Abstract 776: Androgen receptor (AR) and non-AR aberrations associated with outcomes in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN
Notice bibliographique
Résumé
Abstract Background: In TITAN, APA improved radiographic progression-free survival (rPFS), overall survival (OS), and second progression-free survival (PFS2) vs placebo (PBO) in patients (pts) with mCSPC receiving ADT. We determined the presence of genomic and transcriptional aberrations and evaluated associations of these aberrations with clinical outcomes in TITAN. Methods: Whole-blood samples from 130 pts were collected at baseline (BL, n = 59) and end of treatment (EOT: APA, n = 47; PBO, n = 83). Circulating tumor (ct)DNA and non-AR aberrations (Table) were assessed from isolated cell-free (cf)DNA (n = 129), and AR aberrations at EOT were assessed from cfDNA and cellular RNA (n = 127) using next-generation sequencing and real-time PCR. Detected biomarkers at BL and EOT were assessed for associations with rPFS, OS, and PFS2 and with OS and PFS2, respectively, using Cox proportional hazards model and multivariate analyses (MVA) in pooled APA and PBO pts. Table.Frequency of aberrations and univariate analyses of the association between aberration status at EOT with outcomesAberrationsBL, n (%)EOT, n (%)HR (95% CI) p value for shorter outcomes by aberration-positive vs -negative status (reference)APAPBOOverallAPAPBOOverallPFS2OSn = 15n = 44n = 59n = 47n = 82n = 129ctDNA6 (40)19 (43)25 (42)32 (68)66 (80)98 (76)3.55 (1.59-7.92)7.77 (2.40-25.13)p = 0.002p = 0.001Any AR aberrationa3 (20)10 (23)13 (22)n = 46n = 81n = 1272.82 (1.58-5.03)3.70 (1.85-7.41)22 (48)54 (67)76 (59)p = 0.0002p = 0.0001TP53 inactivationb1 (7)7 (16)8 (14)14 (30)36 (44)50(39)2.42 (1.45-4.04)2.69 (1.54-4.71)p = 0.001p = 0.001RB1 inactivationb2 (13)2 (5)4 (7)13 (28)19 (23)32 (25)1.86 (1.08-3.21)2.08 (1.18-3.66)p = 0.026p = 0.011PIK3CA amplification/SNV2 (13)2 (5)4 (7)13 (28)16 (20)29 (22)2.30 (1.34-3.94)3.06 (1.75-5.36)p = 0.002p < 0.001MYC amplification/SNV1 (7)3 (7)4 (7)6 (13)7 (9)13 (10)1.64 (0.77-3.48)2.35 (1.10-5.02)p = 0.198p = 0.027CDK12 inactivationb01 (2)1 (2)1 (2)5 (6)6 (5)1.54 (0.56-4.28)2.55 (1.00-6.47)p = 0.406p = 0.050MET amplification/SNV0001 (2)9 (11)10 (8)1.59 (0.72-3.52)2.90 (1.28-6.56)p=0.253p=0.010aDefined as AR ligand-binding domain mutations (L702H, W742C, H875Y, F877L, and T878A), or AR copy number gain, or ARv7 transcript detection.bDefined as either heterozygous or homozygous deletion or single nucleotide variant (SNV) with known pathogenic consequence based on ClinVar, an archive of human variations and phenotypes. Results: From BL to EOT, detection of ctDNA increased 1.8-fold and similarly with APA and PBO; detection of AR aberrations increased 2.7-fold and was less frequent with APA vs PBO (Table; p = 0.04, Fisher exact test). Among non-AR aberrations at EOT, those in TP53, RB1, PI3KCA were the most frequent; detection increased ≥ 2.8-fold from BL to EOT and similarly with APA and PBO (Table). Detection of ctDNA, AR aberrations, and aberrations in TP53, RB1, PI3KCA at EOT were associated with shorter PFS2 and OS (Table). Detection of other non-AR aberrations at EOT and of all aberrations at BL was low for robust conclusions. Only detectable ctDNA at EOT maintained association with shorter OS in MVA. Conclusions: In TITAN pts with mCSPC, AR and several non-AR aberrations were most frequent at progression. APA was associated with decreased frequency of AR aberrations at EOT and similar frequency of detectable ctDNA vs PBO. ctDNA was an independent prognostic variable for shorter PFS2 and OS in pts with mCSPC. Citation Format: Kim N. Chi, Shibu Thomas, Michael Gormley, Dong Shen, Neeraj Agarwal, Felix Feng, Gerhardt Attard, Alex Wyatt, Deborah S. Ricci, Angela Lopez-Gitlitz, Julie S. Larsen, Branko Miladinovic, Simon Chowdhury. Androgen receptor (AR) and non-AR aberrations associated with outcomes in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 776.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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) | 0,001 | 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 ».