How to test for RET
Testing for RET alterations is essential to identify patients who may be eligible for Retevmo1
Consider waiting for RET test results before making therapeutic decisions1
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 for Retevmo.1
- 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®)
For NSCLC:
- recommend testing for RET fusions in eligible 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 certain patients with advanced or metastatic 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
- 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:
NSCLC16:
- 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 testing
- 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
Sanger sequencing
- 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.
Laboratory | Contact Info |
---|---|
Biocept |
Contact Info:
T: 888-332-7729 E: customerservice@biocept.com biocept.com |
Biodesix® |
Contact Info:
T: 866-432-5930 biodesix.com/contact |
Bioreference Laboratories/GenPath |
Contact Info:
T: 800-627-1479 genpathdiagnostics.com |
Caris Life Sciences® |
Contact Info:
T: 888-979-8669 E: CustomerSupport@carisls.com carismolecularintelligence.com |
CSI Laboratories |
Contact Info:
T: 800-459-1185 E: clientservice@csilaboratories.com csilaboratories.com |
Exact Sciences |
Contact Info:
T: 844-232-4719 paradigmdx.com |
Foundation Medicine |
Contact Info:
T: 888-988-3639 E: client.services@foundationmedicine.com foundationmedicine.com |
Genomic™ Testing Cooperative |
Contact Info:
T: 949-450-9421 E: gtc@genomictestingcooperative.com genomictestingcooperative.com |
Guardant Health® |
Contact Info:
T: 855-698-8887 E: clientservices@guardanthealth.com guardant360.com |
Inivata™ |
Contact Info:
T: 844-464-8282 inivata.com |
Integrated Oncology (LabCorp)/OmniSeq® |
Contact Info:
T: 800-710-1800 E: support@omniseq.com omniseq.com |
Intermountain Precision Genomics |
Contact Info:
T: 435-251-5780 E: genomics@imail.org navican.com |
Knight Diagnostic Laboratories |
Contact Info:
T: 855-535-1522 E: KDLClientServices@ohsu.edu knightdxlabs.com |
Mayo Clinic Laboratories |
Contact Info:
T: 800-533-1710 E: mcl@mayo.edu mayocliniclabs.com |
Michigan Medicine Laboratories |
Contact Info:
T: 800-862-7284 mlabs.umich.edu |
NeoGenomics Laboratories |
Contact Info:
T: 866-776-5907 E: Client.Services@neogenomics.com neogenomics.com |
Pathgroup |
Contact Info:
T: 888-474-5227 pathgroup.com |
Quest Diagnostics™/Med Fusion | Quest Diagnostics™: T: 866-697-8378 questdiagnostics.com Med Fusion: T: 844-966-7050 medfusionservices.com |
Sema4 |
Contact Info:
T: 800-298-6470 E: billing@sema4.com sema4.com |
Sonic Healthcare USA/Bernhardt Lab |
Contact Info:
T: 904-296-2333 auroradx.com |
Tempus |
Contact Info:
T: 800-739-4137 E: support@tempus.com tempus.com |
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.
DNA=deoxyribonucleic acid; NCCN=National Comprehensive Cancer Network; NTRK=neurotrophic receptor tyrosine kinase; RET=rearranged during transfection; RNA=ribonucleic acid.
References: 1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 2. Gregg JP, Li T, Yoneda KY. Molecular testing strategies in non-small cell lung cancer: optimizing the diagnostic journey. Transl Lung Cancer Res. 2019;8(3):286-301. 3. Suh JH, Schrock AB, Johnson A, et al. Hybrid capture-based comprehensive genomic profiling identifies lung cancer patients with well-characterized sensitizing epidermal growth factor receptor point mutations that were not detected by standard of care testing. Oncologist. 2018;23(7):776-781. 4. Mertens F, Johansson B, Fioretos T, et al. The emerging complexity of gene fusions in cancer. Nat Rev Cancer. 2015;15(6):371-381. 5. Suh JH, Johnson A, Albacker L, et al. Comprehensive genomic profiling facilitates implementation of the National Comprehensive Cancer Network Guidelines for lung cancer biomarker testing and identifies patients who may benefit from enrollment in mechanism-driven clinical trials. Oncologist. 2016;21(6):684-691. 6. Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. 7. Matsuda K. PCR-based detection methods for single-nucleotide polymorphism or mutation: real-time PCR and its substantial contribution toward technological refinement. Adv Clin Chem. 2017;80:45-72. 8. Oczko-Wojciechowska M, Swierniak M, Krajewska J, et al. Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations. Sci Rep. 2017;7:42074. doi:10.1038/srep42074. 9. Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98(2):E364-E369. 10. Ferrara R, Auger N, Auclin E, et al. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13(1):27-45. 11. Naidoo J, Drilon A. Molecular diagnostic testing in non-small cell lung cancer. Am J Hematol Oncol. 2014;10(4):4-11. 12. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.8.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed September 15, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 13. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed July 15, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 14. Benayed R, Offin M, Mullaney K, et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res. 2019;25(15):4712-4722. 15. Bustin SA, Nolan T. Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction. J Biomol Tech. 2004;15(3):155-166. 16. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET fusion-positive lung cancers. Presented at: 2019 World Conference on Lung Cancer, September 7-10, 2019; Barcelona, Spain. 17. Wirth L, Sherman E, Drilon A, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancers. Presented at: 2019 ESMO Congress. September 27-October 1, 2019; Barcelona, Spain. 18. Santoro M, Carlomagno F. Central role of RET in thyroid cancer. Cold Spring Harb Perspect Biol. 2013;5(12):1-17. 19. Elisei R, Alevizaki M, Conte-Devolx B, et al. 2012 European Thyroid Association guidelines for genetic testing and its clinical consequences in medullary thyroid cancer. Eur Thyroid J. 2013;1(4):216-231. 20. Simbolo M, Mian C, Barollo S, et al. High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas. Virchows Arch. 2014;465(1):73-78. 21. Lee SE, Lee B, Hong M, et al. Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma. Mod Pathol. 2015;28(4):468-479. 22. Yu TM, Morrison C, Gold EJ, et al. Multiple biomarker testing tissue consumption and completion rates with single-gene tests and investigational use of Oncomine Dx target test for advanced non—small-cell lung cancer: a single-center analysis. Clin Lung Cancer. 2019;20(1):20-29.e8.