Secondary genomic alterations and clinical outcomes in myxoid liposarcoma: A multi-institutional analysis.

11580 Background: Myxoid liposarcoma (MLS) is defined by DDIT3 rearrangements. The clinical and prognostic significance of secondary genomic alterations remains incompletely characterized. We retrospectively evaluated the clinical, pathological, and prognostic implications of commonly co-occurring mutations in patients with MLS. Methods: Patients with pathologically confirmed MLS treated at Memorial Sloan-Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) who underwent next-generation sequencing (NGS) on the primary tumor (9/2010-5/2024) were included. To ensure the analysis represented de novo mutations rather than acquired alterations, patients with NGS performed only at the time of recurrent disease were excluded. The primary endpoint was disease-free survival (DFS) among surgically treated patients. Associations between genomic alterations and clinico-pathologic characteristics were assessed using univariable and multivariable analyses. Results: The cohort included 76 patients (67 MSKCC, 9 MDACC) with a median age of 39 years. At diagnosis, 83% of patients (n = 63) had localized disease and underwent definitive surgery, while 17% presented with de novo metastasis; 45% had high-grade disease (≥5% round cell component). Genomic analysis identified TERT promoter mutations in 68%, PIK3CA in 30%, and PTEN in 18%. Notably, PIK3CA and PTEN mutations were not mutually exclusive, with 10.5% of the total cohort harboring concurrent alterations in both genes. TERT promoter mutations were significantly associated with male sex (75% vs 33%, p < 0.001), older age (40 vs 33 years, p = 0.02), high-grade pathology (54% vs 25%, p = 0.026), and larger median tumor size (12.9 vs 7.5 cm, p = 0.002). PIK3CA mutations were associated with male sex (83% vs 53%, p = 0.02) and a trend toward larger median tumor size (13.6 vs 9.3 cm, p = 0.061) and de novo metastasis (30% vs 11%, p = 0.053). For the 63 patients with localized disease, the median DFS was not reached (95% CI: 55.7–NR) with a 24-month DFS rate of 75% (95% CI 61-84). In univariable analysis for DFS, significant predictors of recurrence included PIK3CA mutation (HR 4.61; p = 0.001), PTEN mutation (HR 5.15; p < 0.001), tumor size (HR 1.06 per cm; p = 0.012), high-grade pathology (HR 2.81; p = 0.024) and male sex (HR 2.79; p = 0.049). The presence of both PIK3CA and PTEN mutations conferred particularly poor prognosis (HR 16.34 compared to neither mutation; p < 0.001). In separate multivariable analyses adjusted for grade, both PIK3CA (HR 5.75, p < 0.001) and PTEN (HR 4.27, p = 0.002) remained independent predictors of DFS. Conclusions: Secondary genomic alterations in MLS are highly prevalent and connote distinct clinical phenotypes. While TERT promoter mutations correlate with aggressive pathologic features, PIK3CA and PTEN mutations are independent prognostic factors for DFS and may help risk-stratify patients for potential adjuvant therapies.