Tumour-free ctDNA detection as a decision tool to support organ preservation in node-negative rectal cancer undergoing neoadjuvant chemotherapy, excision, and observation in the phase II NEO trial (CCTG CO.28).
Bibliographic record
Abstract
20 Background: In the NEO trial (CCTG CO.28, NCT03259035) patients with node negative (N0) T1-T3 rectal cancer were treated with neoadjuvant CAPOX/FOLFOX and transanal excision surgery (TES) with the goal of organ preservation. Patients without documented response following neoadjuvant chemotherapy were recommended total mesorectal excision (TME). We present a post-hoc assessment of ctDNA detection in this early-stage population and correlate kinetics with response and outcomes. Methods: Fifty-eight patients enrolled in CO.28. Whole blood was collected in EDTA tubes and processed for future ctDNA analysis at up to six timepoints: pre-chemotherapy, after neoadjuvant chemotherapy (and pre-TES), yearly during surveillance for 3 years and upon progression. A total of 195 samples were analyzed with the Guardant Reveal™ assay: a tissue-free epigenomic assay leveraging >20,000 epigenomic regions for ctDNA detection. Results: Of 48 available pre-treatment samples, ctDNA was detected in 22 (46%). Sensitivity by T-stage was 14% (1/7) for T1, 53% (17/32) for T2, 44% (4/9) for T3 cancers. ctDNA detection was lower following neoadjuvant chemotherapy (4/46, 9%, p<0.001 vs pre-chemotherapy). Of 41 patients with paired pre- and post-chemo samples, 49% (20/41) had undetectable ctDNA at both timepoints, 44% (18/41) had reduced tumour fraction following chemotherapy, the majority of which completely cleared ctDNA (94%; 17/18) and 7% (3/41) had an increased tumour fraction following chemotherapy (67%, 2/3 changing from negative to positive), all three of whom failed to respond to neoadjuvant chemotherapy and had TME recommended (100%). In contrast, of those that cleared ctDNA following chemotherapy, 35% had TME recommended (6/17, p=0.074). Of five recurrences (3 distant, 2 local), all had negative or reduced ctDNA tumour fraction during neoadjuvant therapy before surgical intervention. Among patients with local relapse who were managed with TES, 1/2 (50%) had detectable ctDNA at the time of local progression. No samples were available for those with distant recurrences (3/5) at time of relapse. Conclusions: The Guardant Reveal tissue-free assay was able to detect ctDNA even in this extremely early-stage cohort and identified cancers with inadequate response to therapy and in whom TME was recommended. A tissue-free approach may support timeliness of ctDNA results that would support ctDNA as an additional decision tool with endoscopic and MRI assessments to increase physician and patient comfort with organ preservation. Clinical trial information: 03259035.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".