Abstract B23: Real-time dynamic assessment of RAF-signal transduction capacity as a predictive biomarker in patients with advanced neuroendocrine tumor (aNET) treated with sorafenib (S) and metronomic cyclophosphamide (mC): The SORNET study.
Notice bibliographique
Résumé
Abstract Background: Preclinical rationale exists to combine VEGFR and PDGFR blockade with mC (J Clin Oncol 23:939–52), which led to this phase II trial of S and mC in patients (pts) with aNET. The dynamic evaluation of a signal transduction pathway in both its basal and stimulated states may more accurately reflect its functional status than the basal state alone. S enhances signal transduction through the RAF resulting in increased MEK phosphorylation (pMEK) in the presence of wild type RAS and RAF (Nature 464:427–30). Proof of putative pharmacodynamic effects early on during treatment may help select patients mostly likely to benefit. In this trial, a flow cytometry-based test was performed to measure pMEK dynamically in peripheral blood monocytes (PBMCs). Methods: Eligibility criteria: aNET; disease progression within 6 months prior to study entry; ECOG 0–2; concurrent octreotide and unlimited prior therapy were allowed. A phase II trial with intra-patient dose escalation of S and fixed dose mC of 50 mg daily was conducted. Patients started with a 7-day (d) run-in phase with S at 200 mg BID and fixed dose mC. Dose escalations of S from 200 to 400 to 600 to 800 mg BID occurred every 14 d until occurrence of either ≥ intolerable Gr 2 toxicity or a maximum S dose of 800 mg BID, with 28-d cycles then follow. PBMCs and plasma S trough levels were collected at baseline and at every S dose escalation. The MAPK pathway was stimulated in PBMCs by adding 20 ng/mL of IL3 to fresh blood aliquots. The difference between stimulated and basal pMEK (pShift) was quantified. The pShift value on d7 was compared to the pre-treatment value (d0), with pShift d7>d0=stimulation and pShift d0>d7=inhibition. Results: Demographics: 22 pts (18 carcinoid/4 islet cell cancers; 12 male) were enrolled; median age=58 (range 32–81); ECOG 0:1=7:15; prior treatment regimens 0:1:2:3+ = 8:10:2:2. Final S dose after the escalation process was 200, 400, 600 or 800 mg BID in 4:12:2:1 pts, 3 pts did not complete escalation due to toxicity. A total of 160 cycles of S and mC were administered (median=3; range=1–34). Toxicity: Gr 3 non-hematologic adverse events: diarrhea (3 pts), hand-foot reaction (3), hypophosphatemia (2), amylase/lipase (2/2), AST (1), hypertension, abdominal pain, ileal perforation, ALT, and vomiting (1 each). Efficacy: 1 pt had PR (5%), 13 SD (59%), 5 PD (23%) and 3 non-evaluable (14%). Median progression-free survival (PFS)=3 months (95% CI: 2–10.7); median overall survival (OS)=11.7 months (95% CI: 4.3-not reached (NR)). Biological Correlates: pShift change from d0 to d7 was predictive of clinical outcome, with 6 pts (27%) experiencing pShift stimulation and 16 pts (73%) inhibition. All 5 pts with PD had pShift inhibition. PFS in pts with pShift stimulation vs. inhibition: 14.9 (3-NR) vs. 2.8 months (1.8−6.7) (p=0.047); OS: 21.3 (7.9-NR) vs. 6.4 (2.8−6.4) (p=0.17). Neither S trough levels nor S dose were able to predict PFS, OS or pShift. pShift was not associated with toxicity (p=0.24). Conclusions: The combination of S and mC had modest antitumor activity in unselected pts with aNET. In this limited study, pShift from d0 to d7 seems to identify pts most likely to benefit, and thus may have predictive and/or prognostic significance warranting further validation Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B23.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
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 ».