Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma
Menée à l'aide de lignées cellulaires, d'organoïdes et d'une analyse protéomique d'échantillons tumoraux issus de patients atteints d'un adénocarcinome canalaire du pancréas traité par pancréatectomie, cette étude met en évidence la performance d'un modèle, basé sur l'expression d'un panel de 14 protéines, pour établir un pronostic et identifie deux biomarqueurs (NDUFB8 et CEMIP2) permettant d'évaluer la sensibilité des tumeurs aux chimiothérapies adjuvantes
Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts—a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)—enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.
Nature Medicine , résumé, 2024