Abstract A59: Biologic rationale for radiation-induced release of circulating tumor DNA
Notice bibliographique
Résumé
Abstract Purpose: Rapid release of circulating tumor DNA (ctDNA) during cytotoxic therapy could provide an early indication of treatment efficacy. However, the biologic basis for treatment-induced ctDNA release is poorly understood. To study this phenomenon, we evaluated ctDNA release in head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy (RT) or chemoradiotherapy (CRT). We sought to characterize the kinetics and biologic underpinnings of this process. Methods: 33 HPV+ HNSCC patients treated with RT (n=17) or CRT (n=16) had blood collected at baseline, after the 4th fraction of RT (early-RT), mid-RT, and 3 months post-RT. ctDNA was quantified using digital PCR for HPV-16. Nine HNSCC cell lines (3 HPV+, 6 HPV-) were used for in vitro ctDNA kinetic analysis. Apoptosis was measured by luminescent DEVD cleavage assay, triggered by staurosporine and blocked by z-vad-fmk. Senescence was measured by SA-β-galactosidase activity, triggered by HrasG12V-transduction of fibroblast cell lines and blocked by navitoclax. Three HNSCC cell lines (2 HPV+, 1 HPV-) were grown as xenografts in NRG mice for in vivo analysis. Endpoint xenograft tumors were assessed for necrotic area and for markers of apoptosis (cleaved-caspase 3) and senescence (p21) by immunohistochemistry. ctDNA was quantified from media or mouse plasma by quantitative PCR using human-specific LINE-1 primers. Results: Of 30 patients with detectable HPV-16 ctDNA (90.9%), we observed variable kinetic patterns of release. We grouped patients into three categories: pattern 1, peak at early RT (12, 40%); pattern 2, peak at mid RT (7, 23.3%); pattern 3, no peak (11, 36.7%). Based on these findings, we characterized the mechanisms dictating RT-induced ctDNA release in preclinical models of HNSCC. Following RT, HNSCC cell lines exhibited variable kinetics of ctDNA release in vitro and in vivo with peak release observed after 72-96 hours. RT-induced ctDNA release was not associated with intrinsic radiosensitivity, HPV status, or propensity to undergo apoptosis. Although caspase inhibition resulted in a near-complete reduction in RT-induced caspase activity (-84%±8%), a comparatively minor reduction in ctDNA release (-29%±9%) was observed. There was an inverse association between RT-induced senescence and ctDNA release. HrasG12V-triggered senescence reduced ctDNA release, while navitoclax treatment reversed this effect. HNSCC models with greater RT-induced ctDNA release displayed more necrosis and less senescence in endpoint xenograft tumors. Conclusion: Dynamic changes in HPV-16 ctDNA are observed during treatment, with variable patterns of release. Preclinical HNSCC models demonstrate RT-induced spikes within 3-4 days of treatment, revealing a complex interplay between distinct mechanisms of cell death and ctDNA release. Necrosis and senescence are the major determinants of RT-induced ctDNA release, while apoptosis has a comparatively minor impact. This study will inform future work on implementing ctDNA as a response biomarker. Citation Format: Ariana Rostami, John N. Waldron, Scott V. Bratman. Biologic rationale for radiation-induced release of circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A59.
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 | 0,000 |
| 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 | 0,001 | 0,001 |
| 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 ».