Driver vs. passenger: Primary resistance to larotrectinib in synovial sarcoma harboring concurrent SS18 rearrangement and PDE3A-NTRK2 fusion

Background: Synovial sarcoma (SS) is molecularly defined by the pathognomonic SS18::SSX fusion, a master epigenetic driver. While NTRK gene fusions are high-priority tissue-agnostic targets for TRK inhibitors like larotrectinib, their co-occurrence with established lineage-defining drivers in sarcomas is exceptionally rare and presents a therapeutic paradox. Case presentation: A 78-year-old female was diagnosed with metastatic biphasic SS. Molecular profiling via targeted RNA sequencing identified a pathogenic PDE3A-NTRK2 fusion (Tier 1A) alongside the canonical SS18 rearrangement. Despite the presence of this usually actionable target, second-line treatment with larotrectinib resulted in rapid clinical deterioration and "explosive" tumor growth, signifying absolute primary resistance to TRK inhibition. The disease followed an aggressive course typical of chemorefractory SS, leading to the patient's death ten months after initial diagnosis. Conclusion: This case provides critical clinical evidence of the "driver versus passenger" phenomenon in precision oncology. It demonstrates that the epigenetic dominance of the SS18::SSX fusion can override the therapeutic relevance of a concurrent NTRK fusion. Our findings serve as a cautionary note: actionable targets detected via next-generation sequencing must be interpreted within the tumor’s canonical biological context, as lineage-defining translocations may render secondary kinase alterations therapeutically inert.