Key result
Integrating DNA biomarkers with the S-GRAS score improves overall survival prediction in adrenocortical carcinoma.
Why the study?
Adrenocortical carcinoma has heterogeneous clinical outcomes and recent studies proposed clinical/histopathological scores or molecular biomarkers to improve prognostication, but their comparative added value was unclear.
Does the addition of DNA-based biomarkers to the S-GRAS score improve prognostication in patients with adrenocortical carcinoma?
Cohort (n=194)
Does the addition of DNA-based biomarkers to the S-GRAS score improve prognostication in patients with adrenocortical carcinoma?
Targeted DNA-based biomarkers improve the prognostication of adrenocortical carcinoma beyond routinely available clinical and histopathological parameters.
Supports addition of DNA biomarkers to refine adrenocortical carcinoma risk stratification; hypothesis-generating and requires prospective validation before adoption.
OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve prognostication. We performed a comparative analysis of DNA-based BMs by evaluating their added prognostic value to the S-GRAS score. DESIGN AND METHODS: A total of 194 formalin-fixed, paraffin-embedded (FFPE) ACC samples were analysed, including a retrospective training cohort (n = 107) and a prospective validation cohort (n = 87). Targeted DNA sequencing and pyrosequencing were used to detect somatic single-nucleotide variations in ACC-specific genes and methylation in the promoter region of paired box 5 (PAX5). The European Network for the Study of Adrenocortical Tumors (ENSAT) tumour stage, age, symptoms at presentation, resection status, and Ki-67 were combined to calculate S-GRAS. Endpoints were overall (OS), progression-free (PFS), and disease-free survival (DFS). Prognostic role was evaluated by multivariable survival analysis and their performance compared by Harrell's concordance index (C index). RESULTS: In training cohort, an independent prognostic role was confirmed at multivariate analysis for two DNA-based BMs: alterations in Wnt/β-catenin and Rb/p53 pathways and hypermethylated PAX5 (both P< .05 for PFS and DFS, hazard ratio [HR] 1.47-2.33). These were combined to S-GRAS to obtain a combined (COMBI) score. At comparative analysis, the best discriminative prognostic model was COMBI score in both cohorts for all endpoints, followed by S-GRAS score (C index for OS 0.724 and 0.765, PFS 0.717 and 0.670, and DFS 0.699 and 0.644, respectively). CONCLUSIONS: Targeted DNA-based BM evaluated on routinely available FFPE samples improves prognostication of ACC beyond routinely available clinical and histopathological parameters. This approach may help to better individualise patient's management.
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Lippert et al. (2023) conducted a cohort in Adrenocortical carcinoma (n=194). Combined (COMBI) score (DNA-based biomarkers + S-GRAS score) vs. S-GRAS score alone was evaluated on Overall (OS), progression-free (PFS), and disease-free survival (DFS) (HR 1.47-2.33, p=<.05). A combined prognostic model integrating DNA-based biomarkers with the S-GRAS score improved discrimination for overall survival in adrenocortical carcinoma compared to S-GRAS alone (C index 0.765 vs 0.724).
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