1133P - SF3B1 mutation predicts improved overall survival in metastatic uveal melanoma patients: Molecular and clinical correlates

Background

Metastatic uveal melanoma (MUM) is a rare and lethal disease with varied clinical course. Despite the existence of well-characterized molecular drivers none have been associated with clinical outcomes in MUM. We aimed to study how uveal melanoma genetic alterations affect MUM prognosis.

Methods

From a prospective database of MUM patients, we analysed molecular alterations of primary tumors, including mutations (GNAQ/GNA11 and SF3B1) and chromosomal imbalances (chr3 monosomy (M3),chr8q amplification (+8q), chr8p deletion (-8p),chr8p amplification (+8p), chr1p deletion (-1p), chr6p deletion (-6p), and chr6q amplification (+6q)). Relevant clinical features at the time of MUM diagnosis, such as age, sex, disease-free survival from primary tumor, ECOG score, size of liver metastasis, and levels of LDH, alkaline phosphatase (ALP), bilirubin (BIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) were recorded. Survival analysis was calculated from MUM diagnosis to death or last follow-up.

Results

Molecular data was obtained from 59 of 119 MUM patients treated at our institution from 2007 to 2022. The mutational driver profile was: 46% GNAQ and 40% GNA11; 42% Q209P and 44% Q209L; 19% SF3B1 mutation being 10% R625H, and 9% R625C. Chromosomal alterations were: M3 81%, +8q 60%, +8p 15%, -8p 12%, -1p 30%, -6q 17%, and +6p 17%. The median overall survival (mOS) for the entire cohort was 16 months(m). Among all genetic alterations, only SF3B1 had a significant impact on mOS: 13m (95% CI 10-15) for wild-type (WT) vs 31.6 m (95% CI 16-46) for mutant (MUT), p=0.01, HR=0.32. Survival probability was higher at 12, 24, and 48m for WT vs MUT (57% vs 81%, 17% vs 70%, and 6% vs 37%). SF3B1 mutation was not statistically associated with any clinical variable. In the multivariate analysis using all clinical variables and SF3B1 status, only DFS ≥2y (HR=2.3), elevated LDH (HR=3.5), elevated ALP (HR=6.1), and SF3B1 MUT (HR=0.2, 95%CI 0.1-0.8, p=0.02) remained significant.

Conclusions

SF3B1 mutation is independently associated with improved OS in MUM patients. Results may affect MUM care, treatment development, and trial stratification. More research is needed to confirm these findings.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.