MPTH-01. ARE MUTATIONS IN MISMATCH REPAIR (MMR) GENES OUR NEXT BIOMARKER OF ALKYLATING AGENT INDUCED HYPERMUTATOR PHENOTYPE? PRELIMINARY RESULTS FROM THE IVY PRECISION TRIAL Free

Mutations in the MMR gene MSH6 have been shown to confer resistance to alkylating agents and unleash accelerated mutagenesis, manifesting as recurrent progressive glioma with hypermutator phenotype. The IVY precision trial (IRB# 144-13086) tested the feasibility of using molecular profiling to guide treatment in patients with recurrent GBM from which we identified two patients with the hypermutator phenotype.

A total of 15 recurrent GBM tumors were analyzed (Ashion Analytics, CAP/CLIA Lab) by whole-exome sequencing for relevant single nucleotide substitutions (SNS)/deletions, focal deletions/amplification and structural break-points across 20,536 genes.

Two (M/F, 40/60 year of age) of 15 patients’ (13%) genotypes expressed the hypermutator phenotype. Prior therapy included RT + TMZ. Each tumor was MGMT methylated, had MSH6 mutations/loss, one with an additional MLH1 (G67E) mutation and one with an IDH1 (R132H) mutation. Neither specimen had polymerase mutations. SNS mutational loads for the 2 tumors were 1538 & 2786 compared to the average of 58 (SD ± 25.5) for the other 13 tumors without MMR mutations. Treatment with an Anti-PD-1 mAb was recommended by the IVY tumor board for both patients. In contrast to the two hypermutator phenotype patients, two additional TMZ-treated patients with IDH1 mutations, MGMT methylation+ and no MMR alterations had SNS mutational loads of 150 and 80. Thus, MGMT status and IDH1 mutations were not concordant with the hypermutator phenotype in this small sample.

Mutations/loss in MMR genes appear to be a biomarker for alkylator-induced hypermutator phenotype. Testing for IDH1 mutation and MGMT methylation alone may be insufficient to predict accelerated mutagenesis. Hypermutator phenotypes associated with high neoantigen loads may represent a therapeutic opportunity for ­tumor-specific immunotherapy. Prospective screening for MMR mutations prior to TMZ may be therapeutically indicated. The IVY early clinical trial consortium will test this hypothesis in our upcoming immunotherapy precision bucket trial.