Association between beta-catenin (<i>CTNNB1</i>) mutations and clinical outcomes of pembrolizumab in advanced hepatocellular carcinoma (aHCC): Exploratory analyses from KEYNOTE-240.
Notice bibliographique
Résumé
4109 Background: CTNNB1 mutations ( CTNNB1mut) occur in approximately 30% of HCC tumors and may result in constitutive activation of CTNNB1, leading to the transcription of genes that regulate cell survival and proliferation via the WNT pathway. This exploratory analysis of the global randomized phase 3 KEYNOTE-240 study (NCT02702401) of second-line pembrolizumab + best supportive care (BSC) versus placebo + BSC investigated the association between clinical outcomes and circulating tumor DNA (ctDNA)-derived CTNNB1mut status in patients with aHCC. Methods: The analysis population includedpatients with previously treated aHCC who were enrolled in KEYNOTE-240 and had available pretreatment cycle 1 day 1 ctDNA data. The presence of ctDNA in plasma as well as ctDNA-derived CTNNB1was evaluated using the Guardant Health G360 LDT assay. CTNNB1 was also measured in tissue using whole exome sequencing (WES) of tumor and matched germline from blood for a subset of patients with available data. One objective of this analysis was to evaluate the concordance between ctDNA- and WES-derived CTNNB1mut status by positive percent agreement (PPA) and negative percent agreement (NPA) with Wilson CIs using WES as the gold standard. Another objective was to evaluate the association between ctDNA-derived CTNNB1mut status and clinical outcomes (PFS, OS, and ORR) using 1-sided (pembrolizumab; hypothesized negative association) or 2-sided (placebo; no hypothesized direction of association) nominal P-values for Cox proportional hazard regression (PFS; OS) and logistic regression (ORR) adjusted for ECOG performance status. Significance was prespecified at P = 0.05. The database cutoff date was January 2, 2019. Results: Overall, 361 of 413 patients (87%) had evaluable CTNNB1 mutation data from ctDNA; of these, 137 (38%) had CTNNB1mut tumors per ctDNA. Two patients had a ctDNA burden of 0. A total of 41 patients had evaluable CTNNB1mutation data from both ctDNA and WES. Concordance was high between the assays, with agreement in 95% (39 of 41) of the evaluable samples. Of the 41 patients with both ctDNA and WES data available, 13 were CTNNB1mut by both assays, 26 were wild type by both assays, and 2 were wild type by ctDNA and CTNNB1mut by WES. PPA was 86.7% (Wilson CI, 62.1-96.3) and NPA was 100% (Wilson CI, 87.1-100). There was no association between ctDNA-derived CTNNB1mut status and PFS, OS, or ORR with pembrolizumab ( P =0.525, 0.558, and 0.132, respectively) or with placebo ( P = 0.295, 0.387, and 0.717, respectively). Conclusions: ctDNA-derived CTNNB1mut status was highly concordant with WES-derived CTNNB1mut status in patients with aHCC. There was no association observed between ctDNA-derived CTNNB1mut status and clinical outcomes with pembrolizumab or placebo in patients with aHCC enrolled in KEYNOTE-240 . Clinical trial information: NCT02702401 .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,002 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».