NTRK1 positive

Case Presentation and We report two cases with RAI-resistant lung metastases treated with larotrectinib: 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation)...In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

Three patients recurred after first-line therapy: 1 with BRAF mutated GBM, 1 with GBM harboring FGFR3-TACC3 fusion, and 1 with NTRK1 fusion positive glioneuronal tumor received specific BRAF/MEK inhibitor (dabrafenib/trametinib), FGFR inhibitor (pemigatinib), and NTRK inhibitor (larotrectinib), respectively. The incidence of actionable molecular alterations in IDH wt gliomas and glioneuronal/neuronal tumors was low. However, the use of targeted therapies may lead to significant impact on the outcome.

NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.

No abstract available

However, ORR was the lowest among entrectinib-treated NTRK+ CRC (20%, 2/10) and selpercatinib treated RET+ CRC (20%, 2/10)...Thus, NTRK+ and RET+ CRC patients may benefit more from FDA approved immunotherapy (single agent pembrolizumab or dostarlimab) than TKIs in NTRK+ and RET+ CRC. We surveyed all 58 human RTKs to identify RTK fusions in CRC using AACR GENIE cBioPortal public version 13.0... In this comprehensive survey of human RTK fusions in CRC, NRTK1+ and RET+ CRC harbor significantly higher mean co-occurring genomic alterations compared to other RTK+ CRC consistent with previous reports. Hypothesis-generating randomized trials comparing pembrolizumab versus target-specific TKIs should be performed to address optimal treatment of NTRK1/3/RET+ CRC.

Regarding break-apart FISH, NTRK detection is difficult because of the diversity of signal patterns. Further research is warranted to identify the characteristics of NTRK-fusion CRCs.

This study provides new insights and facilitates our current understanding of clinicopathological features and survival outcomes of different fusion oncogenes in PTCs. It may help clinicians better counsel the patients and tailor appropriate treatment decisions.

In 2020, UK NICE approved a histology-independent TRK-inhibitor drug, larotrectinib, for treatment of such tumours in both children and adults.Methodology: We present the case of a 49-year old female who presented with recurrence of an NTRK1-TPM3 fusion positive cervical sarcoma nine months following primary total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). The patient was initially referred with a large cervical mass measuring 9cm on imaging...Although four cycles of doxorubicin were administered, the pulmonary masses continued to progress... Excellent durable response and improved survival was achieved. Testing for NTRK should be done and NTRK inhibitors considered for advanced gynaecological sarcomas. Future research will further assess the efficacy of TRK-inhibition therapy as primary, neoadjuvant and adjuvant treatment.

The capability of AZD4547 to inhibit TRKA, TRKB and clinically relevant mutants (TRKA G595R, G667S, G667C and G667A) was also evaluated using Ba/F3 cells harboring the ETV6-NTRKs fusion gene. The combined observations demonstrate the potential application of AZD4547 for treatment of NTRK fusion driven cancers.

"In our series, 20% (1/5) of MSI-H KRAS/NRAS/BRAF wt CRC were NTRK rearranged. All methodologies were optimal to detect NTRK rearrangements. Different methodologies provide complementary information about rear- rangements, being NGS the most specific."

We investigated the prevalence and concomitant genomic landscape of NTRK fusions, predicted patient ancestry and compared the FoundationCORE cohort with entrectinib clinical trial cohorts (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267])...NTRK gene fusion prevalence varied greatly by age, cancer type and histology. Interrogating large datasets drives better understanding of the characteristics of very rare molecular subgroups of cancer and allows identification of genomic patterns and previously unreported fusion partners not evident in smaller datasets.

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.

Very high expression of ALK mRNA in NSCLC is associated with EML4-ALK translocations.In contrast, a significant number of fusion negative patients show high ROS1, RET and NTRK1 mRNAvery high levels. Further research is warranted to determine the clinical relevance of this finding.

Background: NTRK rearrangements, though rare in common cancers, are clinically actionable targets with two FDA-approved drugs for pan-cancer indications, larotrectinib and entrectinib. NTRK1 fusions were detected in cfDNA at a similar prevalence to tissue NGS, demonstrating high sensitivity of plasma-based assays to detect these fusions. NTRK1 fusion partners were diverse, with the majority of partner genes observed only once across the cohort. Both clonal and subclonal NTRK1 rearrangements were detected, affirming that this biomarker can emerge as an oncogenic driver or as a mechanism of resistance.

Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.

Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.

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.