External validation of the S-GRAS score for predicting recurrence in patients with adrenocortical carcinoma: implications for adjuvant mitotane therapy.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with variable outcomes post-adrenalectomy. The S-GRAS score integrates five clinical and pathological factors to predict prognosis but requires external validation in diverse settings. We validated the S-GRAS score in 138 ACC patients from the Spanish ICARO-GETTHI/SEEN registry (1998-2023). Model performance was assessed using discrimination, calibration, and accuracy. Exploratory refinements included nonlinear modeling of age and Ki-67% and an expanded model incorporating venous invasion and tumor size. Cox models examined the interaction between S-GRAS and adjuvant mitotane. A total of 76 recurrence events were recorded. The S-GRAS score demonstrated good discrimination for overall survival (C-index 0.706, 95% CI: 0.628-0.785) and recurrence-free survival (C-index 0.673, 95% CI: 0.601-0.745) with well-calibrated predictions. Five-year survival rates differed significantly across score groups: 100% for scores 0-1, 81.6% for 2-3, 55% for 4-5, and 33.8% for 6-7. Nonlinear modeling of Ki-67% improved performance (C-index 0.738 for RFS, 0.761 for OS), but adding clinical variables offered minimal benefit, leaving 75% of recurrence variability unexplained. Higher S-GRAS scores correlated with increased mitotane benefit (HR 0.57, 95% CI: 0.34-0.97 for score 4; HR 0.46, 95% CI: 0.23-0.94 for score 5), indicating a potential incremental benefit pattern. Our findings validate the S-GRAS score in a multicenter cohort and support its use in identifying candidates for adjuvant mitotane. Nonlinear modeling of Ki-67% enhances predictive precision without increasing complexity, but the performance plateau of clinical variables suggests that integrating molecular biomarkers may be necessary to improve prognostic accuracy.