DOI: 10.1177/03008916261458950 ISSN: 0300-8916
Driver vs. passenger: Primary resistance to larotrectinib in synovial sarcoma harboring concurrent SS18 rearrangement and PDE3A-NTRK2 fusion
Rashad Ismayilov, Buge Oz, Arzu Oguz, Ozden Altundag
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.