Study on the Extent of Resection Threshold in Different Molecular Subtypes of Newly Diagnosed IDH-wildtype Glioblastoma

Introduction

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Although surgical resection, radiotherapy, and chemotherapy are the current standard treatment regimens, the prognosis of GBM remains poor, with a median survival of only about 15 months. An increasing number of studies have shown that the extent of tumor resection is one of the key factors affecting the prognosis of GBM patients. However, previous studies focused on IDH gene status and MGMT methylation status, while ignoring the relationship between other molecular biological subtypes and the extent of resection.

Study Design

This study included 138 patients with newly diagnosed IDH-wildtype GBM. A semi-automatic software was used to analyze pre- and post-operative imaging data to measure tumor volume and extent of resection. Targeted next-generation sequencing was also performed on tumor specimens to analyze the mutation status of 205 tumor-related genes.

The researchers used recursive partitioning analysis (RPA) and Cox regression models to evaluate the relationship between the extent of resection, residual tumor volume, and overall survival in patients with different gene mutation statuses, and to identify the optimal thresholds for extent of resection and residual tumor volume.

Key Findings

1. In the multivariate analysis, patients with an extent of resection ≥ 88% had a 44% longer overall survival compared to those with an extent of resection < 88% (hazard ratio 0.56, P=0.030).

2. For patients with mutations in the TP53 pathway genes (TP53, MDM2, and MDM4), the median overall survival was 10.5 months for those with an extent of resection < 89% and 18.8 months for those with an extent of resection ≥ 89% (hazard ratio 2.78, P=0.013). However, in patients with wildtype TP53 pathway, the extent of resection was not associated with overall survival.

3. For patients with PTEN gene mutations, the median overall survival was 9.5 months for those with an extent of resection < 87.69% and 20.4 months for those with an extent of resection ≥ 87.69% (hazard ratio 4.53, P<0.001). In PTEN wildtype patients, the extent of resection was not associated with prognosis.

4. A residual tumor volume ≥ 1.09 cm³ was associated with poor prognosis, but no differences in residual tumor volume thresholds were found among different gene subtypes.

Significance

This study found that the mutation status of the TP53 pathway and PTEN genes can divide IDH-wildtype GBM patients into different subgroups, in which the impact of tumor resection extent on prognosis differs. Patients with TP53 pathway or PTEN mutations may benefit from more extensive surgical resection. Therefore, the molecular biological features of the tumor should be considered when formulating surgical strategies for GBM. Additionally, for patients with incomplete initial surgical resection, a second surgery to optimize the extent of resection based on their genotype may be beneficial.

The novelty of this study lies in its first attempt to link GBM genotypes with the extent of resection, providing a theoretical basis for individualized surgical plans. The results can help guide neurosurgeons in developing optimal surgical strategies based on the patient’s molecular subtype.

Study Overview

This study was conducted by a multidisciplinary team from the McGovern Medical School at The University of Texas Health Science Center at Houston, including experts in neurosurgery, pathology, and computer science. The research findings were published online in the journal Neurosurgery on April 30, 2024.