The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Langenberg, Karin P.S.; Looze, Eleonora J.; Molenaar, Jan J.

doi:10.3390/cancers13174324

Cited by 34 publications

(34 citation statements)

References 123 publications

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“…Molecularly guided targeted therapies have a high potential to improve outcomes for pediatric cancer patients. Yet, only 3-58% of patients receive molecularly guided therapies and even fewer report a positive response to treatment in NGS-guided trials (15). These unsatisfactory outcomes are likely the result of multiple limitations, including the reliance on genomics for target identification, which cannot capture plasticity of downstream transcriptional, translational and post-translational processes that impact target abundance and drug sensitivity, and the restricted debate by contributing new evidence of high retention of druggable targets in pediatric ALL.…”

Section: Discussionmentioning

confidence: 99%

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Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia

Lorentzian

Guo

Ergin

et al. 2022

Preprint

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Childhood acute lymphoblastic leukemia (ALL) genome landscapes indicate that relapses often arise from subclonal outgrowths. However, the impact of clonal evolution on the actionable proteome and response to targeted therapy is not known. Here, we present a comprehensive retrospective analysis of paired ALL diagnosis and relapsed specimen. Targeted next generation sequencing and proteome analysis indicated persistence of genome variants and stable proteomes through disease progression. Although variant-targeted therapies showed poor selectivity against viably-frozen tumor samples, paired samples showed high correlation of drug response. Proteome analysis prioritized PARP1 as a new pan-ALL target candidate; diagnostic and relapsed ALL samples demonstrated robust sensitivity to treatment with two PARP1/2 inhibitors. Together, these findings support initiating prospective precision oncology approaches at ALL diagnosis and emphasize the need to incorporate proteome analysis to prospectively determine tumor sensitivities, which are likely to be retained at disease relapse.

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Section: Discussionmentioning

confidence: 99%

“…To supplement NGS-guided target identification, some precision oncology initiatives are complementing genome analysis with additional molecular strategies such as RNA-seq or Methyl-seq (15,16,28). Our study is among the first to conduct comprehensive targeted and non-targeted, paired Dx and Relapse proteome analyses of pediatric ALL.…”

Section: Discussionmentioning

confidence: 99%

Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia

Lorentzian

Guo

Ergin

et al. 2022

Preprint

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“…Along with the development of precision medicine, a multidisciplinary molecular tumour board ( Figure 3 ) which provides individual patient reports is a significant step in the management of paediatric patients. The key role of the board is to assess the feasibility of pursuing actionable findings and the evaluation of a possible matched treatment and/or clinical trial [ 120 , 121 , 122 , 123 ].…”

Section: Incorporating Molecular Findings Into Clinicmentioning

confidence: 99%

“…A high percentage of reportable germline alterations in paediatric patients diagnosed with neoplasms, estimated between 6 and 35%, with an average of 12%, underlines the importance of performing germline NGS [ 120 , 121 , 122 , 123 ]. Haematological malignancies and solid tumours have a similar number of germline variants.…”

Section: Incorporating Molecular Findings Into Clinicmentioning

confidence: 99%

Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review

Filipiuk

Kozakiewicz

Kośmider

et al. 2022

Cancers

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The view of paediatric cancer as a genetic disease arises as genetic research develops. Germline mutations in cancer predisposition genes have been identified in about 10% of children. Paediatric cancers are characterized by heterogeneity in the types of genetic alterations that drive tumourigenesis. Interactions between germline and somatic mutations are a key determinant of cancer development. In 40% of patients, the family history does not predict the presence of inherited cancer predisposition syndromes and many cases go undetected. Paediatricians should be aware of specific symptoms, which highlight the need of evaluation for cancer syndromes. The quickest possible identification of such syndromes is of key importance, due to the possibility of early detection of neoplasms, followed by presymptomatic genetic testing of relatives, implementation of appropriate clinical procedures (e.g., avoiding radiotherapy), prophylactic surgical resection of organs at risk, or searching for donors of hematopoietic stem cells. Targetable driver mutations and corresponding signalling pathways provide a novel precision medicine strategy.Therefore, there is a need for multi-disciplinary cooperation between a paediatrician, an oncologist, a geneticist, and a psychologist during the surveillance of families with an increased cancer risk. This review aimed to emphasize the role of cancer-predisposition gene diagnostics in the genetic surveillance and medical care in paediatric oncology.

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“…Molecular profiling of tumors can lead to the identification of molecular targets that, in turn, can be actioned by new agents [ 2 , 3 , 4 , 5 , 6 ]. The concept of “cancer precision medicine” is now being implemented to guide treatment in patients with advanced malignancy in pediatric malignancies though several programs worldwide [ 7 ]. Precision medicine can lead to impactful modification of treatment, as shown recently by the INFORM registry and the MAPPYACTS trial [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Blood-Derived Liquid Biopsies Using Foundation One® Liquid CDx for Children and Adolescents with High-Risk Malignancies: A Monocentric Experience

Cahn

Revon‐Rivière

Min

et al. 2022

Cancers

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Precision oncology requires tumor molecular profiling to identify actionable targets. Tumor biopsies are considered as the gold standard, but their indications are limited by the burden of procedures in children. Blood-derived liquid biopsy (LB) is a potential alternative that is not yet documented in real-world settings, especially in pediatric oncology. We performed a retrospective analysis of children and teenagers with a relapsing or refractory disease, upon whom LB was performed using the Foundation One® liquid CDx from 1 January 2020 to 31 December 2021 in a single center. Forty-five patients (27 boys) were included, with a median age of 9 years of age (range: 1.5–17 years old). Underlying malignancies were neuroblastoma (12 patients), bone sarcoma (12), soft tissue sarcoma (9), brain tumors (7), and miscellaneous tumors (5). Forty-three patients had metastatic disease. Six patients had more than one biopsy because of a failure in first LB. Median time to obtain results was 13 days. Overall, analysis was successful for 33/45 patients. Eight patients did not present any molecular abnormalities. Molecular alterations were identified in 25 samples with a mean of 2.1 alterations per sample. The most common alterations concerned TP53 (7 pts), EWS-FLI1 (5), ALK (3), MYC (3), and CREBBP (2). TMB was low in all cases. Six patients received treatment based on the results from LB analysis and all were treated off-trial. Three additional patients were included in early phase clinical trials. Mean duration of treatment was 85 days, with one patient with stable disease after eight months. Molecular profiling using Foundation One® Liquid CDx was feasible in pediatric patients with high-risk solid tumors and lead to identification of targetable mutations in a subset of patients.

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The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Cited by 34 publications

References 123 publications

Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia

Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia

Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review

Blood-Derived Liquid Biopsies Using Foundation One® Liquid CDx for Children and Adolescents with High-Risk Malignancies: A Monocentric Experience

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