Algorithm for NTRK Gene Fusion Testing

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In 2018, ESMO published the ESCAT (ESMO Scale of Clinical Actionability of molecular Targets) to harmonise and standardise the reporting of clinically relevant genomics data [1]. The ESCAT is a unified framework that classifies targets for precision medicine based on clinical evidence of utility to aid clinicians in their prioritization of potential targets for clinical use based on results of sequencing panels.

The tiers of the ESCAT are shown in the following table [1]. Of note, larotrectinib is an ESCAT Tier 1C treatment (i.e. considered standard of care based on evidence from basket trials ).

Table 28: ESCAT Tiers for the Harmonisation and Standardisation of the Reporting of Genomics Data

Tier Description Level of evidence Clinical implication
1
(ready for routine use)
Alteration-drug match is associated with improved outcome in clinical trials 1A: prospective, randomised clinical trials Treatment is considered standard of care
1B: prospective, non-randomised clinical trials
1C: basket trials
2
(investigational)
Alteration-drug match is associated with anti-tumour activity, but magnitude of benefit has not been elucidated 2A: retrospective studies Treatment considered ‘preferable’ in the context of evidence collection either
as a prospective registry or prospective clinical trial
2B: prospective clinical trials
3
(hypothetical)
Alteration-drug match is suspected to improve outcome based on clinical trial data in other tumour types or with similar molecular alteration 3A: clinical benefit demonstrated in patients with the specific alteration but in a different tumour type. Limited/absence of clinical evidence available for the patient-specific cancer type or broadly across cancer types Clinical trials should be discussed with selected patients
3B: alteration has a similar predicted functional impact as an already studied Tier I abnormality in the same gene or pathway, but does not have associated supportive clinical data
4
(hypothetical)
Pre-clinical evidence 4A: evidence that the alteration or a functionally similar alteration influences drug sensitivity in pre-clinical models Treatment should only be considered in early clinical trials; the lack of clinical
experience should be stressed to patients
4B: actionability predicted in silico
5
(combination development)
Alteration-drug match is associated with objective response, but without clinically meaningful benefit Clinical trials assessing drug combination strategies could be considered
6
(combination development)
No evidence that genomic alteration is a therapeutic target The genomic alteration should not be considered in clinical decisions

In conjunction with the ESMO guidelines published in 2019, a general algorithm for NTRK gene fusion testing to identify patients who would benefit from therapies targeting TRK fusion proteins is outlined in the following figure.

ESMO guidelines note:

  • That in the scenario where the presence of an NTRK gene fusion needs to be confirmed, which  happens for patients affected by tumours in which NTRK gene fusion are known to be highly prevalent if not pathognomonic of the lesion, any technique could work in principle, however the best options as confirmatory techniques are FISH, RT-PCR or RNA-based targeted panels.
  • In the scenario where the challenge is the identification of NTRK gene fusion in an unselected population, using a DNA- or RNA-based NGS targeted panel that reliably detects NTRK gene fusion would be ideal. In addition:
    • Targeted RNA sequencing methods may represent the gold standard for screening, if the RNA quality is optimal
    • If an NTRK gene fusion is identified, then the most exhaustive approach would be to include IHC to confirm protein expression of the detected NTRK fusions
  • Alternatively, a “two-step approach” could be considered, which includes IHC first and confirmation of any positivity detected with IHC by NGS.

Figure 14: Algorithm for NTRK gene fusion testing [2, 3]a

Figure 14: Algorithm for NTRK gene fusion testing

aBased on ESMO 2019 guidelines for NTRK fusion detection and guidelines for TRK fusion cancer in children by Albert et al. 2019; bUsing specific probes for the rearrangement involving the known NTRK gene; cAlbert et al., note that RT-PCR is not routinely used in clinical practice and limited data are available using this technique for NTRK fusion detection; dESMO guidelines note that this population would be likely represented by “any malignancy at an advanced stage, in particular if it has been proven wild type for other known genetic alterations tested in routine practice, and especially if diagnosed in young patients”.

FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MPS, massively parallel sequencing; NGS, next-generation sequencing; RT-PCR, reverse transcriptase-polymerase chain reaction.

References

  1. Mateo J, Chakravarty D, Dienstmann R et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol 2018; 29: 1895-1902.
  2. Albert CM, Davis JL, Federman N et al. TRK Fusion Cancers in Children: A Clinical Review and Recommendations for Screening. J Clin Oncol 2019; 37: 513-524.
  3. Marchio C, Scaltriti M, Ladanyi M et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019 Jul 3. pii: mdz204. doi: 10.1093/annonc/mdz204. [Epub ahead of print].
Last update: 24 June 2019