CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response

Stallard, Stefanie; Savelieff, Masha G.; Wierzbicki, Kyle; Mullan, Brendan; Miklja, Zachary; Bruzek, Amy K.; García, Teresa; Siada, Ruby; Anderson, Britt E.; Singer, Benjamin H.; Hashizume, Rintaro; Carcaboso, Ángel M.; McMurray, Kaitlin Q.; Heth, Jason; Muraszko, Karin M.; Robertson, Patricia L.; Mody, Rajen; Venneti, Sriram; Garton, Hugh; Koschmann, Carl

doi:10.1186/s40478-018-0580-7

Cited by 54 publications

(55 citation statements)

References 17 publications

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“…Liquid biopsy has emerged as a promising diagnostic tool for improved patient monitoring, also in H3K27M glioma (30,52). The utility in real-world application, however, has not yet been widely investigated.…”

Section: Discussionmentioning

confidence: 99%

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

et al. 2020

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Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either Gojo et al.Personalized Treatment of H3K27M Glioma miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

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Section: Discussionmentioning

confidence: 99%

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

et al. 2020

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“…48 CSF-tDNA for DMG Our literature review returned 4 publications that reported the results of CSF-tDNA assays in diffuse gliomas. 21,29,39,49 We describe these studies in the order in which they were published.…”

Section: Methods Of Ctdna and Csf-tdna Detectionmentioning

confidence: 99%

Liquid biopsy for pediatric diffuse midline glioma: a review of circulating tumor DNA and cerebrospinal fluid tumor DNA

Azad

Jin

Bernhardt

et al. 2020

Neurosurgical Focus

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Diffuse midline glioma (DMG) is a highly malignant childhood tumor with an exceedingly poor prognosis and limited treatment options. The majority of these tumors harbor somatic mutations in genes encoding histone variants. These recurrent mutations correlate with treatment response and are forming the basis for molecularly guided clinical trials. The ability to detect these mutations, either in circulating tumor DNA (ctDNA) or cerebrospinal fluid tumor DNA (CSF-tDNA), may enable noninvasive molecular profiling and earlier prediction of treatment response. Here, the authors review ctDNA and CSF-tDNA detection methods, detail recent studies that have explored detection of ctDNA and CSF-tDNA in patients with DMG, and discuss the implications of liquid biopsies for patients with DMG.

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“…CSF may also be centrifuged to rid the sample of any accidentally collected debris and flash frozen at −80°C. Stallard et al 20 have shown that ctDNA, specifically copy numbers of the H3K27 mutation, could be isolated from DIPG cells in vitro through the use of ddPCR. In their study, DIPG007 cells were cocultured with normal human astrocytes, and samples from the culture media were intermittently harvested and analyzed.…”

Section: Ctdnamentioning

confidence: 99%

“…The clinical utility of liquid biopsies lies not only in the possibility of diagnosis but also in the monitoring of tumor burden and response to treatment over time. In addition to showing that ctDNA can be isolated from DIPG cells in vitro, Stallard et al 20 demonstrated a change in ctDNA after the irradiation of tumor cells. Specifically, ctDNA containing the H3K27 mutation increased significantly in the 72-120 hours after treatment with 8 Gy of radiation.…”

Section: Monitoring the Response To Treatmentmentioning

confidence: 99%

Liquid biopsies for the diagnosis and surveillance of primary pediatric central nervous system tumors: a review for practicing neurosurgeons

Bounajem¹,

Karsy

Jensen

2020

Neurosurgical Focus

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OBJECTIVEPrimary brain tumors are the most common cause of cancer-related deaths in children and pose difficult questions for the treating physician regarding issues such as the risk/benefit of performing a biopsy, the accuracy of monitoring methods, and the availability of prognostic indicators. It has been recently shown that tumor-specific DNA and proteins can be successfully isolated in liquid biopsies, and it may be possible to exploit this potential as a particularly useful tool for the clinician in addressing these issues.METHODSA review of the current literature was conducted by searching PubMed and Scopus. MeSH terms for the search included “liquid biopsy,” “brain,” “tumor,” and “pediatrics” in all fields. Articles were reviewed to identify the type of brain tumor involved, the method of tumor DNA/protein analysis, and the potential clinical utility. All articles involving primary studies of pediatric brain tumors were included, but reviews were excluded.RESULTSThe successful isolation of circulating tumor DNA (ctDNA), extracellular vesicles, and tumor-specific proteins from liquid biopsies has been consistently demonstrated. This most commonly occurs through CSF analysis, but it has also been successfully demonstrated using plasma and urine samples. Tumor-related gene mutations and alterations in protein expression are identifiable and, in some cases, have been correlated to specific neoplasms. The quantity of ctDNA isolated also appears to have a direct relationship with tumor progression and response to treatment.CONCLUSIONSThe use of liquid biopsies for the diagnosis and monitoring of primary pediatric brain tumors is a foreseeable possibility, as the requisite developmental steps have largely been demonstrated. Increasingly advanced molecular methods are being developed to improve the identification of tumor subtypes and tumor grades, and they may offer a method for monitoring treatment response. These minimally invasive markers will likely be used in the clinical treatment of pediatric brain tumors in the future.

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CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response

Cited by 54 publications

References 17 publications

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

Liquid biopsy for pediatric diffuse midline glioma: a review of circulating tumor DNA and cerebrospinal fluid tumor DNA

Liquid biopsies for the diagnosis and surveillance of primary pediatric central nervous system tumors: a review for practicing neurosurgeons

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