Читать книгу Intracranial Gliomas Part II - Adjuvant Therapy - Группа авторов - Страница 35

It has being long recognized that diagnosis of oligodendroglial tumor is associated with significantly longer survival of patients in comparison to astrocytoma of the same WHO grade [22]. Also the oncological outcome in cases of sGBM is somewhat better than that of pGBM, but this may be related to the younger age of patients in the former cohort [3]. Nevertheless, there has been multiple suggestions for genotype-based grouping of diffusely infiltrating gliomas carrying comparable prognosis. Many of these schemes look very similar, and some are presented herein.

Kim et al. [22] assessed 360 LGG in adults (174 DA, 122 OD, and 64 oligoastrocytomas) for IDH1/IDH2 and TP53 mutations, and 1p/19q co-deletion. In this study IDH1/IDH2 mutations did not demonstrate statistically significant prognostic value, but the number of cases without this genetic abnormality was disproportionally small (239 vs. 29 cases). Four groups of tumors were defined:

•IDH1/IDH2-mutant, 1p/19q co-deleted (median survival 58.7 months; HR for survival 1);

•IDH1/IDH2-mutant, TP53-mutant (median survival 51.8 months; HR 0.563; p = 0.0087);

•IDH1/IDH2-mutant only (HR 0.778; p = 0.2955);

•“Triple-negative” (HR 0.910; p = 0.7773).

Figarella-Branger et al. [38] evaluated 88 LGG in adults (19 DA, 23 OD, and 46 oligoastrocytomas) for IDH1/IDH2 mutations, p53 immunopositivity, and 1p/19q co-deletion. In this study p53 immunopositivity and 1p/19q co-deletion were always associated with IDH1/IDH2 mutations. Four groups of tumors were defined:

•IDH1/IDH2-mutant; p53 immunonegative; 1p/19q non-codeleted (5-year survival rate 100%; median survival not reached; HR for death 1);

•IDH1/IDH2-mutant; p53 immunonegative; 1p19q co-deleted (5-year survival rate 95.5%; median survival not reached; HR 1.6; p = 0.625);

•IDH1/IDH2-mutant; p53 immunopositive; 1p19q non-codeleted (5-year survival rate 81.4%; median survival 7.5 years; HR 3.7; p = 0.110);

•“Triple-negative” (5-year survival rate 57.1%; median survival 5.7 years; HR 16.9; p = 0.003).

Leu et al. [8] investigated 210 LGG in adults (including 92 DA, 53 OD, and 63 oligoastrocytomas) for IDH1/IDH2 mutations, MGMT promoter methylation, p53 immunopositivity, and 1p/19q co-deletion. Four molecular groups of tumors were defined:

•IDH1/IDH2-mutant, MGMT-methylated, 1p/19q co-deleted (HR for death 0.18; p < 0.001);

•IDH1/IDH2-mutant, MGMT-methylated, 1p/19q non-codeleted, p53 immunonegative (HR 0.33; p < 0.01);

•IDH1/IDH2-mutant, MGMT-methylated, p53 immunopositive (HR 0.88; p > 0.05);

•IDHwild-type (HR 1).

In this study PPV of IDH1/IDH2 mutations (HR 0.64) and 1p/19q co-deletion (HR 0.58) alone did not reach statistical significance. Among evaluated clinical parameters increased age at diagnosis showed a statistically significant negative impact on prognosis.

Suzuki et al. [32] performed extensive genetic analysis of WHO grade II and III gliomas by combining two independent sets of high-throughput sequencing data from Japanese and The Cancer Genome Atlas (TCGA) Consortium cohorts (in total 757 samples). In this study TP53 mutations and 1p/19q co-deletion were nearly always (99.6% of cases) associated with IDH1/IDH2 mutations. Three genetic types of tumors were defined:

•Type I: IDH1/IDH2-mutant, 1p/19q co-deleted (HR for death 1);

•Type II: IDH1/IDH2-mutant, 1p/19q non-codeleted (HR 2.06); all but one of these tumors harbored TP53 mutation with frequent (77% of cases) coexisting ATRX mutation;

•Type IIIa: IDH wild-type, WHO grade II (survival comparable to types I and II tumors);

•Type IIIb: IDH wild-type, WHO grade III (HR 6.41).

Multiple additional genetic abnormalities were revealed and those ones were largely grouped into 3 major categories with regard to defined tumor types, demonstrating positive correlations within each category and being mutually exclusive with those within different categories. Type IIIb tumors had a significantly greater number of glioblastoma-like genetic alterations and were noted in older patients. WHO grade did not substantially affect overall survival in cases of Types I and II tumors, whereas age demonstrated statistical significance as an independent prognostic factor in multivariate analysis.

Weller et al. [9] performed microarray-based genome- and transcriptome-wide analysis followed by comprehensive integrative bioinformatics data assessment in 62 WHO grade II and 76 WHO III gliomas (including 87 astrocytic, 6 oligodendroglial, and 44 oligoastrocytic tumors). Genomic and gene expression profiling identified, respectively, 5 and 8 distinct groups of neoplasms, which were only partially linked to each other. Three major prognostic groups of tumors with characteristic genomic aberrations were defined with significantly different PFS and overall survival:

•IDH1/IDH2-mutant, 1p/19q co-deleted (median survival not reached; HR for death 1);

•IDH1/IDH2-mutant, 1p/19q non-codeleted, as well as IDH wild-type lacking glioblastoma-like molecular alterations (median survival 9 years; HR 3.81; p = 0.006);

•IDH wild-type with glioblastoma-like molecular alterations, such as combined +7q/–10q, TERT promoter mutation and oncogenes’ amplification (median survival 2.4 years; HR 8.28; p < 0.001).

Addition of gene expression data to this genomic classifier did not result in improved prognostic stratification. Tumor type and WHO grade provided only non-significant information, while age >40 years was associated with a significantly higher risk of death (HR 3.99; p < 0.001).

Jiao et al. [7] evaluated alterations of IDH1/IDH2, TP53, ATRX, DAXX, 1p/19q, CIC, and FUBP1 in 363 brain tumors (81% were of astrocytic, oligodendroglial, or oligoastrocytic origin) and performed related clinical analysis in a combined set of 199 adult gliomas (31 WHO grade II, 69 WHO grade III, 99 WHO grade IV). Three molecular groups of neoplasms were defined with statistically significant (p < 0.001) survival differences, which were preserved after stratification of lesions by WHO grade:

•IDH1/IDH2-mutant, 1p/19q co-deleted or CIC/FUBP1-mutant (median survival 8 years);

•IDH1/IDH2-mutant, ATRX loss (median survival 4.25 years);

•All other tumors with possible mutations of IDH1/IDH2 (13% of cases) and TP53 (26% of cases), but without alterations of ATRX,1p/19q, CIC, and FUBP1, or with their presence in combination with wild-type IDH (median survival 1.1 year).

Hartmann et al. [5] assessed the prognostic significance of IDH1/IDH2 mutations, MGMT promoter methylation, and patient age (≤60 vs. >60 years) in a combined set of AA and pGBM. Analysis of 338 cases revealed four molecular groups of tumors with significantly (p < 0.0001) different overall survival:

•IDH1-mutant, MGMT-methylated;

•IDH1-mutant, MGMT-unmethylated;

•IDHwild-type, MGMT-methylated;

•IDHwild-type, MGMT-unmethylated.

In general, tumors carrying IDH1 mutations were associated with better survival irrespective of MGMT promoter methylation status. Distinction between WHO grade III and IV neoplasms within defined molecular groups had only a moderate, albeit important, effect on prognosis.

Labussière et al. [36] evaluated TERT promoter mutations along with mutations of IDH1/IDH2 and TP53, HD of CDKN2A, EGFR amplification, MGMT promoter methylation, and LOH of chromosomes 9p and 10q, in 395 pGBM in adults. Four molecular groups of tumors were defined:

•IDH1/IDH2-mutant, TERT promoter wild-type, EGFR wild-type (median overall survival 37.6 months);

•IDH wild-type, TERT promoter wild-type, EGFR wild-type (median overall survival 26.5 months);

•TERT promoter mutation (median overall survival 13.8 months).

•TERT promoter wild-type, EGFR-amplified (median overall survival 13.3 months).

In general, absence of both TERT promoter mutations and EGFR amplification (21% of cases) was associated with significantly longer survival of patients, thus the two latter groups of tumors might be combined.

Since IDH1/IDH2 mutation in diffusely infiltrating gliomas is associated with the lowest prognostic hazard followed by that of 1p/19q co-deletion [4], in our opinion it is possible to define the following prognostic subgroups of such tumors (Fig. 5):

•“Double-positive” (IDH1/IDH2-mutant, 1p/19q co-deleted) with possible mutations of CIC,FUBP1, and TERT promoter, and intact ATRX, which incorporates “classic” OD/AOD and carry favorable prognosis;

Fig. 5. A model for genotype-based prognostic grouping of diffusely infiltrating gliomas in adults, mainly based on the presence of IDH1/IDH2mutations, 1p/19q co-deletion, and TP53 mutation. “Double-positive,” “single-positive,” and “triple-negative” tumors carry favorable, intermediate, and ill-defined prognosis, respectively, whereas primary glioblastoma (GBM) is associated with poor outcome. DA, diffuse astrocytoma; AA, anaplastic astrocytoma; OD, oligodendroglioma; AOD, anaplastic oligodendroglioma; mt, mutation; wt, wild-type; codel, co-deletion. Modified from Komori [4].

•“Single-positive” (IDH1/IDH2-mutant, 1p/19q non-codeleted) with associated mutation of TP53 and/or ATRX loss, which incorporates typical DA and their malignant derivatives, and carry intermediate prognosis; this group probably includes very rare (IDH wild-type, 1p/19q co-deleted) tumors; identification of glioblastoma-like genetic alterations among these neoplasms may serve as an additional prognostic marker indicating aggressive biological behavior;

•“Double-negative” (IDH wild-type, 1p/19q non-codeleted) with associated TERT promoter mutation and/or other genetic abnormalities typical for pGBM (e.g., alterations of CDKN2A, PTEN, EGFR, PDGFRA, etc.), which carry unfavorable prognosis;

•“Triple-negative” (IDH wild-type, TP53wild-type, 1p/19q non-codeleted) without ATRX loss, TERT promoter mutation or other specific genetic alterations; it may be encountered in tumors with variable morphology and WHO grades, and is associated with ill-defined prognosis.