Systematic population-based identification of NTRK and RET fusion-positive thyroid cancers

Systematic population-based identification of NTRK and RET fusion-positive thyroid cancers

Eszlinger M, Stewardson P, McIntyre JB, et al. Eur Thyroid J. 2022;11(1). doi:10.1530/ETJ-21-0061.

• Integrated molecular stratification strategies can help identify patients with rearranged during transfection (RET) fusions/mutations or neurotrophic tyrosine receptor kinase (NTRK) fusions, who may benefit from RET or NTRK inhibitor treatment
• Early detection of these patients allows for early stratification to possible treatment with a RET or TRK inhibitor

The activity profiles of rearranged during transfection (RET) inhibitors and neurotrophic tyrosine receptor kinase (NTRK) inhibitors are specific and selective, requiring that patients are stratified on the basis of RET gene fusion/mutation and NTRK gene fusion detection, respectively.

Previous studies have reported on the prevalence of these fusions/mutations:

• In one study, in mostly non-metastatic thyroid cancers, RET fusions were detected in 6.8% of cancers while NTRK fusions were detected in 1.2%¹. Thyroid cancer showed the greatest proportion of tumours with druggable kinase fusions (8.7%)²
• In another study, NTRK fusions were detected in 3.1% of primary thyroid carcinoma cases. Six of eleven patients with this fusion had distant metastases³. In papillary thyroid carcinomas, NTRK fusions were detected in 12.6% of patients and RET gene fusions were detected in 14.3%⁴
• Fusion prevalence reportedly increases for patients with advanced/metastatic cancers with wild type of other aberrations:
  • In one study, 12% of 60 samples demonstrated gene fusions in radioiodine (RAI)-resistant metastatic thyroid cancers without BRAF, KRAS, NRAS or HRAS mutations⁵
  • In another study, 67% of patients with BRAF mutation-negative papillary thyroid carcinoma (PTC) and distant metastases had RET, NTRK or ALK fusions⁶
  • The prevalence of RET mutations has been reported as 90% in advanced metastatic medullary thyroid cancer (MTC)⁷

The researchers identified the need to develop integrated molecular stratification strategies, aiming to formulate a process that would identify patients with RET fusion/mutation-positive and NTRK fusion-positive thyroid cancer who may benefit from RET or TRK inhibitor treatment.

What did the researchers do?

In order to identify patients who may be suitable candidates for treatment with a RET or NTRK inhibitor, the researchers used a recurrence risk-adapted, stepwise prioritisation approach, applying molecular screening tests sequentially and investigating mutations with ever-increasing coverage.

The researchers utilised the electronic medical record system of Alberta Health Services to find people with newly diagnosed thyroid cancer in the Southern Alberta and Calgary regions, who had already consented to participate in research. Records dating back to April 2017 were included, with 482 patients identified. As part of standard procedure, the patients had been prospectively assessed for:

• their American Thyroid Association (ATA) recurrence risk
• tumour-nodes-metastases (TNM)/distant metastasis
• age
• completeness of resection
• local invasion
• tumour size (MACIS) staging
• whether radioactive iodine treatment was indicated

Table 1 outlines the stratification of patients according to ATA recurrence risk and the presence of medullary thyroid cancer or non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

Table 1. Stratification of patients according to ATA recurrence risk and medullary thyroid cancer or NIFTP. ATA, American Thyroid Association; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear features.

Two separate analyses were then conducted on the sample (N = 482), Analysis A and Analysis B, in which a total of 86 patients were eligible.

• Analysis A targeted patients with RAI-resistant distant metastases (n = 42)
• Analysis B focused on patients at ATA high and intermediate recurrence risk and those with metastatic medullary thyroid cancer (MTC) (n = 44)

In Analysis A, pre-screening of primary tumours was performed to identify patients who were BRAF mutation-negative, and the following MassARRAY^® tests were performed with increasing mutation coverage respectively: BRAF Test, Colon Panel, Melanoma Panel, or ThyroSPEC™. In Analysis B, those patients at ATA intermediate and high risk had previously been investigated with a MassARRAY^® test. See Figure 1 for details on the two analyses performed, including the detection methods utilised.

Figure 1. Outline of the screening approach undertaken by the researchers for detection of NTRK and RET gene fusions in Analyses A and B. NTRK and RET gene fusion screening by Eszlinger et al. is licensed under CC BY 4.0 / Notations removed. ATA, American Thyroid Association; BRAF, B-Raf proto-oncogene, serine/threonine kinase; RAI, radioiodine; BRAF, B-Raf proto-oncogene; ETV6-NTRK3, ETS variant transcription factor 6-neurotrophic receptor tyrosine kinase 3; MTC, medullary thyroid cancer; NCOA4, nuclear receptor coactivator 4; NTRK, neurotrophic tyrosine receptor kinase; RAS, resistance to audiogenic seizures; RET, rearranged during transfection; TERT, telomerase reverse transcriptase. telomerase reverse transcriptase.

What did the researchers find?

Twenty-two patients in Analysis A were excluded from additional Oncomine™ Comprehensive Assay v3 (OCAv3) analysis, leaving 20 patients who were identified as BRAF mutation-negative with RAI-resistant distant metastases. Of these patients, the OCAv3 panel detected four NTRK fusions (20%) and four RET gene fusions (20%). Overall, in patients with RAI-resistant distant metastases (n = 42), actionable fusions were identified in 19% of tumours, comprising 9.5% RET gene fusions and 9.5% NTRK gene fusions.

Thirty-five patients in Analysis B were excluded from OCAv3 analysis due to the presence of BRAF mutations (n = 30), RET point mutations (n = 2) and other gene fusions in ATA high recurrence risk patients with indeterminate response to treatment. Further OCAv3 analysis was performed in the primary tumours of the remaining nine patients in this group, detecting one RET fusion (11%) and one NTRK fusion (11%). Overall, NTRK fusions, RET mutations or RET/PTC fusions were detected in 14% of the 42 patients at ATA high and intermediate risk and the two MTC patients (n = 44), comprising 4.5% RET gene fusions, 4.5% RET point mutations and 4.5% NTRK gene fusions.

What were the key findings?

1. The 40% prevalence of RET fusion or NTRK fusion in 20 patients who were BRAF mutation-negative with RAI-resistant metastatic thyroid cancer, was significantly higher than the previously reported prevalence of 12%⁵
2. The prevalence of RET fusions and NTRK fusions was 36% in 11 BRAF mutation-negative patients with follicular thyroid cancers at ATA high and intermediate recurrence risk

These results suggest that rates of RET fusions and NTRK fusions are far higher in these pre-selected patient groups than were reported in The Cancer Genome Atlas study, in which the majority of patients had non-metastatic thyroid cancers, or RAI-resistant metastatic thyroid cancers without KRAS, HRAS, BRAF or NRAS mutations^1,8.

What are the main clinical implications?

Consider screening the following patients for RET fusions and NTRK fusions:

• BRAF mutation-negative with RAI-resistant metastatic thyroid cancer
• BRAF mutation-negative with progressive structural incomplete response to total thyroidectomy and RAI treatment
• ATA high/intermediate recurrence risk with progressive structural incomplete response

If mutations are detected, this allows for early stratification to possible treatment with a RET or NTRK inhibitor, which are associated with lower adverse reactions and better response rates than current standard of care^9–12.

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References

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