Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations

Abstract

Background: Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines.

Methods: From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods.

Results: In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine.

Conclusion: The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.

Keywords: IDH testing; biomarker; cost-effectiveness; reimbursement; turn-around time.

Fig. 1

Detection rates. (A) Overview of all study cases with pertinent clinicopathological features showing original (WHO 2007) and reclassified diagnoses (WHO 2016). Arrows indicate cases with WHO grade changes. (B) Reclassification according to WHO 2016 guidelines resulted in upgrading from WHO grade III to IV in N = 12 cases. These tumors had oligodendroglioma-like histology but failed to meet the molecular requirements for a diagnosis of anaplastic oligodendroglioma of the 2016 WHO classification. (C) Blue boxes outline cases tested by sequencing, while red boxes outline cases tested by immunohistochemistry (IHC). Overlapping boxes represent cases tested by both methods. In all, 482 cases received DNA testing, with 331 cases testing negative and 151 testing positive. Of 541 total cases tested by IHC, 406 were negative and 135 were positive. (D) Cases tested by both methods were binned by 5-year age intervals, except at the extremes. Detection rate is the percentage of cases testing positive for an IDH variant by each method. Black boxes designate IHC detection rate and gray boxes designate sequencing detection rate. Sequencing outperforms IHC detection at younger ages (<55 y), suggesting higher rates of noncanonical IDH1 and IDH2 variants in younger patients. (E) IDH-variant detection rate by age binned at 55 years. Black bars represent IHC and gray bars represent sequencing. In patients <55 years, DNA testing reveals a significantly higher detection rate compared with IHC (*P < 0.001, t-test), whereas there was no difference between both methods in patients ≥55 years. Abbreviations: GBM, glioblastoma; WT, wild-type; MUT, mutant; NOS, not otherwise specified (WHO 2016; here IHC only, no DNA testing performed); AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma, IDH-mutant, 1p/19q codeleted; AO NOS, anaplastic oligodendroglioma, not otherwise specified; A, diffuse astrocytoma; O, oligodendroglioma, IDH-mutant, 1p/19q codeleted; O NOS, oligodendroglioma, not otherwise specified; AOA, anaplastic astrocytoma (WHO 2007). For details of cases, see Table 1.

Fig. 2

Detection rates by age and IDH genotype. Comparison of IDH mutations in (A) glioblastoma vs (B) WHO grade II/III glioma by age in the 482 patients assessed by next-generation sequencing; noncanonical IDH mutations are depicted in red on stacked bar-graphs (insets show breakdown of number per IDH mutation). (C) Overall comparison in the 343 patients assessed by both methods shows significantly higher prevalence of non–R132H-IDH1 and -IDH2 variants in the younger age group (P < 0.001; Fisher’s exact test). (D) Comparison of the age-based prevalence of noncanonical IDH mutations by histological diagnosis.

Fig. 3

Test cost per positive. Cost is modeled using the same population as in Fig. 2. Cases are binned into 5-year age groups except at the extremes. Cost represents the total cost of the cases screened ($1800 per case sequenced by NGS, $420 × 2 per case sequenced by single gene sequencing [IDH1 and IDH2], and $135 per case screened by immunohistochemistry) divided by the number of non–R132H-IDH1 and -IDH2 variants detected in that age group. The cost to detect variants that would be missed by R132H-IDH1 immunohistochemistry increases dramatically in the older age group, in which noncanonical variants are rare.