Comprehensive tumor-agnostic evaluation of genomic and epigenomic-based approaches for the identification of circulating tumor DNA in early-stage breast cancer
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
BACKGROUND: The detection of circulating tumor DNA (ctDNA) after curative-intent therapy, referred to as molecular/minimal residual disease (MRD), is prognostic of disease recurrence in early-stage breast cancer (EBC). Tumor-agnostic approaches that rely on mutation-based assessment in fixed panels of common cancer driver genes have shown limited utility for detecting MRD in EBC. Methylation-based MRD (mMRD) may overcome the limitations of genomic-based MRD (gMRD), though limited clinical validation is available. MATERIALS AND METHODS: To investigate this, we analyzed 290 longitudinally banked plasma samples from 95 participants diagnosed with early-stage estrogen receptor (ER)-positive/human epidermal growth factor receptor 2-negative (ER-positive) and triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy using a high-sensitivity genomic and epigenomic-based, tumor-agnostic ctDNA platform. RESULTS: The baseline (pre-chemotherapy) ctDNA detection (mMRD) rate was 72.5% (66/91) across all participants (ER-positive: 33/48, 69%; TNBC: 33/43, 77%). Baseline ctDNA detection (mMRD) was associated with a higher risk of recurrence [hazard ratio (HR) 9.4, 95% confidence interval (CI) 1.3-70.3, P = 0.03]. Detection of ctDNA (mMRD) in the post-operative and follow-up periods were prognostic of worse event-free survival (EFS) (HR 17.0, 95% CI 6.0-48.0, P < 0.0001) with 62.5% sensitivity and 100% specificity for recurrence (positive predictive value 100%). The median lead time from mMRD detection to clinical recurrence was 152 days (range 15-748 days). gMRD, derived from plasma-only panel-based next-generation sequencing, was evaluated in all matched time points; the prognostic value was limited by clonal hematopoiesis of indeterminate potential, including pathogenic mutations in common cancer driver genes. Despite refinements in gMRD analysis, it remained inferior to mMRD. A combination of mMRD and gMRD did not outperform mMRD alone. CONCLUSION: These results support further development of tumor-agnostic mMRD assays for the detection of ctDNA and assessment of these assays to develop clinical utility in this setting.
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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 | 0.000 |
| 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 it