final model increased to 0.827 after including the genetic variants. After thirty-fold cross-validation the area under the ROC curve for the model was 0.807. Conclusions: Germline risk alleles in the MGMT and ANKS1B genes, among others, improve prediction of TMZ myelotoxicity when combined with clinical-pathologic factors. TMZ myelotoxicity is a significant clinical issue, and being able to predict risk should allow treatment optimization. NIH grant-1R01NR013707-01A1, U10CA21661, U10CA180868, U10CA180822, U10 CA37422, U24CA180803 (NCI), NIH grant- 1R01NR013707-01A1 and Genentech.
Source: Neuro-Oncology
Authors: T. S. Armstrong, M. R. Gilbert, M. Bondy, E. Sulman, Y. Yuan, R. Zhou, E. Vera, M. Wendland, S. Pugh, M. Scheurer
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2979186010