Abstract P2-05-19: Impact of TP53 functional mutation type on clinical outcomes of advanced breast cancer patients
Notice bibliographique
Résumé
Abstract Background: Next-generation sequencing (NGS) has improved our understanding of breast cancer (BC) biology. Somatic TP53 mutations (TP53m) are present in 30% of BC, and are particularly common in triple negative (TN) tumors. Although multiple studies have indicated poor prognosis in BC patients (pts) with TP53m, there is still uncertainty regarding its correlation with clinical outcomes, which may be influenced by other molecular, histological and clinical factors. Our aim was to investigate the functional effect of TP53m in advanced BC pts and evaluate associations with clinical outcomes in different BC subtypes. Methods: Advanced BC pts enrolled in an institutional molecular screening program (NCT01505400) were evaluated. TP53m were assessed on archived FFPE tumor samples using NGS Illumina MiSeq TruSeq Amplicon Cancer Panel (500x depth of coverage; 10-15% variant detection threshold). Functional effect of TP53m was classified as gain of function (GOF), loss of function (LOF) and variants of unknown significance (VUS), as adapted from IARC TP53 database. Patients' medical records were reviewed for clinical data. TP53m functional effect class was correlated with BC subtypes using Fisher's exact test. TP53m were correlated with time from surgery with curative intent to distant relapse (TTR) and overall survival from diagnosis to death (OS) using Log-rank test. Impact of TP53m functional type on TTR and OS was determined by Cox proportional hazard model. Results: The study enrolled 220 pts from Oct 2012 - Nov 2015. Median age at diagnosis was 46 years (range 21-80). The cohort included 141 ER+/HER2- (64%), 25 HER2+ (11%) and 54 triple negative (TN) (25%) BC pts. Stage at diagnosis was: I (14%), II (33%), III (24%), IV (21%) and not documented in 8%. Median follow-up was 15 months (m) (range 1-41). Somatic TP53 variants were identified in 80 patients [36%; 23 ER+/HER2- (16%), 18 HER2+ (72%), 39 TN (72%)]. By TP53 functional class, there were 19 GOF (24%), 35 LOF (44%) and 26 VUS (32%). Histologic subtypes were not correlated with TP53m function (p = 0.09). TTR for 174 pts, who underwent surgery with curative intent at diagnosis, and OS (94 death events, 43%) are reported in Table 1. TTR and OS were shorter in TP53m compared to TP53 wild type (wt) in the overall cohort and the ER+/HER2- subgroup, but not the HER2+ and TN subgroups. TABLE 1: Log rank test resultsTP53mTP53wtP valueTotal cohortTTR (m)2054<0.001 OS (m)58195<0.001ER+/HER2-TTR (m)2958<0.001 OS (m)52208<0.001HER2+TTR (m)32940.1 OS (m)1132750.42TNTTR (m)17180.54 OS (m)46490.89 In the ER+ subgroup TP53m was significant prognostic factor associated with poor outcome in univariate analysis and remained significant after adjusting for age, stage and grade at diagnosis, neoadjuvant chemotherapy and germline BRCA1/2 status, with HR for TTR 3.4 (95%CI: 1.9-6.0, p<0.001) and OS 10.2 (95% CI: 4.5-23.4, p<0.001). Within the TP53m group, the functional class of TP53m (GOF, LOF, VUS) was not associated with TTR (23 m, 28 m, 17m, p =0.94) or OS (75 m, 58 m, 49 m, p =0.47). Conclusions: In advanced breast cancer, somatic TP53m status is prognostic for outcome in ER+/HER2- but not TNBC or HER2+ subtypes. TP53m functional class was not associated with any difference in survival outcomes. Citation Format: Stjepanovic N, Garg S, Berman H, Warr D, Amir E, Cescon D, Elser C, Wang L, Kamel-Reid S, Siu L, Bedard PL, Stockley T. Impact of TP53 functional mutation type on clinical outcomes of advanced breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-19.
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 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 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 ».