Association of rapid progression on CDK4/6 inhibitor (CDKi) for metastatic HR+HER2- breast cancer (mHRBC) with genomic, proteomic, and immune microenvironment alterations.
Notice bibliographique
Résumé
e13102 Background: First-line CDKi and endocrine therapy has improved survival for many patients (pts) with mHRBC. Yet, some pts still experience rapid disease progression within 6 months of CDKi initiation and require a tailored therapeutic approach. To understand tumor and microenvironment factors associated with rapid progression, we performed digital spatial protein profiling (DSP), RNA sequencing (RNAseq) and multiplexed immunohistochemistry (mIHC) on samples collected from pts before and after CDKi. Methods: We retrospectively identifiedpts with mHRBC treated with a CDKi with available archival samples obtained within 2.5 years of CDKi initiation and 1 year of CDKi discontinuation. FFPE slides from each sample were processed for DSP, RNAseq, and mIHC. DSP protein expression was normalized by geometric mean, with expression for each protein averaged across 3 regions-of-interest per pt. Gene set variation analysis was performed on RNA signatures. For mIHC, tumor and stromal regions were segmented, and cells were phenotyped and quantified. Means comparisons for each assay were made between groups using the t-test, and unadjusted p values are presented. This study was approved by the OHSU Institutional Review Board. Results: Samples from 25 unique pt cases were submitted for profiling (Table). On pre-CDKi samples, pts progressing ≤6 months of CDKi therapy had greater mitotic spindle (p = 0.00092), E2F (p = 0.0087) and G2M checkpoint (p = 0.0087) RNA signature expression. By comparison, in post-CDKi samples, reduced mitotic spindle signature expression (p = 0.016), but not E2F or G2M, occurred in pts treated ≤6 months. A decrease in TGF-beta signature expression (p = 0.032) was also observed. On post-CDKi samples, PI3K/AKT RNA signature expression numerically decreased in those treated ≤6 months. Although a concomitant decrease in pan-AKT protein expression was not detected in these pts, an increase in pan-AKT protein expression following CDKi (p = 0.0055) was observed in pts treated for > 6 months. Pts with ≤6 months of CDKi had greater pre-CDKi density of various immune cell subsets including CD20+ B cells, TIM3+ CD8+ T cells, Th-like and Th1 T cells. Conclusions: Pts who progress rapidly despite CDKi treatment have tumors with distinct RNA signatures and immune contexture. CDKi treatment appears to exert differential effects on the mitotic spindle, TGF-beta pathways, and PI3K/AKT pathways based on the duration of CDKi response, whether related to underlying tumor biology or an effect of drug mechanism. Efforts to integrate RNA-seq with DSP protein expression and spatial analysis of mIHC data are ongoing. Patient sample characteristics. No. patients Assay performed DSP 23 (pre-CDKi: 18, post-CDKi: 10) RNAseq 18 (pre-CDKi: 14, post-CDKi: 8) mIHC 17 (pre-CDKi: 13, post-CDKI: 8) Clinical NGS 18 PIK3CAmut 8 ESR1 mut 5 RB1 mut 4
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 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 | 0,000 | 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) | 0,000 | 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 tête enseignante, 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 ».