How to test for RET
Testing for RET alterations is essential to identify patients who may be eligible for Retevmo1
Next-generation sequencing (NGS) can be an accurate and tissue-efficient method to test for driver RET alterations and other targetable biomarkers2-5*
An FDA-approved test for the detection of RET gene fusions and RET gene mutations is not currently available.
- Immunohistochemistry (IHC) is not preferred for detecting RET alterations due to low sensitivity and variable specificity10,11
- In the clinical trial, identification of a RET gene alteration was prospectively determined in local laboratories using NGS, PCR, or FISH1
- Immunohistochemistry (IHC) testing was not used in LIBRETTO-0011
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
- recommend testing for RET fusions in patients with metastatic non-small cell lung cancer12
- recommend molecular testing and strongly advise broad molecular profiling for multiple biomarkers, including RET, in eligible patients with metastatic NSCLC12†‡§
†The NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays.
‡It is recommended at this time that, when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS. For patients who, in broad panel testing, don’t have identifiable driver oncogenes (especially in never smokers), consider RNA-based NGS, if not already performed, to maximize detection of fusion events.
§Testing should include NTRK gene fusion.
For Thyroid Carcinoma:
- recommend molecular testing for RET fusions and RET point mutations for patients with thyroid carcinomas13
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
- NGS testing for RET fusions: When properly designed, NGS testing is able to detect known and unknown fusion events4
- A combination of RNA- and DNA-based NGS testing may be a more comprehensive approach to identify oncogenic drivers missed by DNA-based NGS alone14
Fluorescence in situ hybridization (FISH)
- FISH testing allows for detection of fusions regardless of fusion partner10
- Testing for RET fusions using FISH has demonstrated the potential to generate false negative results due to close proximity to partner genes10,21
Reverse transcription polymerase chain reaction (PCR)
- Reverse transcription PCR testing provides sensitive detection of known RET fusions with relatively fast turnaround time10,11,15
- Reverse transcription PCR testing does not detect unknown fusion partners and therefore may underestimate the prevalence of RET fusions10
Most common RET fusion partners identified in the LIBRETTO-001 phase I/II clinical trial:
- 59% KIF5B
- 22% CCDC6
- 11% Unknown||
- 6% Other¶
- 2% NCOA4
Thyroid cancer other than MTC17:
- 52% CCDC6
- 33% NCOA4
- 15% Other#
||Unknown includes positive by FISH or PCR.
¶Others included KIAA1468(2), ARHGAP12, CCDC88C, CLIP1, DOCK1+RBPMS, ERC1, PRKAR1A, and TRIM24 (all 1 each).16
#Others included CCDC1686, ERC1, KTN1, and RUFY (all 1 each).17
- RET testing in germline is well established18
- When germline testing is negative or unknown, the tumor should be tested for somatic RET point mutations18,19
- NGS allows for multiplex testing on a small amount of tissue for the detection of rare, as well as common, cancer-related biomarkers2,5,22
- RET point mutations can be detected by NGS2-4
Quantitative PCR (qPCR)
- Established option that can detect RET-activating point mutations in MTC7-9
- Can detect driver RET mutations; however, the sensitivity may be lower than NGS testing20
Most common RET mutations identified in the LIBRETTO-001 phase I/II clinical trial17:
- 57% M918T
- 19% Extracellular cysteine mutations
- 16% Other**
- 8% V804M/L
**Others included D631-L633delinsE(5), E632-L633del(4), A883F(4), D631-L633delinsV(2), L790F(2), D898-E901del(2), D898_E901del + D903_S904delinsEP, K666N, T636-V637insCRT, D378-G385delinsE (all 1 each).17
Select testing that can detect driver RET fusions and point mutations in the appropriate tumors
The following commercial reference laboratories may offer testing for driver RET fusions and point mutations:
This list is not all-inclusive and does not represent all laboratories and tests. This list is intended for informational purposes and your consideration only, and is based on publicly available information for these organizations. Eli Lilly and Company (Lilly) makes no representations regarding the clinical or analytical validity, manufacturing quality, or design of the testing offered by the laboratories included on this list. Inclusion on this list does not represent an endorsement, referral, or recommendation by Lilly. Contact the laboratory for more information.
|Caris Life Sciences®||
|Genomic™ Testing Cooperative||
E: firstname.lastname@example.org genomictestingcooperative.com
|Integrated Oncology (LabCorp)/OmniSeq®||
|Intermountain Precision Genomics||
|Knight Diagnostic Laboratories||
|Mayo Clinic Laboratories||
|Michigan Medicine Laboratories||
|Quest Diagnostics™/Med Fusion||Quest Diagnostics™:|
Test for RET1
Ensure your test can detect driver RET fusions in NSCLC and non-medullary thyroid cancer and driver RET mutations in MTC
*Through design and validation, the test has established high sensitivity, specificity, and reproducibility for the detection of genomic alterations.