Progressive metastatic infantile fibrosarcoma with multiple acquired mutations

Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly byNTRKfusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. TheNTRKfusion acts as a driver for tumor formation, which can be targeted by first- and second-generationTRKinhibitors. AlthoughNTRKgatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy andTRKinhibition that developed metastatic, progressive disease with multiple acquired mutations, includingTP53,SUFU, and anNTRKF617L gatekeeper mutation. Alterations in pathways ofSUFUandTP53have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response toTRKinhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma withETV6::NTRK3and acquiredSUFU,TP53, andNTRKF617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.