Incidence of non-canonical IDH mutations and IDH co-mutations in a multicenter prospective study of patients with glioma.

Abstract

e14033 Background: IDH-mutant tumors are a distinct disease entity accounting for one third of gliomas with a more favourable prognosis despite still harboring high morbidity and mortality rates. Most IDH mutations (muts) in gliomas group at R132/R172 hotspots in IDH1/IDH2, respectively. Our aim was to study IDH non-canonical muts and IDH co-mutations (co-muts) since the evidence is still limited. Methods: Prospective study of patients (pts) with gliomas at 4 third-level hospitals in Spain (Hospital Clinico Universitario San Carlos, Hospital Universitario La Paz, Hospital Universitario de Canarias, Hospital Universitario Nuestra Señora de la Candelaria). High throughput next generation sequencing (NGS) using a customized gene panel ((Illumina, Inc) including IDH1 and IDH2 was used in FFPE and/or fresh tumor samples, and run in an Illumina MiSeq instrument (Illumina, Inc). Only pathogenic mutations were considered as valid. Clonal IDH (cIDH) muts were defined as those with a MAF ≥ 1% and subclonal IDH (scIDH) muts as those with a MAF < 1%. Results: Between February 2017 and February 2021, 49 glioma pts enrolled and sequenced for IDH1/IDH2 tumor muts. Median age 51 (Min-max: 20-78). WHO 5th Ed (n = 42): IDH-MUT astrocytoma (n = 14), IDH-MUT oligodendroglioma (n = 7), IDH-WT glioblastoma (n = 21). 37/49 pts (75.5%) presented cIDH and/or scIDH muts, of which 21 pts (43%) harbored cIDH muts in IDH1 (R132H (n = 17), R132C (n = 1), R132G (n = 1), R100Q (n = 1), G161R (n = 1)) and in IDH2 (R140W (n = 1), R140Q (n = 1)). In 17/21 pts (81%) cIDH-mut MAF ≥ 10%. Of 21 cIDH-mutant pts, there were IDH co-muts in 11 pts (52%). Of these 11 pts, IDH co-muts were scIDH in 91%: #2 (IDH1 R100Q/G161R), #3 (IDH1 R132H/R119Q/G161R), #4 (IDH1 R132H/R132C; IDH2 R172G/R140Q), #11 (IDH1 R132H/R132C), #21 (IDH1 R132H/G161R; IDH2 R140Q), #23 (IDH1 R132H/R132C), #31 (IDH1 R132H/G161R; IDH2 R140Q/P162L), #32 (IDH1 R132H/R100Q), #33 (IDH1 R132H/R100Afs*29/I130V), #37 (IDH1 R132H; IDH2 R159H), #40 (IDH1 R132H; IDH2 R172G). Median overall survival (OS) longer in cIDH-mut vs IDH-wt (159 vs 16 months, P = 0.000). No difference in OS in: cIDH vs cIDH + scIDH (NR vs 67 m, P = 0.437), in scIDH vs cIDH (79 vs 159 m, P = 0.111), and scIDH vs IDH-wt (79 vs 12 m, P = 0.229). Conclusions: Subclonal (defined as MAF < 1%) canonical and non-canonical IDH-mutations and co-mutations occur frequently in gliomas. This may have implications for the design of future clinical trials and in the development of IDH inhibitors including the anticipation of potential resistance mechanisms.