Distinct prognostic roles of <i>IDH</i> mutation and high-risk genomic alterations in patients with primary chondrosarcoma.

11550 Background: Prior studies report mixed associations between IDH mutation and survival in chondrosarcoma. We evaluated the prognostic impact of IDH mutation and high-risk genomic alterations in one of the largest multi-institutional cohorts while accounting for established prognostic factors. Methods: We retrospectively analyzed patients with histologically confirmed chondrosarcoma treated at the University of Miami and University of Florida. Patients with available molecular data were included. High-risk genomic alterations were defined as TP53, TERT, or cell-cycle pathway alterations. Endpoints included median overall survival (mOS), progression-free survival (mPFS) after treatment and distant metastasis–free survival (mMFS). Patients with metastatic disease at diagnosis were excluded from mMFS analyses. Multivariable Cox regression models were adjusted for age, sex, tumor grade and tumor type. Results: A total of 144 patients were included; 85 (59%) had NGS data. Median age was 60 years, and 46% had grade 3 disease. The majority of patients had conventional chondrosarcoma; 52 patients (36.1%) had dedifferentiated pathology. Among 64 IDH-mutant and 62 IDH-wildtype tumors, high-risk genomic alterations were identified in 48 patients, with comparable positive margin rates between IDH-mutant (14.1%) and IDH-wildtype (14.5%) cases. After multivariable adjustment for age, sex, tumor grade, and tumor type, IDH mutation was not independently associated with mOS (HR 1.26; p=0.48). However, IDH mutation demonstrated a trend toward inferior mPFS that did not reach statistical significance (HR 1.52; p=0.07) and was independently associated with inferior mMFS (HR 2.60; p=0.004). In contrast, high-risk genomic alterations were independently associated with inferior mOS (HR 2.45; p=0.025), mPFS (HR 2.94; p=0.003) and mMFS (HR 2.71; p=0.009) as compared to those patients without high-risk genomic alterations. Conclusions: After multivariable adjustment, IDH mutation conferred increased metastatic risk without an overall survival disadvantage, whereas high-risk genomic alterations consistently predicted poor outcomes across all survival endpoints. Multivariable Cox regression analyses by survival endpoint in chondrosarcoma. Endpoint Comparison Adjusted HR (95% CI) p-value Overall Survival IDH mutant vs IDH wildtype 1.26 (0.66–2.40) 0.48 High-risk NGS vs Low-risk NGS 2.45 (1.12–5.38) 0.025 Progression-Free Survival IDH mutant vs IDH wildtype 1.52 (0.95–2.43) 0.077 High-risk NGS vs Low-risk NGS 2.94 (1.45–5.96) 0.003 Metastasis-Free Survival IDH mutant vs IDH wildtype 2.60 (1.35–5.01) 0.0043 High-risk NGS vs Low-risk NGS 2.71 (1.28–5.74) 0.009