Abstract P2-09-10: Comprehensive gene expression biomarker analysis of CDK 4/6 and endocrine pathways from the PALOMA-2 study
Notice bibliographique
Résumé
Abstract Background: Palbociclib (P) is a potent, oral, highly selective, inhibitor of cyclin-dependent kinase (CDK) 4 and 6. In the Phase 3 PALOMA-2 study, P in combination with letrozole (L) demonstrated a significant improvement in progression-free survival (PFS) versus placebo (PBO) plus L. To further explore predictive markers for sensitivity and resistance to CDK4/6-based therapy or endocrine therapy (ET) alone, we performed a large gene expression analysis of baseline tumor tissues using mature PFS data with extended follow-up. Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2- ABC were randomized 2:1 to P+L or PBO+L until disease progression, death, unacceptable toxicity, or consent withdrawal. All patients provided tumor tissues to participate in the study. 455 of 666 intent-to-treat (ITT) patients had tumor tissue appropriate for gene expression evaluation (303 [68%] P+L arm and 152 [68%] PBO+L arm). EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling, assessing 2534 genes involved in a variety of cancer-related pathways. Using systematic and unsupervised approaches, gene expression levels were interrogated for identification of potential genes and/or pathways associated with a treatment effect of P+L compared with PBO+L. Results: With median follow-up of 38 months, mPFS of P+L vs L + PBO was 27.6 mos vs 14.5 mos (HR=0.563 [p<0.000001] in ITT). PFS in the biomarker-assessed group was similar. Using a supervised approach, expression of genes involved in the Cyclin D-CDK4/6-RB pathway were analyzed. This demonstrated that patients receiving P+L had a consistent benefit similar to the ITT population irrespective of various expression levels of CCND1, CCNE1/2, CDK2/4/6, RB1, and CDKN2A. These results are consistent with findings from previous IHC data (CCND1, RB, p16). Unsupervised analysis revealed that tumors with higher levels of growth factor receptors (eg. FGFR2 FDR 0.032, interaction p=0.056 and ERBB3 FDR 0.221, interaction p=0.043,) were associated with greater sensitivity to P+L vs L alone. Using parallel gene signature-based analyses, tumors with higher expression of a growth factor signature had longer PFS in the P+L arm. In addition, higher CDK4 expression was identified as a resistance marker for PBO+L arm (FDR 0.095, interaction p=0.016). Gene expression-based molecular subtyping demonstrated that both luminal A and B subtypes benefited equally from P+L vs PBO+L. Patients with lower level of tumor PD-1 expression showed more benefit from P+L (FDR 0.099, interaction p=0.021). Conclusion: These results confirm efficacy of palbociclib + letrozole in ER+/HER2- breast cancer, and support the use of ER+ as a biomarker for sensitivity to CDK 4/6 inhibition. Expression levels (whether high or low) of genes in the Cyclin D-CDK4/6-RB pathway did not correlate with benefit from palbociclib + letrozole. These data provide evidence that the interplay between steroid hormone and peptide growth factor signaling in ER+ breast cancer drives dependence on CDK 4/6 and benefit from CDK 4/6 inhibition with palbociclib. These data can be used to guide additional therapeutic opportunities in ER+/HER2- ABC. Sponsor: Pfizer Citation Format: Finn RS, Liu Y, Martin M, Rugo HS, Dieras V, Im S-A, Gelmon K, Harbeck N, Zhu Z, Lu D, Gauthier E, Bartlett CH, Slamon DJ. Comprehensive gene expression biomarker analysis of CDK 4/6 and endocrine pathways from the PALOMA-2 study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-10.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».