Abstract PR-17: Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial
Notice bibliographique
Résumé
Abstract Overall survival for patients with advanced PDAC remains less than 1 year. Biomarkers are needed to select chemotherapy regimens, either alone or in combination with novel agents. PASS-01 compared mFOLFIRINOX and Gemcitabine/nab-Paclitaxel in a phase II randomised control trial while prospectively exploring tissue, liquid and organoid biospecimens to interrogate putative biomarkers of chemotherapy response and resistance. Methods PASS-01 was conducted across 6 sites in North America. Patients with de novo metastatic disease and a lesion amenable to core biopsy were included. Cases with germline pathogenic variants in BRCA1/2 or PALB2 were excluded. Up to 6 core biopsies were obtained with priorities for clinical diagnosis, patient derived organoids (PDOs), and whole genome and transcriptome sequencing (WGTS). WGTS were performed at a single site following laser capture microdissection. WGS reports were clinically (CAP) accredited and annotated mutations, copy number alterations, mutational signatures, TMB and structural variant patterns. KRAS allelic states were documented with major imbalances in mutant KRAS (KRASmaj) defined as mutant: WT copy number >3. Transcriptomic subtypes (classical vs. basal-like) were classified as previously described (Moffitt et al., 2015). WGTS results were discussed at a molecular tumor board with PDO pharmacotyping to determine best second line options. Results: 160 patients were included in the intention to treat population, of these WGS was available in 127 (79%) and additional NGS reports in 20 (13%). RNA-seq was successful in 119 (74%) and the basal-like subtype accounted for 29% and was associated with inferior outcomes. KRASm were evident in 91% and KRASG12D represented 45%. Tumor suppressors TP53, CDKN2A and SMAD4 were lost in 81%, 76% and 39% respectively. MTAP deletion was present in 40%, largely synonymous with CDKN2A deletions. Commonly co-altered genes in the dataset included epigenetic regulators (ARID1A, KMT2C, KDM6A) and TGFBR2. KRASmaj was present in 30% of cases and polyploid tumors in 50%. 50% of basal-like PDAC harboured KRASmaj compared to 22% of classical PDAC, p<0.01. Dominant signatures (SBS) included age related SBS1, 5 and 8. Additionally, we saw a prevalence of SBS17 and APOBEC SBS2/13, signatures which occurred more frequently compared to a similarly characterised resected cohort. Unstable genotypes were present in 24% with somatic-HRD evident in 3%. Of KRASWT PDAC, 58% harboured class I-II BRAF variants. KRAS WT PDAC had fewer co-mutations and in one case where an NGS report did not find a driver, a novel fusion in SLC4A4-RASGRF2 was identified. 28 molecular tumor boards took place throughout the trial influencing 50% obtaining a 2nd-line treatment. Conclusion: The PASS-01 cohort exhibits a heterogeneous group of genotypes and molecular subgroups. Certain mutational processes are more evident in advanced compared to resected PDAC. The impact of subgroups on survival and chemotherapy response is ongoing with a planned data lock on July 15th. Results will be presented at the meeting. Citation Format: Grainne M O'Kane, Gunho Jang, Trevor J Pugh, Julie Wilson, Stephanie Ramotar, Daniel A King, Dan Laheru, Ken H Yu, Kimberly J Perez, Amber Habowski, Erica S Tsang, Robert C Grant, Andrew J Aguirre, Raymond W-J Jang, Craig E Devoe, Eileen M O'Reilly, Anna Dodd, Brian M Wolpin, Xiang Y Ye, Elizabeth M Jaffee, David Tuveson, Steven Gallinger, Jennifer J Knox, Faiyaz Notta. Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-17.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».