Dataset Information

Predictors of outcome in pleomorphic xanthoastrocytoma.

ABSTRACT:

Background

Pleomorphic xanthoastrocytomas (PXA) are circumscribed gliomas that typically have a favorable prognosis. Limited studies have revealed factors affecting survival outcomes in PXA. Here, we analyzed the largest PXA dataset in the literature and identify factors associated with outcomes.

Methods

Using the Surveillance, Epidemiology, and End Results (SEER) 18 Registries database, we identified histologically confirmed PXA patients between 1994 and 2016. Overall survival (OS) was analyzed using Kaplan-Meier survival and multivariable Cox proportional hazard models.

Results

In total, 470 patients were diagnosed with PXA (males = 53%; median age = 23 years [14-39 years]), the majority were Caucasian (n = 367; 78%). The estimated mean OS was 193 months [95% CI: 179-206]. Multivariate analysis revealed that greater age at diagnosis (≥39 years) (3.78 [2.16-6.59], P < .0001), larger tumor size (≥30 mm) (1.97 [1.05-3.71], P = .034), and postoperative radiotherapy (RT) (2.20 [1.31-3.69], P = .003) were independent predictors of poor OS. Pediatric PXA patients had improved survival outcomes compared to their adult counterparts, in which chemotherapy (CT) was associated with worse OS. Meanwhile, in adults, females and patients with temporal lobe tumors had an improved survival; conversely, tumor size ≥30 mm and postoperative RT were associated with poor OS.

Conclusions

In PXA, older age and larger tumor size at diagnosis are risk factors for poor OS, while pediatric patients have remarkably improved survival. Postoperative RT and CT appear to be ineffective treatment strategies while achieving GTR confer an improved survival in male patients and remains the cornerstone of treatment. These findings can help optimize PXA treatment while minimizing side effects. However, further studies of PXAs with molecular characterization are needed.

SUBMITTER: Dono A

PROVIDER: S-EPMC8049416 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

Project description:Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A-PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild-type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A-PXA. Methylation-based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non-recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow-up data were available (median follow-up, 5.4 years). Overall survival was significantly different between PXA and A-PXA (5-year OS 80.8% vs. 47.6%; P = 0.0009) but not progression-free survival (5-year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation-based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation-based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well-defined morphology.