Does serial circulating tumor DNA (ctDNA) monitoring identify additional acquired actionable alterations in metastatic colorectal cancer (mCRC)?
Notice bibliographique
Résumé
3540 Background: Traditionally, biomarker ascertainment occurred once for patients (pts) with mCRC. An advantage of ctDNA is the ease of repeated assessments. However, real-world evidence about the value of serial ctDNA in revealing actionable alterations is needed. Methods: We retrospectively evaluated 3350 pts with mCRC and a Guardant360 ctDNA assay (Guardant Health) revealing ≥1 somatic alteration who underwent ≥1 subsequent Guardant360 test to compare detection of mutations (mut: single nucleotide variants (SNVs) and indels), amplifications (amps), fusions, microsatellite instability (MSI), and blood tumor mutational burden (bTMB). Variants were filtered to pt-specific levels of detection by limiting variants across assays to those above a 0.1% mutant allele frequency (MAF) threshold on the serial test with the lowest somatic MAF for that pt. Clonal muts were defined as those at ≥10% of max MAF per sample. Results: A total of 9130 assays (mean of 2.7 assays/pt) occurring a median of 165 days apart were evaluated. Among 1476 pts initially with no alteration in MAPK pathway genes ( RAS and EGFR SNV or indel, BRAF V600E SNV, or ERBB2/ MET amplifications), 382 (25.8%) acquired a MAPK alteration on their second test. More gains were clonal than subclonal (231:151, 60.5%:39.5%). In pts with a subsequent assay after an acquisition (N = 80), 12 (15.0%) clonal and 15 (18.8%) subclonal acquisitions disappeared in the third assay, a median of 150 days later. Among alterations with a therapy, KRAS G12C/D, BRAF V600E, and ERBB2 amps acquisitions occurred at any later assay in 84/1476 (5.7%), 29/1476 (2%), and 21/1476 (1.4%) pts without an initial MAPK alteration, respectively. Of these, 84/134 (62.6%) emerged without another concurrent MAPK alteration, 61/84 (72.6%) of which are subclonal. Of 92 fusions noted in 86 pts, 87/92 (94.5%) were subclonal and only 28/92 (30.4%) were initially present. The majority of fusions were acquired de-novo subclonal fusions (58/64, 90.6%) but 2 pre-existing subclonal fusions subsequently became clonal. Among pts evaluable for MSI, 56/3030 (1.8%) were initially MSI-H and 30 (1%) subsequently had MSI detected on a future assay. New MSI detection was more common in pts with DNA repair muts ( BRCA1/BRCA2/ATM/CHEK2/MLH1/RAD51D) on an initial assay (OR 7.52, 95% CI 3.39-16.69, P < 0.0001). Among pts evaluable for bTMB, 60/1387 (4.3%) initially had bTMB≥20 muts/Mb, and 256/1327 (19.3%) subsequently rose above 20 muts/Mb on a future assay, a median of 417 days after initial assay. Rising bTMB associated with rising max somatic MAF (Spearman rho = 0.50, P < 0.0001). Pts with DNA repair muts on an initial assay were more likely to have bTMB rise to ≥20 muts/Mb (OR 2.58, 95% CI 1.81-3.68, P < 0.001). Conclusions: In this large mCRC cohort, serial ctDNA appears to be a feasible approach to identify acquired alterations with therapeutic implications.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,004 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».