Molecular Markers in Low-Grade Gliomas: Predictive or Prognostic?

Abstract

Purpose: To investigate whether TP53 mutation, 1p/19q codeletions, O 6 -methylguanylmethyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation predict natural course of disease or response to radiotherapy or chemotherapy or both in low-grade glioma patients.Experimental Design: Cohort A consisted of 89 patients with diffuse astrocytoma World Health Organization (WHO) grade II (n ¼ 40), oligoastrocytoma (n ¼ 23), or oligodendroglioma (n ¼ 26) who did not receive radiotherapy or chemotherapy after first operation and were monitored until progression [progressive disease (PD); n ¼ 59] and beyond or until the end of follow-up (n ¼ 30). Cohort B consisted of 50 patients with WHO grade II gliomas who received radiotherapy or chemotherapy at diagnosis. Tumors were analyzed for TP53 mutations, 1p/19q codeletions, MGMT promoter methylation, and IDH1 mutations.Results: Median progression-free survival (PFS) in cohort A was 4.1 years (95% CI: 3.1-5.1). No molecular marker was prognostic for PFS after surgery alone, using multivariate adjustment for histology, age, and extent of resection. IDH1 mutations were associated with prolonged survival from the diagnosis of PD in oligoastrocytomas (OA II)/oligodendrogliomas (O II) and with overall survival (OS) in all tumors. 1p/19q codeletion and IDH1 mutation were prognostic for PFS and OS in cohort B.Conclusions: None of the parameters are sensitive prognostic biomarkers in WHO grade II glioma patients who do not receive radiotherapy or chemotherapy after surgery. Limitations of this study include the selection of patients with favorable outcome, the nonrandomized allocation of treatment, and the insufficient sample size to distinguish between effects of radiotherapy versus chemotherapy. Regardless of histology, IDH1 mutation status is the strongest prognostic marker for OS. Clin Cancer Res; 17(13); 4588-99. Ó2011 AACR.

Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution

“…Interestingly, the tumors in this latter group relatively infrequently showed copy number changes in EGFR, CDKN2A or PTEN, ie, markers reported to be indicative of aggressive biological behavior. Although IDH1 mutations are infrequently detected in glioblastomas from older patients (eg, in 8/144 older than 50 years (current study) or in 2 out of 126 glioblastoma patients older than 60 years, 17,34 these patients do not show a survival benefit, underlining once again that patient age in our study (450) should be considered when using molecular markers for assessment of prognosis. Knowing that IDH1 mutations are especially common in low-grade and anaplastic diffuse gliomas, in secondary glioblastomas and in younger patients, the lack of favorable prognostic meaning of IDH1 in the two groups just mentioned might be explained by assuming that molecular analysis was performed in these patients relatively late in their disease process.…”

NDRG1 prognosticates the natural course of disease in WHO grade II glioma

“…1p/19q deletion status, MGMT promoter methylation as well as IDH and TP53 mutational status have been determined as described previously [8,14].…”

“…From this cohort, we identified 40 patients with a diagnosis of a supratentorial WHO grade II astrocytoma or oligodendroglial tumor confirmed by history taking and central pathology review [20], as well as adequate follow-up at least until progression, who were followed by a watch-and-scan policy according to investigators' discretion supported by risk factor profiles [21]. Some of these patients were included in previous publications addressing the same clinical correlative question, but assessing different markers [8,14]. Clinical data were prospectively assembled as outlined before (http://www.gliomnetzwerk.de) [5].…”

“…Interaction analyses between IDH1 and MGMT, however, have revealed that MGMT promoter methylation is probably a predictive biomarker for response to chemotherapy in patients with IDH1 wild-type, but not IDH1 mutant gliomas, irrespective of WHO grade [13]. All currently known biomarkers unravel their prognostic properties only if genotoxic treatment is used and none of the biomarkers discussed so far, including IDH or TP53 status, MGMT promoter hypermethylation or 1p/19q codeletion, show a good relation to the natural course of disease [8,14]. In low-grade gliomas, guidance whether a patient with a newly diagnosed tumor needs early genotoxic treatment or not is pivotal, as the most commonly used treatment, radiotherapy of the involved part of the brain [15], is not associated with an overall survival (OS) benefit but possibly with long-term adverse sequelae especially in patients with a favorable prognosis [16].…”

“…This has been confirmed across gliomas of World Health Organization (WHO) grades II-IV, including both astrocytic and oligodendroglial tumors [2][3][4]. However, most studies have failed to link IDH1 mutations to better responsiveness to specific types of treatment, neither in glioblastoma [5], anaplastic glioma [2,6] nor low-grade glioma crucial to distinguish the prognostic significance, defined as overall better outcome irrespective of management, from the predictive significance, defined as a better outcome given a specific treatment is administered [8].…”