Abstract 5465: HRDetect as a predictive score of platinum response in advanced PDAC
Notice bibliographique
Résumé
Abstract Background: Predictors of response to DNA damaging agents may expand the population of patients who could benefit from platinum and/or PARP inhibition in pancreatic cancer (PDAC). The HRDetect score derived from whole genome sequencing (WGS) incorporates patterns of substitution base signatures and structural variation and is associated with tumours deficient in homologous recombination repair (HRD). Methods: The prospective COMPASS trial (NCT 02750657) enrolls patients with advanced PDAC prior to systemic treatment for WGS and RNAseq. Choice of combination chemotherapy is at the discretion of the physician. HRD tumours are identified by the presence of a number of known genomic characteristics including evidence of biallelic inactivation of BRCA/PALB2 or the RAD51 family of genes, the presence of signature 3, the number and proportion of indels that are deletions of at least 4 base pairs (bp), and the presence of rearrangement signatures 3 and 5. We ascertained the number of patients with high HRDetect scores (>0.7) and evaluated outcomes and response to chemotherapy including platinum regimens. Results: As of 1st May 2019 204 eligible patients were enrolled. High HRDetect scores (HRDetecthi ) were present in 26/204 (13%). Only half of these cases were represented by HRD tumours including: 9 germline BRCA1/2 or PALB2 cases with biallelic inactivation and 3 tumours with somatic biallelic inactivation of BRCA2, RAD51C and XRCC2. 1 additional HRD case was of unknown aetiology. All HRD cases were HRDetecthi. Two germline carriers of BRCA2 without a second somatic hit were HR intact with low HRDetect scores. Of the remaining 13 non-HRD tumours identified as HRDetecthi, 6 exhibited a tandem duplicator phenotype (TDP) with tandem duplications ranging from 10Kbp to 1Mbp in size. These tumours did not have any other genomic characteristics of HRD. Notably, of the 204 patients included in this analysis, a TDP was present in 15 (7%), of which 40% were HRDetecthi. In patients treated with modified FOLFIRINOX(mFFX) (n=111, *includes 2 patients treated with cisplatin/gemcitabine) the response rate in HRDetecthi patients (n=16) was 56% vs 20% in HRDetectlo patients (n=95) p=0.005. There was no difference in response rates according to HRDetect score in patients treated with gemcitabine-nab-paclitaxel; HRDetecthi (n=7) 14.3% vs. HRDetectlo(n=71) 32.8%, p=0.42. Median OS in all patients receiving mFFX (n=111) was 10.2 months; in patients with HRDetecthi PDAC, median OS was 15.5 mths vs. 9.9 mths in HRDetectlo PDAC, (HR 0.42, 95% CI 0.24-0.87, p=0.01). In all patients (n=78) receiving gemcitabine based combination treatment the median OS was 8.1 mths; in HRDetecthi patients median OS was 11.5mths vs 7.8 mths in HRDetectlo patients (HR 0.94, 95% CI 0.42-2.13, p=0.8). Conclusions: In patients with advanced PDAC with high HRDetect scores, response rate to FFX is over 50% and survival is significantly longer compared to patients with PDAC and low HRDetect scores. HRDetect identifies an additional population of patients with non-HRD PDAC who benefit from DNA damaging agents. Citation Format: Grainne M. O'Kane, Robert E. Denroche, Amy Zhang, Sarah Picardo, Robert C. Grant, MIchael J. Allen, Gun Ho Jang, Yifan Wang, Anna Dodd, Stephanie Rampotar, Shawn Hutchinson, Mustaphe Tehfe, James J. Biagi, Dianne Chadwick, Bernard Lam, Julie Wilson, Faiyaz Notta, Sandra E. Fischer, George Zogopoulos, Steven Gallinger, Jennifer J. Knox. HRDetect as a predictive score of platinum response in advanced PDAC [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 5465.
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) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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) | 0,004 | 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 ».