TPM3-NTRK1 fusion

Here we report a large cohort of NTRK fusions detected in a broad range of tumor types during routine clinical care in the community setting. The number of unique and novel fusion partners identified highlights the value of RNAbased NGS, and demonstrates that when performed along with DNA NGS, provides a comprehensive assessment of NTRK fusions and actionable gene alterations to inform the routine clinical care of cancer patients.

The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

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.

No abstract available

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.

Interestingly, pan-TRK positivity was observed in one case with precursor lesions in both precancerous and cancerous regions, whereas MLH1 loss was restricted to the cancerous region. In summary, an optimized multi-step algorithm using pan-TRK IHC as a screening method was proposed to identify CRC patients harboring NTRK fusions.

There was homozygous deletion of CDKN2A/B, and there were ROS1, TLX3, FAT1, ABL1, MSH2, and PALB2 mutations. The additional genetic alterations in this case may expand the genotypic spectrum of this distinct cohort.

Herein, we present an acquired TPM3-NTRK1 fusion resistant to larotrectinib in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib.Case Presentation: A 48-year-old male with stage IV adenocarcinoma of lung with metastatic disease of bone was initially treated with carboplatin, pemetrexed, and pembrolizumab...Upon progression of disease (PD), systemic therapy regimen was switched to combination of carboplatin, paclitaxel, and bevacizumab...Subsequently, he was started on alectinib 600 mg twice a day given EML 4-ALK fusion mutation [4.8% of variant allele frequency (VAF)] in circulating tumor DNA (ctDNA) NGS assay...We report the case of acquired TPM3-NTRK1 fusion resistant to larotrectinib and acquired ALK L1196M in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Further investigations are warranted to explore the mechanism of resistance to ALK TKIs.

"Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS."

All 3 patients are alive without the disease (median follow-up, 9 mo; range, 4 to 87 mo). The cases present herein demonstrate that NTRK-rearranged spindle cell neoplasms may occur primarily in the lung, albeit extremely rare, and should be included in the differential diagnosis of primary pulmonary spindle cell neoplasms.

Regarding the limit of detection, this panel could detect the target fusions from a tumor sample containing a 1% fusion-positive tumor cellular fraction. Taken together, our ThyChase panel would be useful to identify gene fusions in the clinical field.

Our findings show that we were able to successfully identify NTRK fusions that resulted in targeted therapy. However, our results suggest limited sensitivity of pan-TRK IHC for NTRK3 fusions, and that the reduced specificity for pan-TRK IHC in tumors with physiologic or non-specific TRK expression, results in false positive samples that require confirmatory testing by RNA based NGS.

NTRK fusion-positive entities presented with a wide clinical and histologic spectrum, in a third of which the finding was unexpected. Uncommon/novel NTRK fusions may be present in classic entities negative for canonical fusions by targeted testing and comprehensive fusion detection should be pursued in such cases. Positivity for pan-TRK IHC, diffuse or focal, may be helpful in uncommon clinical presentations.

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.

The CANTRK study demonstrated a high level of agreement in detection of NTRK fusions by NGS RNA testing across different NGS panels. Fusions not detected by certain panels were due either to absence of targets in amplicon primer panels, or potential bioinformatic challenges. Issues encountered during the study, such as defining quality criteria for reporting a positive result, types of results requiring confirmation, and reporting requirements, will be used to formulate a best practice guideline for analysis and reporting of gene fusions detected by NGS methods.

In the present study, we investigated anticancer mechanisms in the KM12SM cell line using three different form of dovitinib (dovitinib (free base), dovitinib lactate (mono acid), and dovitinib dilactic acid (diacid)) and four TRK inhibitors (LOXO-101, entrectinib, regorafenib, and crizotinib). These drugs significantly reduced expression of the phosphorylated proteins NFκB and COX-2 in the KM12SM cell line, and significantly attenuated KM12SM cell migration, according to a Transwell migration assay. Together, these results suggest that TRK inhibitors block products of carcinogenesis by negatively regulating the NFκB signaling pathway and positively regulating the antioxidant NRF2 signaling pathway.

While many assays have technical limitations that disallow the detection of all relevant fusion partners, hybrid capture RNA sequenc- ing can identify novel as well as known partners, permitting a more complete evaluation. The low frequency of NTRK fusions in most tu- mour types suggests that routine screening may be the most effective approach for identifying patients who are candidates for TRK inhibitor therapy. CGP provides a complete assessment of actionable gene alter- ations to inform the routine clinical care of cancer patients.

NTRK fusions were detected only in SSLs of patients aged ?50?years, whereas BRAF mutation was found in younger age-onset SSLs. In conclusion, NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI-high/CIMP-high.

"Our study shows that Pan-Trk IHC detects NTRK1 fusions with 100% specificity in CRC. Our results confirm that NTRK1 fusions are frequently detected in dMLH1/BRAFV600Ewt (11%) and especially in dMLH1/MLH1ph/BRAFV600Ewt (16%) CRCs justifying screening for NTRK fusions in these subsets of CRCs. Our findings of NTRK1 fusions with partners LMNA, PLEKHA6 and TPM3 in CRC are consis- tent with previous studies but noteworthy, we introduce a novel IRF2BP2-NTRK1 fusion in CRC."

NTRK gene fusions occur with many partners with the majority occurring at a low frequency across multiple tumour types, supporting the need for validated and appropriate testing methodologies that work agnostic of 5’ partners.

Conclusions Testing for NTRK fusions should be considered for gynaecological sarcomas not readily classifiable. Future research might further assess the comparative efficacy of Trk-inhibition therapy as primary, neoadjuvant and adjuvant treatment.

It correlates well with RNA sequencing result and has the potential to replace SS18 FISH testing. A positive IHC result supports the diagnosis of SS, while a tumour with atypical FISH pattern and negative IHC result should undergo further molecular testing.

NTRK fusion products are diverse across tumor types, but the significance of these variations is not clear . The biological and clinical implications of retaining certain domains of NTRK and of fusion partners warrants further investigation.

According to this study's results, they are independent oncogenic drivers, mutually exclusive with other driver mutations. We demonstrated that NTRK rearrangement analysis using a DNA-based approach should be verified with an RNA-based assay.

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.

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) .

This is the first report of IFS related to BS, for which we show that both BLM alleles are maintained in the tumor and demonstrate a TPM3-NTKR1 fusion transcript in the IFS. Our communication emphasizes the importance of long-term follow up after treatment for pediatric neoplastic conditions, as clues to important genetic entities might manifest later, and the identification of a heritable tumor predisposition often leads to changes in patient surveillance and management.

No abstract available

Our cohort displayed occurrence of NTRK fusions in a spectrum ranging from rare solid tumors (infantile fibrosarcoma >75% incidence) to AML (<5% incidence). Demonstration of the remarkable efficacy of larotrectinib and entrectinib in clinical trials led to their accelerated tissue-agnostic US Food and Drug Administration (FDA) approval for adult and pediatric patients with NTRK gene fusion solid tumors. Thus, it appears beneficial to screen all solid tumors without any known oncogenic driver for NTRK fusions.

Two patients were receiving larotrectinib...Pan-TRK immunohistochemistry is useful for diagnosis. NTRK-targeted therapy may be an option for unresectable, recurrent or metastatic cases.

TRK inhibitors such as LOXO-101, entrectinib, X396, AB-106, TL118 had remarkable and durable antitumor activities in patients (pts) with TRK fusion-positive cancers, regardless of age or tumor type. NTRK fusions are a rare molecular subtype in Chinese solid tumors. The NTRK gene fusions more commonly occurred in NSCLC (0.3%), CRC (0.4%) and BC (0.2%), and may occur without other targetable alterations such as EGFR, ALK, ROS1. The clinical evidence for responsiveness of NTRK fusions driven solid tumors provides an opportunity to personalize treatments and improve clinical outcomes for patients (pts).