Abstract B012: Clinical utility of real-time comprehensive molecular profiling in childhood brain tumors
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".