TPR-NTRK1 fusion

In pediatric fusion-oncogene PTC cases with 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric PTC patients.

Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers.

NTRK -rearranged uterine sarcomas are a rare subset of uterine sarcomas that exhibit a characteristic morphology and immunophenotype allowing for distinction from morphologic mimics. Our series is the largest to date and contributes significantly to the existing body of knowledge on this tumor type, including reporting the youngest and oldest patients, confirming corpus as a primary location of disease, and by identifying a novel fusion partner ( C16orf72) .

The patient was offered chemotherapy; however, he experienced rapid local progression of the tumor, leading to respiratory obstruction and finally, death. The present case underpins the value of next-generation sequencing as a useful technique for uncovering NTRK-fusion-positive mesenchymal tumors, which are associated with treatment implications.

All cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.

Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

The present case underpins the value of next-generation sequencing as a useful technique for uncovering NTRK-fusion-positive mesenchymal tumors. Review of similar cases, diagnostic challenge, and treatment implications in such cases are discussed.

Mice treated with the entrectinib/cobimetinib combination revealed the durability of the tumor regression was significantly increased compared to single-agent entrectinib. Additionally, the combined therapies also induced more stable expression of BIM than the single-agent, by delaying degradation of BIM by the proteasome following BIM phosphorylation. Collectively, these data provide a compelling rationale for the clinical deployment of the targeted combination of TRKA inhibition plus MEK1/2 inhibition first-line in patients whose cancers are driven by NTRK1 gene fusions.