Clinical utility of serial circulating tumor DNA (ctDNA) to identify acquired resistance to anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Bibliographic record
Abstract
158 Background: Real-world evidence informing on the value of incorporating serial ctDNA into clinical practice is lacking. We aimed to explore the utility of serial ctDNA for identifying mechanisms of resistance and new targets for patients (pts) receiving anti-EGFR therapy for mCRC. Methods: We retrospectively reviewed 2801 pts with mCRC who had ≥1 alteration detected on a Guardant360 assay (Guardant Health) and subsequently had serial ctDNA assessments with known intervening therapies. We compared detection of new MAPK pathway alterations ( RAS/EGFR/BRAFV600 SNV or indel, MET or ERBB2 amplification) among patients who initially lacked these alterations by whether patients received anti-EGFR antibody alone (panitumumab or cetuximab), in combination with chemotherapy, or if they had never received an anti-EGFR antibody between ctDNA assays. Patients with a subsequent ctDNA assay after therapy initiation were included for analysis of acquired alterations. Results: Of 2801 pts, 1308 (47%) harbored ≥1 MAPK alteration in their first ctDNA timepoint and were excluded from analysis. Of the remaining 1493 without a MAPK alteration prior to therapy, 588 (39.4%) had a MAPK alteration detected in a subsequent ctDNA timepoint. Among 447 of 1493 pts (31.8%) with subsequent exposure to anti-EGFR antibodies, acquisition of a MAPK alteration occurred in 229/447 (51.2%). This was more common (OR 2.01. 95% CI 1.61-2.51, P<0.0001) than in patients without exposure to anti-EGFR antibodies (359/1046 [34.3%]). Acquired MAPK alterations were more common among those receiving single agent antibodies (42/66, 63.6%) than anti-EGFR plus chemotherapy (187/381, 49.1%) (OR 1.82, 95% CI 1.05-3.08, P=0.030). Patients with anti-EGFR antibody exposure were found to have higher blood TMB scores in the first assay after treatment compared to patients treated with chemotherapy alone (11.5 vs. 8.8 mut/MB, respectively; P=0.001), with no significant blood TMB difference between those receiving single agent anti-EGFR versus anti-EGFR plus chemotherapy (median 12.4 vs. 11.5 mut/MB; P=0.52). Patients who acquired MAPK alterations after anti-EGFR therapy had higher blood TMB scores compared to patients who did not acquire MAPK alterations (median 14.3 vs 8.6 mut/MB, respectively; p<0.0001). Conclusions: In this large cohort of pts with mCRC and treatment information, we demonstrate serial ctDNA identified a large proportion of patients acquiring resistance alterations that may impact response to future therapies. These results suggest serial ctDNA analysis may provide additional molecular insights for patients receiving anti-EGFR therapy and inform future anti-EGFR rechallenge strategies.
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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 | 0.005 |
| 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".