Clinical and immunological correlates of long term survival in glioblastoma

Abstract

Glioblastoma (GBM) is the most common and most aggressive type of primary brain tumour in adults. It represents 54% of all gliomas and 16% of all brain tumours (Ostrom et al. 2016). Despite surgery and treatment with radiotherapy plus an oral alkylating agent, temozolomide (TMZ), tumours invariably recur, and the patient survival is an average of ~14–16 months. In this review we summarise the current understanding of multiple factors that may affect survival of patients with GBMs. In particular, we discuss recent advancements in surgery and detection of genomic-based markers with prognostic values, such as IDH1/2 mutations, MGMT gene promoter methylation, and TERT gene promoter alterations. We address the issue of tumour heterogeneity and evolution that may result in different parts of the same tumour exhibiting different GBM subtypes and in subtype switching, which may restrict the usefulness of the expression-based classification as a prognostic marker before relapse. The determinants of long-term survival in patients with IDH1/2wt GBM, beyond MGMT promoter methylation, remain to be identified, and even the absence of both IDH1/2 mutations and MGMT promoter methylation does not preclude long-term survival. These findings suggest that host-derived factors, such as immune system responsiveness may contribute to long-term survival in such patients. We report the results of high-throughput approaches, suggesting links between long-term survival and enhanced immune-related gene expression. The further search for new gene candidates, promoter methylation status, and specific features of host immunity should provide prognostic biomarkers for the evaluation of survival of IDH1 wild-type/non-G-CIMP GBMs.

Improved survival of Swedish glioblastoma patients treated according to Stupp

“…These factors were not investigated in this study, apart from the MGMT‐status for the 2‐year survivors. The majority of the survivors in our study had methylated MGMT, as would be expected from the literature . The low survival rate in patients younger than 50 years is somewhat conflicting and probably due to the low number of patients.…”

Genetic secrets of long-term glioblastoma survivors

“…Major issues in glioblastoma management are its intracranial location, fast growth, and infiltrative nature that leads to incomplete surgical resection and development of therapy resistance [37]. Furthermore, chemotherapy offers limited options due to poor drug penetration through the blood-brain barrier [51]. Identifying the cell of origin of glioblastoma is of great importance for patient care.…”

“…So far, the only confirmed molecular biomarkers for glioblastoma are O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation, IDH1/2 mutations, and loss of heterozygosity in chromosome 1p/19q [3,14,51,52]. The alkylating agent temozolomide causes DNA damage by adding alkyl groups to guanine O 6 position.…”

“…Nevertheless, when MGMT promoter is methylated, the protein expression is decreased, which leads to better sensitivity of tumor to temozolomide chemotherapy [53]. The survival of patients with MGMT promoter methylation is significantly higher (21.7 months) compared to patients with non-methylated promoter (15.3 months) [51]. IDH mutations are correlated with excessive genome methylation resulting in A schematic representation of appearance of symptoms and glioblastoma diagnosis by immunohistochemistry, followed by two possible treatment approaches: conventional therapy is aiming at the majority of cells, which in most cases results in tumor recurrence; and targeted therapy that targets a specific cell type or cell property that will ultimately lead to tumor shrinking.…”

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

“…The study of exceptional responders can be viewed in this light, as the tumors in these patients are often characterized by genetic or epigenetic events that confer exquisite sensitivity to the treatment rendered. Most studies define exceptional responders as the <10% of patients who markedly respond to a therapy that confer little benefit to the remaining population (2). Here, we adopt this definition and study the <10% of patients with glioblastoma (World Health Organization grade IV glioma), the most common form of primary brain cancer in adults, who survive beyond two years after the standard-of-care treatment with concurrent radiation and temozolomide (TMZ).…”