Progressive metastatic infantile fibrosarcoma with multiple acquired mutations.

Infantile fibrosarcoma is the most common soft tissue sarcoma in children under the age of 1 year and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, metastasis are rare. The NTRK fusion acts as a driver for tumor formation which can be targeted by first and second generation NTRK inhibitors. While NTRK gatekeeper mutations have been well described as mechanisms of resistance to these agents, alternative pathway acquired mutations are rare. Here we report the case of a patient with infantile sarcoma treated with chemotherapy and NTRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53, SUFU, and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors, however, not yet in infantile fibrosarcoma. While most patients have a sustained response to TRK inhibitors, 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 with ETV6::NTRK3 and acquired SUFU, TP53, and NTRK F617L 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.