Neoplastic and blood-based biomarkers of response in patients with advanced endometrial cancer: Results from NRG GY012.
Notice bibliographique
Résumé
5525 Background: NRG GY012 is a randomized, 3-arm phase II study, comparing olaparib (O) and the combination of cediranib and olaparib (CO) to the reference arm cediranib (C) for metastatic pre-treated, endometrial cancer (EC). The trial found a trend towards benefit for CO and no benefit for O compared to C. Archival tumor and prospective blood samples were collected for biomarker analysis. Methods: Targeted next-generation sequencing (BROCA-GO) was used to detect pathogenic variants (PV) and loss of heterozygosity (LOH) in DNA from paired blood and archival cancers. The LOH cut-off was identified at 11% for HRD based on testing ovarian cancers with known HRD. Plasma samples collected at baseline, cycle 2 day 1, and end-of-treatment were analyzed via multiplex ELISA for 25 angiogenic and inflammatory circulating protein biomarkers (Angiome); IL6 was of specific interest. Prognostic associations with PFS and OS were analyzed using proportional hazards models (PhM) stratified by histology and adjusted for treatment assignment. Predictive associations (PFS and OS) were analyzed using PhM stratified by histology and including main effects for both treatment assignment and biomarker group plus an interaction term. Results: In 97 patients (pts) with evaluable tumor, BROCA-GO identified 370 somatic PV; TP53 (61%) was the most commonly mutated gene. PV in homologous recombination repair (HRR) genes were identified in 5 cases (5%). Somatic PVs were identified in BRCA2, RAD51B and PALB2. 1 pt had a germline BRCA1 PV. 2 cases had somatic PV that might restore HRR: 1 case with a somatic BRCA2 PV had somatic PVs in CHD4 and TP53BP1; the TP53BP1 frameshift PV was present only in the recurrent and not primary cancer. LOH was available for 45 cases. LOH high occurred in 16 (35.6%) cases and was exclusive to EC with TP53 mutations (p=0.0003). LOH was not associated with outcome in any of the arms. For the circulating biomarker analysis (N=96), median IL-6 was 4pg/ml. IL-6 levels >4pg/ml were associated with increased risk of progression (HR: 1.59; 95% CI: (1.04-2.42); p-value=0.032). In predictive analyses, pts with IL-6 > 4 pg/ml receiving C or C+O had increased PFS (3.8 mo vs 1.9 mo) and OS (11.9 mo vs 5.7 mo) compared to pts receiving O, the interaction p value did not reach statistical significance. Conclusions: LOH high status was not associated with outcome to O. There were too few cases with HRR PVs to determine their relationship to PARPi response. The restriction of LOH high to cancers with TP53 mutation may suggest that genomic LOH in ECs correlates better with aneuploidy than with HRR function indicating that at least some biomarkers of PARPi response vary between tumor types. IL-6 levels were prognostic of PFS but were not predictive of either OS or PFS for pts receiving C compared to pts receiving O in this small study. Further analysis of the complete Angiome and integration with the BROCA-GO dataset are ongoing. Clinical trial information: NCT03660826 .
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 | 0,001 |
| 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 | 0,000 | 0,001 |
| 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 ».