Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma

Background Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. Methods We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. Results The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. Conclusions We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

PEDT-1 Integrated diagnoses of pediatric gliomas in our institute by cIMPACT-NOW recommendations

Purpose:Since many genetic abnormalities in glioma have been revealed in recent years, Integrated diagnoses are necessary in the updated fourth edition of the WHO Classification of Tumors of the Central Nervous System(CNS) published in 2016. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classification. We retrospectively classified pediatric gliomas in our hospital in accordance with cIMPACT-NOW recommendations. Methods: This study includes 13 consecutive glioma patients under the age of 18 who underwent surgical resection at our hospital from 2000 to 2021. Histopathological diagnoses and molecular status such as IDH, H3F3A and BRAF were analyzed. Results: There were four females and nine males, ranging in age from 0 to 17 years, median 9.0 years. Three pilocytic astrocytomas (PA) and a polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had BRAF fusion. Four cases were classified as Diffuse midline glioma, H3K27M-altered. Two cases were classified as Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. No genetic alteration was observed in two diffuse astrocytoma cases. An anaplastic oligodendroglioma case with PDGFRA amplification could not be classified as any new entity. All three PA cases with BRAF fusion occurred in cerebellum and all four H3K27M altered cases occurred in midline location such as thalamus, brainstem and cervical spinal cord. Six cases which were classified as pediatric-type diffuse high grade gliomas had poor prognosis. Conclusion:Genetic status is associated to tumor location and patients prognosis. Integrated diagnoses are important in pediatric glioma patients.

CTNI-06. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

SYST-04. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Dataset Size Sensitivity Analysis of Machine Learning Classifiers to Differentiate Molecular Markers of Pediatric Low-Grade Gliomas Based on MRI

Machine learning (ML) approaches can predict BRAF status of pediatric low-grade gliomas (pLGG) on pre-therapeutic brain MRI. The impact of training data sample size and type of ML model is not established. In this bi-institutional retrospective study, 251 pLGG FLAIR MRI datasets from 2 children’s hospitals were included. Radiomics features were extracted from tumor segmentations and five models (Random Forest, XGBoost, Neural Network (NN) 1 (100:20:2), NN2 (50:10:2), NN3 (50:20:10:2)) were tested to classify them. Classifiers were cross-validated on data from institution 1 and validated on data from institution 2. Starting with 10% of the training data, models were cross-validated using a 4-fold approach at every step with an additional 2.25% increase in sample size. Two-hundred-twenty patients (mean age 8.53 ± 4.94 years, 114 males, 67% BRAF fusion) were included in the training dataset, and 31 patients (mean age 7.97±6.20 years, 18 males, 77% BRAF fusion) in the independent test dataset. NN1 (100:20:2) yielded the highest area under the receiver operating characteristic curve (AUC). It predicted BRAF status with a mean AUC of 0.85, 95% CI [0.83, 0.87] using 60% of the training data and with mean AUC of 0.83, 95% CI [0.82, 0.84] on the independent validation data set.

Evaluation of BRAF Gene Status in Gliomas

Background: Development of different molecular markers has given a new insight in the glioma management. KIAA1549-BRAF gene fusion has a diagnostic and prognostic significance. Aim: The aim of this study was to determine the KIAA1549-BRAF gene fusion in glioma and their correlation with various clinical parameters. Material and Methods: Forty cases of glioma were studied for KIAA1549-BRAF gene fusion by reverse transcription-PCR (RT-PCR). Results: Overall, KIAA1549-BRAF gene fusion was found in 22% (9/40) cases of glioma. Children had higher KIAA1549-BRAF fusion (72%; 8/11) as compared to adults (10%; 3/29) and this difference was statistically significant. Cerebellar location of tumor was significantly associated with KIAA1549-BRAF fusion. KIAA1549-BRAF fusion was highest in pilocytic astrocytoma (89%), and this difference was statistically significant. Statistically significant difference was noted between KIAA1549-BRAF fusion expression and WHO grade I glioma. Conclusion: Overall, KIAA1549-BRAF gene fusion was found in 22% (9/40) cases of glioma. Childhood age, pilocytic astrocytoma histology, cerebellar location and WHO grade I tumor were significantly associated with KIAA1549-BRAF gene fusion.

The MKRN1-BRAF exon4-exon9 fusion is a targetable oncogenic driver

Background: BRAF, when mutated at V600E, is a potent oncogenic driver in melanoma, lung and colorectal cancer with well understood signaling mechanisms and established treatment guidelines. Non-V600E mutations are less common, more functionally diverse and do not yet have clear treatment guidelines. One class of non-V600E mutations are BRAF fusion genes which typically involve the C-terminal kinase domain of BRAF joined to one of a wide repertoire of potential N-terminal fusion partners. Here, we functionally characterized an MKRN1-BRAF fusion gene which we detected in multi-gene panel sequencing of a metastatic colorectal tumor. Methods: Levels of MEK/ERK pathway activity were evaluated by western blotting in HEK293 cells ectopically expressing MKRN1-BRAF or a series of other BRAF constructs. Dependence on dimerization was evaluated by introducing a dimerization deficiency mutation and drug sensitivity was evaluated by treatment with sorafenib, dabrafenib and trametinib. Results: MKRN1-BRAF potently activated MEK/ERK signaling and did not require dimerization for activity. Among the inhibitors evaluated, trametinib most effectively suppressed MKRN1-BRAF driven pathway activity. Conclusion: Our data demonstrate that the MKRN1-BRAF fusion gene encodes an oncoprotein that strongly activates MEK/ERK signaling in a trametinib-sensitive manner.

Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event

Infantile/congenital fibrosarcoma (IFS) is the most common soft tissue tumor in children less than one year of age. The most common anatomic site of IFS is in the extremities or trunk, and rarely in the abdomen or retroperitoneum. Approximately 70-90% of cases are characterized by a distinct t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. As such, TRK inhibitors are considered frontline therapy in TRK-fusion positive IFS. The ETV6-NTRK3 fusion is also detected in congenital mesoblastic nephroma (CMN) and less frequently in myeloid leukemias, secretory breast carcinoma, and mammary-type secretory carcinoma of the skin and salivary glands. Infrequently, cases of tumors with IFS-like morphology without the characteristic ETV6-NTRK3 gene fusion have been identified. Herein, an ETV6-NTRK3 fusion negative spindle cell sarcoma with IFS-like morphology subjected to genomic profiling revealed a PDE10A-BRAF fusion, a fusion event that has been detected previously in an isolated case of undifferentiated infantile sarcoma.