BIOM-10. PREDICTION OF BRAIN METASTASIS DEVELOPMENT FROM LUNG ADENOCARCINOMA USING DNA METHYLOMES AND THEIR NON-INVASIVE DETECTION IN CSF AND PLASMA
Bibliographic record
Abstract
Abstract INTRODUCTION Brain metastases (BM) are the most common intracranial tumor, with a poor prognosis of 10-16 months, and lung adenocarcinoma (LUAD) is the most common source. Currently, we cannot reliably predict which patients will develop BMs clinically, so most are detected after they develop and growing to cause deficits. Here, we use tumor DNA methylomes to predict which patients are likely to develop BM through the course of disease and we use both cerebrospinal fluid (CSF) and plasma methylomes for BM liquid biopsy, enabling their early detection and treatment. METHODS DNA methylomes were acquired from 419 tumor and plasma samples from 363 LUAD and BM patients. We built DNA methylation-based models that predict BM development and that also identify BMs non-invasively from CSF and plasma in discovery data subsets. A nomogram was built that predicts BM risk using methylation scores and clinical stage together. Models were evaluated in independent validation sets. RESULTS Our model predicting BM development was accurate (Univariable Cox: HR=5.7, 95% CI=1.9-17.2), p=0.0023), independent of clinical factors (Multivariable Cox: HR=8.9, 95% CI=2.0-40.5, p=0.0046), and more predictive than cancer staging used currently clinically (AUC=0.81 versus 0.65). Our combinatorial nomogram using methylation and staging data together showed enhanced BM prediction (Univariable Cox: HR=17.2, 95% CI=4.1-71.3, p<0.0001; AUROC=0.82). Our models identifying BM through biofluid methylomes accurately distinguished BM from differential diagnoses of gliomas and lymphomas in plasma (AUROC=0.80, 95% CI=0.68-0.93) and with greater accuracy in CSF (AUROC=0.93, 95% CI=0.71-1.0). CONCLUSION Overall, we show the first approaches for robust molecular prediction of BM development and for reliable liquid biopsy of BM. This work is expected to transform cancer management by identifying high-risk lung cancer patients after initial treatment for inclusion in screening protocols using neuroimaging and liquid biopsy, to identify BM development early with less advanced disease and more optimal therapeutic outcomes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".