Abstract B012: Clinical utility of real-time comprehensive molecular profiling in childhood brain tumors
Notice bibliographique
Résumé
Abstract Introduction: The ZERO Childhood Cancer Program offers precision medicine for all children with cancer in Australia through the ZERO2 Study. The study has been open at all 9 Australian pediatric oncology centres since October 2023, with the goal to evaluate the clinical utility of real-time comprehensive molecular profiling in different cancer types and risk groups. Methods: The ZERO precision medicine platform includes paired tumor-germline whole genome sequencing, whole transcriptomic sequencing and DNA methylation. Samples are sent for sequencing in parallel with diagnostic work-up and oncologists receive somatic and germline results in real-time. Here we report the clinical utility in the first 181 consecutive CNS tumors. Results: Of the 181 patients with CNS tumor, 80% were enrolled at diagnosis and 20% had relapse/refractory disease. Low-grade glioma was the most frequent (39%), followed by medulloblastoma (15%), ependymoma (11%), high-grade glioma (9%), other CNS embryonal tumors (9%), diffuse midline glioma H3 K27M-altered (DMG) (8%) and other tumor types (9%). Comprehensive molecular profiling provided clinical utility for 161/181 (89%) of CNS tumor patients in 4 categories: diagnosis, molecular classification, therapy, and germline. In 16/181 (9%) patients, results were non-informative due to very low tumor content, none of which were DMG samples. 64 (35%) patients derived clinical benefit from 1 category, 74 (41%) from 2 categories and 23 (13%) from 3 categories. Diagnostic utility in 77 (43%) included confirming histologic diagnosis in 64, solving diagnostic dilemma in 7 (e.g., high-grade glioneuronal tumor to CNS neuroblastoma with FOXR2 activation; embryonal tumor to ETMR without C19MC alteration) and changing diagnosis in 6 (e.g., rhabdomyosarcoma to intracranial DICER1-mutant sarcoma; low-grade to high-grade glioma in Li Fraumeni syndrome). Molecular classification was refined in 82 (45%) including 40 with prognostic significance (e.g., Group 3/4 medulloblastoma subtypes; IDH mutant glioma subtypes). Therapeutic molecular targets were identified in 92 (51%). Of the 62 low-grade gliomas with adequate tumor content, only 30 (48%) had a KIAA1549-BRAF fusion or BRAF V600E mutation. The remaining 32 (52%) included other BRAF fusions, RAF1 fusion, ALK fusion, FGFR1 alterations, IDH1/2 mutation, PDGFRA mutation, and MYB/MYBL1 alterations). 31/181 (17%) patients had reportable germline variants:18 were related to a cancer predisposition syndrome, of which 12 were not previously known. The remaining 13 were secondary findings. Molecular reports were returned at a median of 3.7 weeks from receiving samples, including 13 expedited reports at 3.0 weeks and 25 Group 3/4 medulloblastoma methylation subtype reports at 2.5 weeks. Conclusion: Real-time comprehensive molecular profiling has high clinical utility in childhood brain tumors. Citation Format: Loretta M.S. Lau, Dong-Anh Khuong-Quang, Jordan Staunton, Nicholas Sanders, Shampavi Sriharan, Sarah Trinder, Neevika Manoharan, Paulette Barahona, Ann-Kristin Altekoester, Kimberley Dias, Megan Rumford, Dianne Sylvester, Jasmine Parhar, Marion K. Mateos, Marie Wong, Chelsea Mayoh, Mark J. Cowley, Paul G. Ekert, Michelle Haber, Vanessa Tyrrell, David S Ziegler. Clinical utility of real-time comprehensive molecular profiling in childhood brain tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B012.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».