Abstract
Background: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). Materials and Methods: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. Results: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. Conclusions: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients.
Highlights
High-grade gliomas represent aggressive primary brain tumors in adults; the progress of recent years has allowed us to obtain more information about these diseases, from both a clinical and a molecular point of view, treatment options remain limited and prognosis remains poor
In high-grade gliomas (HGG) patients, immune checkpoint inhibitors demonstrated poor efficacy: nivolumab failed to extend survival compared to standard treatment in two phase III trials analyzing newly diagnosed MGMT (O6-Mthylguanine-DNA Methyltrasferase)-methylated and recurrent glioblastoma patients [14]; pembrolizumab showed poor results in a phase Ib trial compared to bevacizumab, in selected recurrent PD-L1 positive, glioblastoma patients [15]
Molecular analyses were done on the primary tumor in 85% of cases and in 15% on recurrent tumors ; mismatch repair (MMR) status analysis was performed after a first line of concomitant temozolomide and radiation therapy
Summary
High-grade gliomas (grade III and IV gliomas according to 2016 WHO CNS classification [1]) represent aggressive primary brain tumors in adults; the progress of recent years has allowed us to obtain more information about these diseases, from both a clinical and a molecular point of view, treatment options remain limited and prognosis remains poor. In HGG patients, immune checkpoint inhibitors demonstrated poor efficacy: nivolumab failed to extend survival compared to standard treatment in two phase III trials analyzing newly diagnosed MGMT (O6-Mthylguanine-DNA Methyltrasferase)-methylated and recurrent glioblastoma patients [14]; pembrolizumab showed poor results in a phase Ib trial compared to bevacizumab, in selected recurrent PD-L1 positive, glioblastoma patients [15] In all these studies, patient selection according to MMR status or TMB (Tumor Mutational Burden) was not performed. In order to improve knowledge of MMR status in high-grade gliomas and in consideration of its possible predictive role of immune checkpoint inhibitor efficacy, we performed a large multicenter study to investigate the frequency and the type of immunohistochemical loss of MMR protein expression, its association with clinical, histological, and molecular characteristics, and its correlation with survival in HGG patients. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients
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