An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825

Gittleman, Haley; Lim, D.; Kattan, Michael W.; Chakravarti, Arnab; Gilbert, Mark R.; Lassman, Andrew B.; Lo, Simon S.; Machtay, Mitchell; Sloan, Andrew E.; Sulman, Erik P.; Tian, Devin; Vogelbaum, Michael A.; Wang, Tony J. C.; Penas‐Prado, Marta; Youssef, Emad; Blumenthal, Deborah T.; Zhang, Peixin; Mehta, Minesh P.; Barnholtz‐Sloan, Jill S.

doi:10.1093/neuonc/now208

Cited by 115 publications

(129 citation statements)

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“…Temozolomide treatment is more effective in female compared to male GBM patients Sex differences in GBM incidence have been repeatedly reported (5,(7)(8)(9)(10)(11). Moreover, several recent studies have suggested that being female is associated with better outcome from GBM in both adults and children (8)(9)(10)19). The introduction of temozolomide as a component of tri-modal care for adults with GBM has improved outcomes somewhat and highlighted factors, like MGMT promoter methylation, that significantly impact on response and survival (20,21).…”

Section: Resultsmentioning

confidence: 99%

“…While low-grade glioma incidence is nearly identical in males and females, malignant brain tumors in general occur more commonly in males, regardless of patient age or geographical location (6,15) (5,11). From multiple recent reports, GBM occurs with a male to female ratio of 1.6:1 (5,(8)(9)(10). More specifically, while concepts of molecular subtypes of GBM are still evolving (16), of the four originally described transcriptional subtypes of GBM, three -Mesenchymal, Proneural and Neural GBM -exhibit a 2:1 male to female incidence ratio, while Classical GBM occurs with equal incidence (17,18).…”

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confidence: 99%

“…In a study analyzing more than 27,000 patients, Trifiletti et al found that female sex was associated with longer survival (10). Similarly, female patients exhibited longer survival from gliosarcoma (8), and being female was associated with better outcome in a newly developed nomogram for predicting GBM patient survival (9). Thus, the elucidation of mechanisms for sex differences in the development and treatment of GBM has a substantial potential to improve outcome for all patients by refining our understanding of disease causation and outcome.…”

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confidence: 99%

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Clinically Important sex differences in GBM biology revealed by analysis of male and female imaging, transcriptome and survival data

Yang

Warrington

Taylor

et al. 2017

Preprint

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One Sentence Summary: Male and female glioblastoma are biologically distinct and maximal chances for cure may require sex-specific approaches to treatment. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/232744 doi: bioRxiv preprint first posted online Dec. 12, 2017; 2 Abstract:Sex differences in the incidence and outcome of human disease are broadly recognized but in most cases not adequately understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence, and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level, or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that temozolomide chemotherapy is more effective in female compared to male GBM patients. We then applied a novel computational algorithm to linked GBM transcriptome and outcome data, and identified novel sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling were identified as the critical determinants of survival for male and female patients, respectively. The clinical utility of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses, and that improved outcome for all patients might be accomplished via tailoring treatment to sex differences in molecular mechanisms.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Clinically Important sex differences in GBM biology revealed by analysis of male and female imaging, transcriptome and survival data

Yang

Warrington

Taylor

et al. 2017

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“…However, this classification strategy does not reflect the heterogeneity of the tumor, is prone to subjectivity and discordance among neuropathologists, falls short of predicting disease course and cannot reliably guide treatment 2 . Therefore, multiple research efforts have sought to identify molecular signatures that define more discrete glioma subgroups and have a greater impact and relevance in the clinical setting [1][2][3][4][5] .…”

Section: Gliomas: An Overviewmentioning

confidence: 99%

Glioma CpG Island Methylator Phenotype (G-CIMP): Biological and Clinical Implications

Malta

Souza

Sabedot

et al. 2017

Preprint

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Gliomas are a heterogenous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating genotypic and phenotypic features, thereby narrowing defined subgroups. The new classification recommends the molecular diagnosis of IDH mutational status in gliomas. IDH-mutant gliomas are prompt to manifest the CpG Island Methylator Phenotype (G-CIMP).Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provided a further refinement in glioma classification that is independent of grade and histology. This scheme is useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In the present review, we highlight the evolution of our understanding of G-CIMP subsets and how recent advances in characterizing gliomas' genome and epigenome may influence future basic and translational research.

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“…An understudied barrier to effective treatment is the inherent sex differences that exist within GBM (Ippolito et al, 2017;Kfoury et al, 2018;Sun et al, 2015;Sun et al, 2014). These differences are supported at the epidemiological level, with the male to female incidence ratio being 1.6:1 (Gittleman et al, 2017;Ostrom et al, 2016;Sun et al, 2015). Furthermore, these differences manifest clinically, with females showing a more dispersive phenotype radiographically (Yang et al, 2019) and males experiencing a poorer prognosis .…”

Section: Introductionmentioning

confidence: 99%

JAM-A functions as a female microglial tumor suppressor in glioblastoma

Turaga

Silver

Bayık

et al. 2019

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Number of figures: 4 main; 6 supplementalSummary Turaga et al. demonstrate that female microglia drive a more aggressive glioblastoma phenotype in the context of JAM-A deficiency. These findings highlight a sex-specific role for JAM-A and represent the first evidence of sexual dimorphism in the glioblastoma microenvironment. AbstractGlioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and aggressive in male compared to female patients, suggesting the existence of sex-specific growth, invasion, and therapeutic resistance mechanisms. While sex-specific molecular mechanisms have been reported at a tumor cellintrinsic level, sex-specific differences in the tumor microenvironment have not been investigated. Using transgenic mouse models, we demonstrate that deficiency of junctional adhesion molecule-A (JAM-A) in female mice enhances microglia activation, GBM cell proliferation, and tumor growth. Mechanistically, JAM-A suppresses anti-inflammatory/pro-tumorigenic gene activation via interferon-activated gene 202b (Ifi202b) and found in inflammatory zone (Fizz1) in female microglia. Our findings suggest that cell adhesion mechanisms function to suppress pathogenic microglial activation in the female tumor microenvironment, which highlights an emerging role for sex differences in the GBM microenvironment and suggests that sex differences extend beyond previously reported tumor cell intrinsic differences.

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An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825

Cited by 115 publications

References 24 publications

Clinically Important sex differences in GBM biology revealed by analysis of male and female imaging, transcriptome and survival data

Clinically Important sex differences in GBM biology revealed by analysis of male and female imaging, transcriptome and survival data

Glioma CpG Island Methylator Phenotype (G-CIMP): Biological and Clinical Implications

JAM-A functions as a female microglial tumor suppressor in glioblastoma

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