Serial monitoring of ctDNA to highlight mutation profiles in colorectal cancer.
Bibliographic record
Abstract
641 Background: Circulating tumor DNA (ctDNA) represents an ideal platform to obtain the most current genomic profile of a patient’s tumor. We aimed to investigate how stable these profiles remain during serial ctDNA assays in metastatic colorectal cancer (mCRC). Methods: In 77 patients (pts) with mCRC and serial Guardant360 assays with a detectable mutation (mt), we compared mt stability by assessing whether variants were gained/lost between serial assays and changes in relative mutant allele frequency (rMAF). rMAF of a mt was defined as (mt allele frequency / mt present at the maximum allele frequency in that assay). rMAF results were normalized to detected ctDNA concentration changes between assays to ensure changes in rMAF were not due to changes in ctDNA concentration. MAPK pathway mutations were defined as RAS, BRAF, EGFR, KIT, or MET mutations. Results: Of 77 pts, 64 (83%) had 2 serial assays and 13 (16.9%) had 3 or 4 assays performed. Serial assays occurred an average of 138 days apart (+/- SD of 111 days). Only 13/77 (17%) pts had no change in the number of mts detected between assays. A new mt was detected in 42/77 (55%) pts, while 43/77 (56%) lost a previously detected mt. Of 52 mts detected in patients with > 2 assays, 16 (31%) were gained and subsequently lost. After controlling for ctDNA concentration, mts were equally likely to have an increasing (129/308 – 42%) or decreasing (150/308 – 49%) allele frequency. Potentially clinically relevant MAPK variants were gained/lost in 29% of patients; though MAPK mts developed in a large number of pts (16/77 – 21%), many pts also lost MAPK mts (9/77 – 12%), showing ongoing subclonal dynamics. Median time between assays did not differ between pts with gain/lost mts or stable mt profiles (P = 0.73), however mt rMAF shift of > 25% was more common if assays were > 90 days apart (OR 4.3, P < 0.0001). Conclusions: Serial ctDNA assays demonstrate ongoing mutational changes in mCRC, with emergence/disappearance of MAPK variants being more common than expansion of a pre-existing clone. Our results suggest repeated sampling may be important to optimize selection of targeted therapies at each regimen alteration.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".