Tejus A. Bale

PURPOSE: A subset of brainstem gliomas harbor an isocitrate dehydrogenase 1/2 ( IDH1/2 ) mutation, which has important prognostic and treatment implications. We evaluated the radiographic features and the sensitivity of magnetic resonance spectroscopy (MRS) and cerebrospinal fluid cell-free DNA (CSF cfDNA) sequencing at detecting IDH1/2 mutations in a cohort of these tumors. METHODS: We identified IDH-mutant brainstem gliomas by retrospective chart review. IDH1/2 mutation was established by biopsy, CSF cfDNA sequencing, and/or the presence of a 2-hydroxyglutarate (2HG) peak by 3-Tesla MRS. RESULTS: Twenty-one patients with IDH-mutant brainstem gliomas were identified, 57% male with a median age of 26 (6-59) years. All tumors involved the pons and/or abutted the brachium pontis. Although 18 (86%) of 21 were nonenhancing, only one of 21 demonstrated T2-FLAIR mismatch. An IDH1/2 mutation was identified by biopsy in 17 and by CSF cfDNA sequencing in three; in the final patient, an IDH1/2 mutation was inferred by the presence of a 2HG peak. The sensitivity of MRS at identifying 2HG in patients with confirmed IDH1/2 mutations was 64.3% (95% CI, 35.1 to 87.2), which increased to 85.7% (95% CI, 42.1 to 99.6) when the study was performed before treatment. The 2HG peak was absent in all four patients with a repeat MRS after completion of radiation. IDH1/2 mutation was identified in four of seven patients who underwent sequencing of CSF cfDNA. In this cohort, median progression-free survival and overall survival were 57.6 and 90.4 months, respectively. An objective response to radiotherapy was observed in 76%. CONCLUSION: IDH-mutant brainstem gliomas have a characteristic clinical and radiographic phenotype. MRS is more sensitive than CSF cfDNA sequencing for noninvasively identifying the presence of an IDH1/2 mutation when performed before radiotherapy.

A wide spectrum of genomic events leading to dysregulated fibroblast growth factor receptor (FGFR) signaling have been reported across low-grade and high-grade glial/glioneuronal tumors. These events include structural alterations, such as gene fusions and duplications, as well as recurrent mutations in FGFR1–3. Several FGFR-selective tyrosine kinase inhibitors (TKIs) have received regulatory approval for clinical use, and newer isoform-specific FGFR inhibitors are under investigation. Among pediatric patients with FGFR-altered low-grade gliomas (LGGs) enrolled in clinical trials with FGFR inhibitors, promising clinical efficacy regardless of alteration type (fusion or mutation) has been observed in a subset. In contrast, limited responses have been reported in adults with FGFR3–TACC3 fused IDH-wild-type glioblastoma. FGFR inhibitor toxicities include hyperphosphatemia, diarrhea, skin, nail, and ocular toxicity. Importantly, in skeletally immature patients, bone toxicities, such as accelerated growth spurts, limb fractures, and scoliosis, have been reported and require close monitoring. Co-occurring genomic alterations in MAPK pathway signaling components downstream of FGFR may drive intrinsic and acquired resistance to FGFR inhibitors. Further preclinical studies in relevant models of FGFR-altered pediatric gliomas are needed to help inform the development of novel, more effective and less toxic treatment strategies, as well as the rational design of clinical trials.

Supplementary Figure 2. Overview of the analytical pipeline for interpretation of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA).

Supplementary Figure 1. Overview of the workflow involved from patient outreach, screening, enrollment, testing and return of results to local physician/patient.

Supplementary Table 2. Clinical, demographic and molecular characteristics of pediatric solid tumor patients enrolled on the Make an Impact program.

Supplementary Table 1. Table representing country of referral for patients enrolled on the Make An Impact program (n = 63).

Supplementary Table 3. Clinical, demographic and molecular characteristics of pediatric CNS tumor patients enrolled on the Make an Impact program.

Purpose: To address financial barriers that limit access to genomic profiling and precision medicine, philanthropy-supported clinical genomic testing was offered worldwide at no cost to patients with select rare cancers via the Make-an-IMPACT program. Herein, we report our findings in pediatric patients with solid or central nervous system tumors. Experimental Design: Tumor DNA or cerebrospinal fluid (CSF)-derived ctDNA was analyzed using the MSK-IMPACT assay, supplemented by targeted RNA panel sequencing in select cases. The results were returned to the patients/families and treating oncologists. Results: Sixty-three patients from 11 countries had successful MSK-IMPACT testing. The results provided clinically relevant new diagnostic or prognostic information in 41% and 38% of patients with solid and central nervous system tumors, respectively. Potentially therapeutically actionable alterations were identified in 44% of pediatric solid tumor and 21% of pediatric CSF-derived ctDNA samples, respectively. Four patients subsequently received molecularly guided therapy, resulting in partial responses in two and prolonged stable disease in one. Serial tumor and CSF sampling identified resistance mutations in two patients, informing additional molecularly targeted therapy recommendations. Conclusions: The Make-an-IMPACT program provided global access to state-of-the-art tumor and CSF genomic profiling across a diverse cohort of patients with pediatric cancer, providing clinically relevant and actionable diagnostic, prognostic, and therapeutic information reported in real-time to patients and local physicians.

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multimodality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of LM, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of LM and serve as a platform for further discussion and patient advocacy.