Real-World Implementation of Next-Generation Sequencing in Sarcoma: Molecular Insights and Therapeutic Outcomes

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region.