Modified GRAS Score for Prognostic Classification of Adrenocortical Carcinoma: An ENSAT Multicentre Study

Background: Adrenocortical carcinoma (ACC) has an aggressive but heterogeneous behaviour. ENSAT stage and Ki67 proliferation index are used to predict clinical outcome but are limited in distinguishing patients with different risk of disease progress. We aimed to validate the prognostic role of a previously proposed points-based score (mGRAS) in a large ACC cohort. Methods: We included ACC patients who underwent adrenalectomy between 2010 and 2019, had complete clinical and histopathological data, and did not participate in our previous studies (Libe et al. Ann Oncol 2015; Lippert et al. JCEM 2018). The mGRAS score was calculated as follows: age (<50yr=0; ≥50yr =1), symptoms (no=0; yes=1), ENSAT stage (1–2=0; 3=1; 4=2), resection status (R0=0; RX=1; R1=2; R2=3), and Ki67 (0–9%=0; 10–19%=1; ≥20%=2 points), generating scores from 0 to 9 and four mGRAS groups (scores 0–1, 2–3, 4–5, and 6–9). Progression-free survival (PFS) and disease-specific survival (DSS) were the primary and secondary endpoints, respectively. The discriminative performance of mGRAS was investigated using the Harrell’s C-index and Royston-Sauerbrei’s R(2)(D) statistic. Results: A total of 942 ACC patients from 14 ENSAT centres were included (38% men; median age 50yrs (interquartile range 38, 61)). The four mGRAS groups showed superior prognostic discrimination compared to the individual clinical and histological parameters for both PFS and DSS (C-index 0.71, R(2)(D)=0.30 and 0.77, R(2)(D)=0.46, respectively); ENSAT staging was the second best discriminator (C-index 0.67, R(2)(D) 0.21 and 0.72, R(2)(D)=0.35, respectively). An even better prognostic discrimination was observed using the ten mGRAS scores individually (C-index 0.73, R(2)(D)=0.30, and 0.79, R(2)(D)=0.45 for PFS and DSS, respectively). The superiority of mGRAS was confirmed when separately considering patients treated or untreated with adjuvant mitotane (n=481 vs 314). In mitotane-treated patients, the four mGRAS groups showed better performance in predicting PFS than Ki67 index (C-index 0.66, R(2)(D) 0.18 vs C-index 0.62, R(2)(D) 0.12). Conclusion: The prognostic performance of mGRAS is superior to that of ENSAT staging and Ki67. This simple score may guide personalised treatment decisions in patients with ACC, e.g. regarding the need for adjuvant therapy and frequency of monitoring.