Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma

Bosse, Kristopher R.; Giudice, Anna Maria; Lane, Maria; McIntyre, Brendan; Schürch, Patrick M.; Pascual‐Pasto, Guillem; Buongervino, Samantha N.; Suresh, Sriyaa; Fitzsimmons, Alana; Hyman, Adam; Gemino-Borromeo, Maria; Saggio, Jennifer; Berko, Esther R.; Daniels, Alexander A.; Stundon, Jennifer; Friedrichsen, Megan; Liu, Xin; Margolis, Matthew; Li, Marilyn M.; Tierno, Marni Brisson; Oxnard, Geoffrey R.; Maris, John M.; Mossé, Yaël P.

doi:10.1158/2159-8290.cd-22-0287

Cited by 25 publications

(20 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In comparison to other pediatric solid tumors, patients with neuroblastoma have significantly higher amounts of cfDNA circulating in plasma 36 . Additionally, our prior work and that of others have demonstrated that tumor-specific alterations can be monitored during the course of therapy through cfDNA surveillance and that cfDNA profiling captures dynamic tumor evolution in a way not possible with standard tumor biopsies 13,37,38 . Importantly, in the current study we demonstrated that a comparison of cfDNA and diagnostic tumor derived 5-hmC profiles identified a set of differentially hydroxymethylated genes associated with worse clinical outcome, supporting the hypothesis that cfDNA samples are enriched for DNA from the most aggressive, rapidly dividing tumor cells.…”

Section: Discussionmentioning

confidence: 96%

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma

Chennakesavalu

Moore

Chaves

et al. 2023

Preprint

View full text Add to dashboard Cite

Neuroblastoma is the most common extra-cranial solid tumor in childhood and epigenetic dysregulation is a key driver of this embryonal disease. In cell-free DNA from neuroblastoma patients with high-risk disease, we found increased 5-hydroxymethylcytosine (5-hmC) deposition on Polycomb Repressive Complex 2 (PRC2) target genes, a finding previously described in the context of bivalent genes. As bivalent genes, defined as genes bearing both activating (H3K4me3) and repressive (H3K27me3) chromatin modifications, have been shown to play an important role in development and cancer, we investigated the potential role of bivalent genes in maintaining a de-differentiated state in neuroblastoma and their potential use as a biomarker. We identified 313 genes that bore bivalent chromatin marks, were enriched for mediators of neuronal differentiation, and were transcriptionally repressed across a panel of heterogenous neuroblastoma cell lines. Through gene set variance analysis, we developed a clinically implementable bivalent signature. In three distinct clinical cohorts, low bivalent signature was significantly and independently associated with worse clinical outcome in high-risk neuroblastoma patients. Thus, low expression of bivalent genes is a biomarker of ultra-high-risk disease and may represent a therapeutic opportunity in neuroblastoma.

show abstract

Section: Discussionmentioning

confidence: 96%

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma

Chennakesavalu

Moore

Chaves

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…We, therefore, collected research-based serial ctDNA to characterize genomic changes in response to therapy, detect early disease progression and identify evolving alterations driving tumor heterogeneity and lorlatinib resistance. This same assay has already informed on the genetic evolution of relapsed neuroblastoma for patients not on this trial 46 . The full landscape of ctDNA genomic alterations in patients with ALK-driven refractory or relapsed neuroblastoma treated on this trial is detailed in a companion manuscript.…”

Section: Discussionmentioning

confidence: 98%

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results

Goldsmith

Park

Kayser

et al. 2023

Nat Med

Self Cite

View full text Add to dashboard Cite

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45–115 mg/m2/dose in children and 100–150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib’s rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988.

show abstract

“…More recently, Lodrini et al., showed the applicability of detecting tumor-derived cfDNA MYCN and ALK copy number alterations and ALK hotspot mutations in longitudinal plasma samples from patients with neuroblastoma ( 30 ). The study of Bosse et al., that predominantly included neuroblastoma patients with an event (91%), showed at least one pathogenic genomic alteration detected in 56% of the samples ( 31 ). However, only 20% and 10% of neuroblastoma tumors harbor MYCN amplification or ALK mutation, respectively ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors

et al. 2023

View full text Add to dashboard Cite

BackgroundLiquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors.Materials and methodsRegions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed.ResultsTLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse.ConclusionWe demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols.

show abstract

Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma

Cited by 25 publications

References 66 publications

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results

Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors

Contact Info

Product

Resources

About