Palbociclib in Solid Tumor Patients With Genomic Alterations in the cyclinD-cdk4/6-INK4a-Rb Pathway: Results From National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice Trial Arm I (APEC1621I)

JCO Precision Oncology, Journal Year: 2024, Volume and Issue: 8

Published: Sept. 1, 2024

PURPOSE The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis genetic alterations detected in their tumor. Patients tumors that harbored prespecified genomic cyclinD-CDK4/6-INK4a-Rb pathway intact Rb expression were treated cdk4/6 inhibitor palbociclib. METHODS received palbociclib orally once daily 21 days 28-day cycles until disease progression, intolerable toxicity, up 2 years. primary end point was objective response rate; secondary points included safety/tolerability progression-free survival. RESULTS Twenty-three (median age, 15 years; range, 8-21) enrolled; 20 protocol therapy evaluable toxicity response. Of patients, most common diagnoses osteosarcoma (n = 9) rhabdomyosarcoma 6). A single actionable gene amplification found 19 ( CDK4, n 11, CDK6, 2, CCND3, 6), one tumor harboring two amplifications CDK4 CCND2). Hematologic toxicities treatment-related events. No responses seen. Two (neuroblastoma sarcoma) had best stable six three cycles. Six-month progression 10% (95% CI, 1.7 27.2). CONCLUSION CDK4/6 at 75 mg/m tolerable this heavily pretreated cohort. observed histology-agnostic biomarker-selected population treatment-refractory demonstrating alteration alone is insufficient pediatric cancers generate a monotherapy.

Language: Английский

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

Cancers, Journal Year: 2022, Volume and Issue: 14(11), P. 2774 - 2774

Published: June 2, 2022

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

Language: Английский

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Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML

Cancers, Journal Year: 2022, Volume and Issue: 14(24), P. 6240 - 6240

Published: Dec. 18, 2022

Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% children with AML relapse within three years diagnosis. Although recent efforts have focused on developing precise medicine-based approach towards treating in adults, there remains critical gap therapies designed specifically children. Here, we present ex vivo drug sensitivity profiles de novo using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened response to 78 dose conditions by measuring the reduction leukemic blasts relative control. In pediatric patients treated conventional chemotherapy, comprising cytarabine, daunorubicin etoposide (ADE), results correlated minimal residual (r = 0.63) one year relapse-free survival 0.70; AUROC 0.94). ADE analysis cohort 13 patients, cells showed greater bortezomib/panobinostat compared ADE, comparable between venetoclax/azacitidine vivo. Two differential bortezomib/panobinostat, thus supporting incorporation testing clinical trials further evaluate predictive utility this platform AML.

Language: Английский

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The Clinical Utility of a Tiered Approach to Pediatric Glioma Molecular Characterization for Resource-Limited Settings

JCO Global Oncology, Journal Year: 2024, Volume and Issue: 10

Published: May 1, 2024

PURPOSE Molecular characterization is key to optimally diagnose and manage cancer. The complexity cost of routine genomic analysis have unfortunately limited its use denied many patients access precision medicine. A possible solution rationalize use—creating a tiered approach testing which uses inexpensive techniques for most limits expensive with the highest needs. Here, we tested utility this molecularly characterize pediatric glioma in cost- time-sensitive manner. METHODS We used pipeline immunohistochemistry (IHC), customized fusion panels or fluorescence situ hybridization (FISH), targeted RNA sequencing gliomas. Two distinct diagnostic algorithms were low- high-grade gliomas (LGGs HGGs). percentage driver alterations identified, associated costs, turnaround time (TAT) are reported. RESULTS successfully characterized 96% (95 99) For 82 LGGs, IHC, panel FISH, solved 35% (29 82), 29% (24 30% (25 82) cases, respectively. total 64% (53 samples without sequencing. Of 17 HGG samples, 13 by IHC four average per sample was more affordable when using as compared up-front LGG ($405 US dollars [USD] v $745 USD) HGGs ($282 USD USD). TAT also shorter (10 days LGG, 5 14 sequencing). CONCLUSION Our Such an may be feasible neuro-oncology centers worldwide, particularly resource-limited settings.

Language: Английский

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Continuous response despite reduced dose of trametinib as single agent in an adolescent with a relapsed disseminated pediatric low-grade glioma KIAA1549-BRAF fusion positive: a case report and review of the literature

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: May 23, 2024

Dissemination in pediatric low-grade glioma may occur about 4%–10% of patients according to retrospective cohort studies. Due its low incidence, there is no consensus on treatment for these patients. According the constitutional activation MAPK/ERK pathway tumors, MEK inhibitors such as trametinib have been used successfully relapsed setting. Skin toxicity frequent receiving trametinib, normally mild moderate, but sometimes severe, needing discontinue drug, limiting efficacy tumor. There not much information literature regarding whether reducing dose able maintain while, at same time, decreasing toxicity. Here, we present an adolescent, with severe skin toxicity, whose was reduced by 50% and tumor continued while significantly decreased.

Language: Английский

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