IDH Mutation Status May Guide Therapy in Patients With High-Risk Low-Grade Glioma

An analysis of three interrelated biomarkers in high-risk low-grade glioma (LGG) has identified distinct risk groups by isocitrate dehydrogenase (IDH) mutation status and suggested appropriate treatment strategies.

IDH1/2 wild-type LGGs have inferior outcomes that warrant combined-modality strategies that incorporate novel therapies. IDH-mutated tumors with co-deletion of 1p/19q have the most favorable prognosis and can be managed with single-modality treatment with either temozolomide or radiotherapy.

IDH-mutated tumors without co-deletion require radiation therapy with optional use of chemotherapy, as reported during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

“These results should inform decision making for this heterogeneous disease that has widely varying outcomes,” said Brigitta Baumert, a member of the European Organization for Research and Treatment of Cancer (EORTC) radiation oncology group in Maastricht, Netherlands. “Patients often live for many years, so long-term toxicity of treatment matters.”

Given the long-time course and varying outcomes for LGG, accurate methods of risk stratification might lead to more informed clinical decision making, reduced toxicity, and improved outcomes. Current clinical markers have limited prognostic value and serve to identify only those patients with unfavorable prognosis: age 40 years or greater, astrocytoma histology, neurologic deficits, tumor diameter of 6 cm or greater, and tumors that cross the midline.

Data from a recent EORTC/NCI/TROG/MRC intergroup trial provided an opportunity to examine the association of biomarkers and biomarker groupings to clinical outcomes. The trial involved 477 patients with high-risk LGG, all of whom underwent testing for tumor genetics prior to randomization to radiotherapy or single-agent temozolomide.

The results, reported two years ago at ASCO, showed no difference in median overall survival (OS), which was 46 months with radiotherapy and 39 months with temozolomide.

Current molecular markers have proven useful for identifying patients with unfavorable (mitotic index greater than 5 percent and p53 mutation) and favorable prognoses (IDH mutation, methylguanine-DNA methoyltransferase [MGMT] value unknown). Additionally, MGMT, 1p/19q codeletion, and IDH have been shown to correlate strongly, says Baumert.

Investigators studied molecular markers in tissue obtained from 407 patients in the intergroup trial of radiotherapy and temozolomide. IDH status was determined by immunohistochemistry (IHC) for the most common mutant (IDHR132H), complemented by sequencing of IDH1 and 2 for all IHC-negative cases. The 1p/19q co-deletion was determined by loss of heterozygosity (LOH) or fluorescence in situ hybridization (FISH). MGMT promoter methylation was assessed by HM450k beadchip.

The analyses showed that 1p/19q co-deletion (117 tumors) was associated with a 40 percent reduction in the survival hazard and a median OS of 55 months. LGGs without co-deletion (240 tumors) were associated with a median OS of 36 months.

IDH wild-type tumors (65 tumors) were associated with almost a threefold increase in the hazard ratio and a median OS of 20.5 months. In contrast, IDH-mutated tumors were associated with a median OS of 50.7 months.

With respect to MGMT, methylation (135 tumors) was associated with a median OS of 42 months compared with 24 months for unmethylated tumors (15 tumors). The difference translated into a 68% reduction in the hazard in favor of MGMT methylation.

Baumert et al examined the interaction between IDH status and 1p/19q co-deletion. The specimens included tissue from 269 IDH-mutated tumors, 104 IDH-mutated tumors that also exhibited codeletion, and 49 tumors that were IDH wild type.

The analysis showed that IDH wild-type tumors were associated with the worst prognosis. IDH-mutated tumors that also exhibited codeletion had the most favorable prognosis. IDH-mutated tumors without codeletion had a similar prognosis early on but a worse late prognosis compared with IDH-mutated/codeletion tumors.

Comparing the marker findings with treatment assignment in the intergroup trial, investigators found that patients with IDH wild type tumors had similar survival with temozolomide (23.69 months) or radiotherapy (19 months). IDH-mutated tumors with codeletion had a median survival of 61.63 months with radiotherapy and 55.03 months with temozolomide, a nonsignificant difference.

In the subgroup of patients with IDH-mutated tumors without codeletion, treatment assignment had a significant effect on outcome. Patients in the radiotherapy arm had a median OS of 55.36 months versus 36.01 months with temozolomide.

Baumert BG, Hegi ME, Mason WP, et al. Radiotherapy in relation to temozolomide: Subgroup analysis of molecular markers of the randomized phase III study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033) in patients with a high risk low-grade glioma. Presented at 2015 ASCO Annual Meeting: June 2, 2015. Abstract 2006.