scholarly journals ACTR-42. PI3K/mTOR PATHWAY ACTIVATION SELECTED PHASE II STUDY OF EVEROLIMUS (RAD001) WITH AND WITHOUT TEMOZOLOMIDE IN THE TREATMENT OF ADULT PATIENTS WITH SUPRATENTORIAL LOW-GRADE GLIOMA [NCT NCT02023905]

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi22-vi23
Author(s):  
Jennie Taylor ◽  
Annette Molinaro ◽  
Eduardo Rodriguez Almaraz ◽  
Ciara Downey ◽  
Joanna Phillips ◽  
...  
Keyword(s):  
Survival Data ◽  
Primary Outcome ◽  
Pi3k Pathway ◽  
Mtor Pathway ◽  
Low Grade ◽  
Diffuse Glioma ◽  
Eligibility Criteria ◽  
Low Grade Gliomas ◽  
Pathway Activation ◽  
Central Pathology

Abstract Functional activation of the PI3K/AKT/mTOR pathway is seen in ~50% of low-grade gliomas and correlates with worse survival. Everolimus is a selective inhibitor of mTOR that targets mTOR-raptor signaling, halting proliferation and indirectly inhibiting angiogenesis. This phase 2 study evaluated the efficacy of everolimus in untreated grade II diffuse glioma. Patients were stratified by 1p19q status and PI3K pathway activation (via phosphorylation of PRAS-40) into three arms: 1) 1p19q intact, PRAS-40 phosphorylated received everolimus monotherapy; 2) 1p19q intact, PRAS-40 not phosphorylated received everolimus with temozolomide; and 3) 1p19q co-deleted received everolimus monotherapy. Primary outcome was landmark PFS-33 months for Arms 1 and 2; and PFS-38 months for Arm 3 (null hypothesis 50% for all arms individually). Key eligibility criteria included central pathology confirmation, no prior treatment, and initiation of everolimus within 120 days of most recent tissue sampling. From 05/2014 to 07/2018, 27 patients were enrolled – 16 into Arm 1; 2 into Arm 2; and 9 into Arm 3. Median age at enrollment was 38 years (range 21 – 65); median KPS 90 (range 70 – 100) and a majority were male (74%). Although follow-up is not complete, as of 05/2019 11 of 16 patients had progressed prior to 33 months in Arm 1, and 5 of 9 patients had progressed prior to 38 months in Arm 3. Toxicity was as expected with frequent grade 1/2 AEs of diarrhea, rash, and mucositis. Headache was the most common grade 3 AE and was seen in three cases. The study was closed prematurely secondary to slow accrual and loss of drug support. Updated survival data as well as results of secondary and exploratory analyses will be reported. In summary, everolimus was well tolerated in previously untreated low-grade gliomas. However, it failed to meet primary outcome of extending PFS in this population.

Updated predictive analysis of the WHO-defined molecular subgroups of low-grade gliomas within the high-risk treatment arms of NRG Oncology/RTOG 9802.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2002-2002 ◽  
Author(s):  
Erica Hlavin Bell ◽  
Minhee Won ◽  
Jessica L. Fleming ◽  
Aline P. Becker ◽  
Joseph P. McElroy ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Survival Data ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Significant Difference ◽  
Post Hoc

2002 Background: This study sought to update the predictive significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/noncodel, and IDHmt/codel) in the subset of specimens available for analysis in NRG Oncology/RTOG 9802, a phase III trial of high-risk low-grade gliomas (LGGs) treated with radiation (RT) with and without PCV after biopsy/surgical resection. Notably, this is the first phase III study to evaluate the predictive value of the WHO subgroups in LGGs using prospectively-collected, well-annotated long-term overall survival data, in a post-hoc analysis. Methods: IDH1/2 mutation status was determined by immunohistochemistry and/or next-generation sequencing. 1p/19q status was determined by Oncoscan and/or 450K methylation data. Treatment effects on overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a secondary and exploratory analysis. Results: Of all the randomized eligible high-risk G2 patients (N = 251) in NRG Oncology/RTOG 9802, 106(42%) patients had tissue available with sufficient quality DNA for profiling. Of these, 80(75%) were IDHmut; 43(41%) were IDHmut/non-co-deleted, 37(35%) were IDHmut/co-deleted, and 26(24%) were IDHwt. Upon univariate analyses, no significant difference in either PFS or OS was observed with the addition of PCV in the IDHwt subgroup. Both the IDHmut/non-co-deleted and IDHmut/co-deleted subgroups were significantly correlated with longer PFS (HR = 0.32; p = 0.003; HR = 0.13; p < 0.001) and OS (HR = 0.38; p = 0.013; HR = 0.21; p = 0.029) in the RT plus PCV arm, respectively. Conclusions: Our analyses suggest that both IDHmut/non-co-deleted and IDHmut/co-deleted subgroups received benefit from treatment with PCV although sample size is limited and analyses are post-hoc. Our results also support the notion that IDHwt high-risk LGG patients do not benefit from the addition of PCV to RT. Funding: U10CA180868, U10CA180822, and U24CA196067. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01, BTFC, OSU-CCC (all to AC). Clinical trial information: NCT00003375.

Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation

2021 ◽  
Author(s):  
Katherine T Lind ◽  
Hannah V Chatwin ◽  
John DeSisto ◽  
Philip Coleman ◽  
Bridget Sanford ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Immunofluorescent Staining ◽  
Low Grade ◽  
Normal Brain ◽  
Mapk Activation ◽  
Low Grade Gliomas ◽  
Pathway Activation ◽  
Mitogen Activated Protein

Abstract Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

Predictive Evolution Factors of Incidentally Discovered Suspected Low-Grade Gliomas: Results From a Consecutive Series of 101 Patients

Neurosurgery ◽  
2020 ◽  
Author(s):  
Julien Boetto ◽  
Sam Ng ◽  
Hugues Duffau
Keyword(s):  
Surgical Resection ◽  
Incidental Finding ◽  
Prophylactic Surgery ◽  
Histopathological Diagnosis ◽  
Consecutive Series ◽  
Low Grade ◽  
Diffuse Glioma ◽  
Mri Findings ◽  
Low Grade Gliomas

Abstract BACKGROUND Incidentally discovered suspected diffuse low-grade gliomas (LGGs) on brain imaging pose a challenge to neurosurgeons. Modern surgical series of LGGs favor early prophylactic surgery with a maximal extent of resection. However, some nonevolutive lesions may mimic LGGs on magnetic resonance imaging (MRI). OBJECTIVE To determine objective criteria to advocate surgical resection of an incidentally discovered suspected LGG based upon MRI findings. METHODS The prospective cohort of patients referred to our institution for an incidental finding suggestive of LGG was retrospectively reviewed. Stable lesions underwent systematic serial MRI follow-up, while evolutive lesions underwent prophylactic surgery under awake conditions. Initial clinico-radiological features were compared between stable and evolutive lesions in order to determine predictive criteria of further evolution. RESULTS Among 101 patients referred for surgical resection of incidentally discovered suspected LGG in our center, 19 patients (18.8%) had nonevolutive MRI lesions after a mean follow-up of 46.9 ± 34.9 mo. Insular topography (P = .003), higher mean volume at discovery (19.2 vs 5.2 cm3, P &lt; .001), and adjacent sulcal effacement (P = .001) were associated with evolutive lesions. Histopathological diagnosis of LGG was confirmed in all surgical cases. CONCLUSION Increasing volume is an effective predictor of LGG diagnosis in incidental MRI findings, as all patients who subsequently underwent surgery had confirmed histopathological diagnosis of diffuse glioma. Approximately 18.8% of incidental findings were stable over time. Insular topography, adjacent sulcal effacement, and volume greater than 4.5 cm3 were predictive of further radiological progression. These significant elements will help neurosurgeons to define personalized strategies in this complex setting of incidental discovery.

scholarly journals Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival

2009 ◽  
Vol 97 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Sean M. McBride ◽  
Daniel A. Perez ◽  
Mei-Yin Polley ◽  
Scott R. Vandenberg ◽  
Justin S. Smith ◽  
...  
Keyword(s):  
Patient Survival ◽  
Mtor Pathway ◽  
Low Grade ◽  
Low Grade Gliomas

scholarly journals EVEROLIMUS (RAD001) AND THE MTOR PATHWAY IN LOW-GRADE GLIOMAS

2014 ◽  
Vol 16 (suppl 3) ◽  
pp. iii48-iii48
Author(s):  
J. L. Clarke ◽  
S. Chang ◽  
J. Phillips ◽  
A. Molinaro ◽  
M. Berger ◽  
...  
Keyword(s):  
Mtor Pathway ◽  
Low Grade ◽  
Low Grade Gliomas

scholarly journals Novel FGFR2-INA fusion identified in two low-grade mixed neuronal-glial tumors drives oncogenesis via MAPK and PI3K/mTOR pathway activation

2018 ◽  
Vol 136 (1) ◽  
pp. 167-169 ◽  
Author(s):  
Payal Jain ◽  
Lea F. Surrey ◽  
Joshua Straka ◽  
Minjie Luo ◽  
Fumin Lin ◽  
...  
Keyword(s):  
Mtor Pathway ◽  
Low Grade ◽  
Glial Tumors ◽  
Pathway Activation

scholarly journals P.092 The effect of the timing of surgery on outcomes for incidental low-grade gliomas: a systematic review

2019 ◽  
Vol 46 (s1) ◽  
pp. S38
Author(s):  
B Beland ◽  
A Albakr ◽  
D Ben-Israel ◽  
J Kelly
Keyword(s):  
Systematic Review ◽  
Survival Data ◽  
Progression Free Survival ◽  
Timing Of Surgery ◽  
Optimal Timing ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Improved Outcomes ◽  
Long Term Follow Up

Background: Although previous research has suggested that patients with incidentally discovered low-grade gliomas (iLGG) who undergo surgery prior to the appearance of symptoms have improved outcomes compared to those who are symptomatic, an ideal approach to managing iLGG is not well-established. The purpose of this systematic review is to identify all cases of iLGG in the literature and characterize the effect of the timing of surgery on survival. Methods: We searched EMBASE, MEDLINE, and PubMed for articles related to iLGG. After duplicates were removed, the articles were then screened based on strict inclusion and exclusion criteria. Results: We retrieved 24/1377 unique articles with a total of 175 patients who underwent surgery for iLGG prior to symptoms appearing. The average age was 29.1yrs (range 1-62) and the mean follow-up period was 56 months (range 1-234months). Unfortunately, only 6/24 articles reported progression-free survival (average 32.4months) and only 1/24 reported 10-year survival. Conclusions: The articles we identified favored an early intervention for iLGG, however, there was a considerable lack of long-term follow-up and survival data to justify such a claim. Further studies need to be performed with adequate follow-up data in order to determine the optimal timing of surgical intervention for these patients.

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