Abstract 4564: Assessment of genetic alterations using next-generation sequencing in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the BOLERO-2 phase III trial.
Notice bibliographique
Résumé
Abstract The BOLERO-2 phase III trial compared the combination of everolimus and exemestane to placebo and exemestane in 724 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. Results showed significant improvement in progression-free survival, response rate, and clinical benefit rate. Although significant benefit has been observed in all prospectively defined subgroups, variations were seen among patients. As the first step to delineate the molecular determinants of sensitivity to everolimus and interactions between estrogen receptor and mTOR pathways, we used next-generation sequencing technology to comprehensively assess the genetic alterations in archival tumor specimens. Formalin-fixed, paraffin-embedded archival tumor samples were obtained from 496 patients. DNA was extracted from 348 samples of sufficient quantity and 230 samples (representing approximately 1/3 of all patients) qualified for the analysis. No indication of sampling bias was observed when the data were assessed and compared against several covariates as well as to the full trial data. The coding regions of 182 cancer-related genes were analyzed using an Illumina HiSeq 2000. Mutations and copy number variations were evaluated in 230 samples for which DNA extraction, library construction, and hybrid capture were successful and sequencing depth was sufficient (250-1500×). Alterations predicted to be germline events were discarded. One hundred seventy-three genes were found to be altered in at least one tumor sample. The number of alterations per sample varied from 1 to 24 (average 9 ± 4). Sequence variations (N = 1565) consisted primarily of point mutations (85%), followed by deletions (9%) and insertions (6%). 225 of 230 (98%) patients had at least two sequence variations. The most frequently mutated genes included PIK3CA (49%), TP53 (24%), and ARID1A (16%). ESR1 and IGF1R mutations were detected in 9% and 4% of the cohort, respectively. PIK3CA and AKT1 (6%) mutations were found to be mutually exclusive. Copy-number alterations comprised of 524 amplifications and 27 bi-allelic deletions. The most frequently amplified genes included CCND1 (32%) and FGFR1 (18%). Specific rearrangements assayed in 14 genes occurred infrequently (9% of the samples). These results demonstrated the feasibility of performing large-scale next-generation sequencing in a global phase III clinical trial. High alteration frequencies were observed in specific genes, resulting in activated PI3K, FGFR1, and estrogen receptor pathways, corroborating the rationale of concomitant targeting of the mTOR and estrogen receptor pathways. The results generate testable hypotheses for the development of combinations of new targeted therapies in this patient population. Citation Format: Jose Baselga, Martine Piccart, Hope Rugo, David Chen, Howard A. Burris, Mario Campone, Shinzaburo Noguchi, Alejandra Perez, Inas Deleu, Mikhail Shtivelband, Louise Provencher, Adnan Derti, Alan Huang, Rob McDonald, Creton Kalfoglou, Douglas Robinson, Tetiana Taran, Tarek Sahmoud, David Lebwohl, Gabriel N. Hortobagyi. Assessment of genetic alterations using next-generation sequencing in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the BOLERO-2 phase III trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4564. doi:10.1158/1538-7445.AM2013-4564
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 | 0,000 |
| 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 | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».