Abstract 289: Associations between germline genotype and efficacy and safety outcomes in a phase III study of sunitinib (SU) and FOLFIRI in metastatic colorectal cancer (mCRC)
Notice bibliographique
Résumé
Abstract Introduction: SU is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. In a phase III mCRC study, adding SU to FOLFIRI did not improve progression-free survival (PFS) vs. FOLFIRI/placebo. Potential correlations were investigated between germline genotype and safety/efficacy endpoints among patients (pts) in this trial. Methods: Blood sample donation for genotype analysis was optional. Selection of genes and polymorphisms was based on prior reported associations. Twenty-one single-nucleotide polymorphisms (SNPs) in 10 genes (VEGF-A, VEGFR-2, CYP1A1, ABCG2, ABCB1, ABCC2, MTHFR, UGT1A1, FLT1 and FLT3) were analyzed by TaqMan allelic discrimination assay or fragment analysis, using DNA isolated from peripheral blood samples. All 21 polymorphisms were analyzed for associations with efficacy (PFS; overall survival [OS]) and selected safety endpoints. Results were adjusted for multiple testing of SNPs in linkage disequilibrium. Results: Genotyping was performed in 139/768 pts (18%). Age and gender were similar between genotyped and non-genotyped pts, but the genotyped subset had fewer non-Caucasians (13% vs. 39%; Fisher's exact P<0.0001). Therefore, the statistical analysis reported here included Caucasians only. OS was superior in genotyped vs. non-genotyped pts (log rank P<0.0001). For the FOLFIRI/placebo arm only, the ABCC2 gene SNP rs717620 was associated with increased grade 3/4 diarrhea for those with the T allele (0/37 for C/C, 2/15 for C/T, 2/2 for T/T; Fisher's exact P=0.0003), and remained statistically significant after multiple testing adjustment. In the SU/FOLFIRI arm only, the common homozygous genotype A/A in the CYP1A1 gene at rs1048943 was associated with increased grade 3/4 neutropenia (39/59 for A/A, 1/6 for A/G, # of G/G = 0; Fisher's exact P=0.028), but lost significance after multiple testing adjustment. In the FOLFIRI/placebo arm only, a weak association was observed between poorer PFS and the common homozygous genotype T/T for the rs1045642 SNP (C3435T) in the ABCB1 gene (median [T/T] = 36 weeks [95% CI 24.9-40.6]; median [T/C] = 45 weeks [41.9-83.6]; median [C/C] = 55.1 weeks [31.8-55.1], HR [T/C vs. T/T] = 0.21 [95% CI 0.07-0.64]; HR [C/C vs. T/T] = 0.23 [95% CI 0.07-0.81]; log rank P=0.008; not significant after multiple testing adjustment). Conclusions: Presence of the T allele in the ABCC2 gene at rs717620 was associated with increased risk of grade 3/4 diarrhea in a small number of Caucasian pts receiving FOLFIRI/placebo. No significant associations were identified between genotype and safety/efficacy endpoints in pts who received SU/FOLFIRI. As OS was superior in genotyped vs. non-genotyped pts, correlative findings may not be extrapolated beyond the genotyped subset. Further analysis of baseline characteristics is underway in the genotyped group to investigate this difference. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2011-289
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) | 0,001 | 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 | 0,000 |
| Intégrité de la recherche | 0,001 | 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 ».