NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas—a study of 4569 cases

Chou, Angela; Fraser, Tamara; Ahadi, Mahsa; Fuchs, Talia L; Sioson, Loretta; Clarkson, Adele; Sheen, Amy; Singh, Nisha; Corless, Christopher L.; Gill, Anthony J.

doi:10.1038/s41379-019-0417-3

Cited by 58 publications

(76 citation statements)

References 28 publications

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“…A similar result was found in a cohort of 11,500 patients with various solid tumours, where only 0.27% harboured NTRK fusions [12]. Less than 0.31% of colorectal carcinomas are found to be NTRK fusion positive, but rates are substantially higher in the high microsatellite instability (MSI-H) phenotype [13]. Typically, the 5′ region of a partner gene fuses with the 3′ region of an NTRK gene, resulting in ligand-independent receptor activation [14].…”

Section: Introductionsupporting

confidence: 78%

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Immunohistochemistry as a screening tool for NTRK gene fusions: results of a first Belgian ring trial

et al. 2020

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A Belgian ring trial for pan-TRK immunohistochemistry (IHC) staining was organised to harmonise pan-TRK IHC staining protocols and interpretation. As a reference method, the VENTANA pan-TRK Assay (clone EPR17341) on the Benchmark Ultra platform was selected. Six samples were selected: 2 negative, 2 fusion positive and 2 samples with wild-type endogenous TRK expression. Each participating laboratory stained the slides using their routine pan-TRK IHC and reported their results. In addition, they were asked to return one TRK-stained slide from each case. The coordinating lab evaluated these slides, compared them with the reference method and scored them. Two clones were used during the ring trial: A7H6R (Cell Signaling) and EPR17341 (Abcam/Ventana). Seven protocols achieved a sufficient performance mark, and three labs were advised to further optimise the protocol. Interpretation of pan-TRK IHC proved to be challenging in cases with physiological TRK expression. In addition, depending on the NTRK fusion partner, the staining can vary strongly in both intensity and staining pattern. Labs using the Ventana ready-to-use system based on the EPR17341 clone and using the recommended protocol settings scored best. However, given some small optimisation, all labs scored well on the technical staining and the succeeding evaluation.

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Section: Introductionsupporting

confidence: 78%

“…Finally, in a large cohort of over 4000 colorectal cancer samples, both antibodies demonstrated similar staining characteristics and showed diffuse strong cytoplasmic staining in all nine fusion-positive cases. In addition, there was also complete concordance between the two observers in interpreting both antibodies [13].…”

Section: Discussionmentioning

confidence: 59%

Immunohistochemistry as a screening tool for NTRK gene fusions: results of a first Belgian ring trial

et al. 2020

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“…There will be an estimated 26,900 new cases of CRC in Canada in 2020 [ 34 ]. In two retrospective analyses of 4569 and 7008 CRC tumours, the frequency of TRK fusion-positive CRC was 0.2% [ 44 , 45 ].…”

Section: Colorectal Carcinomamentioning

confidence: 99%

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

et al. 2021

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The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.

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“…Intriguingly, the MSI phenotype was consistently reported in association with NTRK fusions. More precisely, these genetic alterations seemed to occur in the context of BRAF WT tumors with hypermethylation of the MLH1 gene promoter [ 124 ]. The incidence of NTRK fusions was estimated at approximately 42% in this molecularly selected population [ 48 ].…”

Section: Ntrk Gene Fusions and Trk Inhibitorsmentioning

confidence: 99%

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Cohen

Pudlarz

Delattre

et al. 2020

Cancers

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Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).

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NTRK gene rearrangements are highly enriched in MLH1/PMS2 deficient, BRAF wild-type colorectal carcinomas—a study of 4569 cases

Cited by 58 publications

References 28 publications

Immunohistochemistry as a screening tool for NTRK gene fusions: results of a first Belgian ring trial

Immunohistochemistry as a screening tool for NTRK gene fusions: results of a first Belgian ring trial

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

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