Retsevmo ® ▼ (selpercatinib)

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Retsevmo® ▼ (selpercatinib): RET Testing

There are several recommended methods to test for RET. RET testing guidelines vary depending on thyroid or lung tumor type.

RET-Altered Cancers

Molecular tumor testing is performed to

  • facilitate a diagnosis by identifying tumor characteristics

  • identify predictive and prognostic biomarkers that can be used when looking at possible clinical outcomes

  • identify appropriate patients for clinical trials, and

  • identify appropriate targeted or systemic therapies.1

Molecular testing may also identify actionable mutations, defined as mutations that a current or investigational product directly or indirectly targets.2

RET-altered cancers is a broad term that encompasses 2 sets of genetic changes including RET fusions and RET mutations.3,4

These alterations activate downstream RET signaling pathways promoting cell proliferation and survival in cancers.3

Molecular Tumor Testing

The most appropriate molecular testing method depends on the alteration type. Table 1 provides an overview of recommended testing methods.

Table 1. Testing Methods by Alteration Type

Testing Method

Alteration Type

Allele-Specific PCR5

FISH6-11

IHC6,11-13

Microarray14

NGS3,15,16

RT-PCR17

Sanger
Sequencing
18

Single nucleotide substitutions and indels

NA

NA

NA

NA

Copy number amplifications

NA

NA

NA

NA

Rearrangements and fusions

NA

NA

NA

NA

Protein level expression

NA

NA

NA

NA

NA

NA

Abbreviations: FISH = fluorescence in situ hybridization; IHC = immunohistochemistry; NA = not applicable; NGS = next-generation sequencing; PCR = polymerase chain reaction; RT = reverse transcription.

There are several testing methods appropriate for diagnosing RET-mutations.

Next generation sequencing is a broad, comprehensive testing method that analyzes DNA and/or RNA to detect RET.6 This method allows for multiplex testing on a small amount of tissue and detection of both common and rare cancer-related biomarkers.15 The NGS platform

  • allows for accurate and sensitive detection of gene fusions, mutations, and amplifications

  • affords the potential identification of RET fusions as in-frame events, and

  • allows the detection of upstream partners and concurrent genomic alterations that involve genes other than RET.3,6,11,15

Next generation sequencing is suitable for formalin-fixed, paraffin-embedded samples, and can be adapted to analyze liquid biopsy specimens.6

Although it is more invasive for the patient, tissue testing is preferred because

  • it is possible that a RET alteration that is found from a biopsy may not be found in the blood through liquid biopsy, and

  • up to 30% of RET alterations may be missed if only ctDNA is tested.19,20

Table 2 provides an overview of RET testing methods in order of preference.

Table 2. RET Testing Methods

Testing Methoda

Description

Advantage

Disadvantage

Appropriate for RET Testing

Time Needed to Complete Test

NGS3,15,16

  • Allows for multiplex testing on a small amount of tissue

  • Detects rare and common cancer-related biomarkers 

  • Highly sensitive and specific

  • Simultaneous query for potentially actionable targets

  • Detects known and novel fusions

  • No standardized model or guidelines regarding NGS in clinical practice

  • May identify low frequency variants with unknown interpretation on significance

Yes

2-4 weeks21

DNA-based NGS15,22-24

 

RET identification/
mutation information

Poor coverage of some intronic areas

Yes


RNA-based NGS6,15,17

 

Unbiased fusion information; no intron coverage issues

Affected by quality of RNA

Yes


RT-PCR11,25-29

Uses RNA from tissue to make cDNA and uses separate probes for each 5’ partner

  • Fast

  • Relatively inexpensive

  • Specific at identifying known RET fusion partner and will not detect novel RET rearrangements

PCRs are designed for the predominant fusions and the actual frequency of RET fusions are underestimated 

Yes

1-2 days21

FISH6-11,30

Locates the positions of specific DNA sequences on chromosomes 

Highly sensitive, definitive standard for detecting a RET rearrangement, regardless of fusion partner

  • Lack of standard cutoffs for defining RET fusion positivity results in poor specificity

  • High rate of FP/FN

  • Unable to detect mutation information

Rare circumstances

2-3 days21

IHC6,11-13

Uses antibodies to find tissue antigens that are expressed with certain cancers

Widely available

  • Unreliable at detecting RET rearrangements

  • Low sensitivity

  • Variable specificity

  • Significant FP/FN

No

2 days31

Abbreviations: cDNA = complementary deoxyribonucleic acid; FISH = fluorescence in situ hybridization; FN = false-negative; FP = false-positive; IHC = immunohistochemistry; NGS = next-generation sequencing; PCR = polymerase chain reaction; RET = rearranged during transfection; RT = reverse transcription.

a Listed in descending order of acceptability.

Clinical Guidelines for Testing

Non-Small Cell Lung Cancer

In general, IASLC, CAP, and AMP recommend that patients with adenocarcinoma be tested for EGFR, ALK, and ROS1 variants. It is also recommended that BRAF could be included in a broader panel.25,26

In addition to these recommendations, the National Comprehensive Cancer Network® (NCCN®) also recommend testing for MET exon 14 skipping mutations and NTRK gene fusions.32

An overview of clinical guidelines for RET testing in lung cancer is provided in Table 3.

Table 3. Clinical Guidelines for RET Testing in Lung Cancer

 

NCCN®32a

IASLC/CAP/AMP25,26

ESMO33

RET testing

Category 2A recommendation as part of routine biomarker screening.bc

Consider testing

Not recommended as a routine stand-alone assay

  • Appropriate as part of a larger panel either initially or if negative for EGFR, ALK, and ROS1

Targeting/testing not currently routinely recommended

Other recommendations

Molecular testing and advise broad molecular profilingin effort to identify rare driver mutations for which therapy is currently available or clinical trials are ongoing.b

Broad multiplex/NGS panels preferred over single-gene testing to identify wider range of actionable alterations

Recruitment into open clinical trials encouraged

Abbreviations: ALK = anaplastic lymphoma kinase; AMP = Association for Molecular Pathology; CAP = College of American Pathologists; EGFR = epidermal growth factor receptor; ESMO = European Society for Medical Oncology; IASLC = International Association for the Study of Lung Cancer; NCCN = National Comprehensive Cancer Network; NGS = next generation sequencing; RET = rearranged during transfection.

a  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.

b 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.

c Category 2A: Based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Thyroid

Molecular testing in thyroid cancer may help in available treatment options, as well as identify patients eligible for clinical trials.34

Medullary thyroid cancer is a subset of approximately 1% to 2% of all thyroid cancer cases.35 Approximately 75% of MTC cases are sporadic and 25% are hereditary.35 Molecular testing can classify somatic MTC as MEN2a (which includes associated conjugated linoleic acid or Hirschsprung’s Disease) or MEN2b. Guidelines vary depending on how somatic MTC is classified.36

Molecular testing can also determine the presence of RET. Most patients with MEN2A or MEN2B and familial MTC have RET germline mutations and approximately 50% of patients with sporadic MTC have somatic RET mutations.36

Approximately 15% to 30% of thyroid nodules are classified as cytologically indeterminate by FNA at the time of diagnosis. Molecular testing has been developed to aid in diagnosis and appropriate management of these lesions and to

  • avoid unnecessary surgery for benign thyroid nodules

  • identify high-risk cancers for possible total thyroidectomy, and

  • identify premalignant nodules with low-to-intermediate risk for possible lobectomy.37

An overview of RET testing guidelines in thyroid cancer is provided in Table 4.

Table 4. Clinical Guidelines for RET Testing in Medullary Thyroid Cancer

 

ATA38
(at Diagnosis)

ATA36
(Somatic Testing of Tumor for Prognostic and Treatment Decisions)

ESMO39

NCCN®ab34

RET testing

Consider testing in suspected cytology with a 7-gene mutation panel

Test in:

  • MTC

  • sporadic MTC

  • 1st-degree relatives of patients with MTC

  • patients with CLA

  • parents of infants with classic phenotype MEN2B

  • infants/children with HD and exon 10 RET germline mutations

  • adults with MEN2A and exon 10 mutations with symptoms of HD

Molecular testing, including RET for thyroid nodules

Test in:

  • MTC on FNA or after thyroid surgery

  • locally recurrent advanced and/or metastatic disease not amenable to RAI therapy

  • newly diagnosed sporatic MTC

  • germline WT or unknown with recurrent or persistent MTC

  • germline mutationc

  • MEN2A MTC

  • MEN2B MTC

  • family  members

Other recommendations

NA

Parents who do not want prenatal RET testing should be offered genetic counseling

NA

Consider testing in FNA samples that are indeterminate

Abbreviations: ATA = American Thyroid Association; CLA = conjugated linoleic acid; ESMO = European Society for Medical Oncology; FNA = fine needle aspiration; HD = Hirschsprung’s Disease; MEN = multiple endocrine neoplasia; MTC = medullary thyroid carcinoma; NA = not applicable; NCCN = National Comprehensive Cancer Network; RAI = radioactive iodine; RET = rearranged during transfection; WT = wild type. 

a Molecular markers should be interpreted with caution, and in the context of clinical, radiologic, and cytologic features of each individual patient.

b 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.

c Specific mutation testing and genetic counseling in family members should be ensued.

References

1. Normanno N, Denis MG, Thress KS, et al. Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer. Oncotarget. 2017;8(7):12501-12516. https://doi.org/10.18632/oncotarget.13915

2. Meric-Bernstam F, Johnson A, Holla V, et al. A decision support framework for genomically Informed investigational cancer therapy. JNCI. 2015;107(7). https://doi.org/10.1093/jnci/djv098

3. Drilon A, Hu ZI, Lai GG, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. https://doi.org/10.1038/nrclinonc.2017.175

4. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173-186. https://doi.org/10.1038/nrc3680

5. Lang AH, Drexel H, Geller-Rhomberg S, et al. Optimized allele-specific real-time PCR assays for the detection of common mutations in KRAS and BRAF. J Mol Diagn. 2011;13(1):23-28. https://doi.org/10.1016/j.jmoldx.2010.11.007

6. Garinet S, Laurent-Puig P, Blons H, Oudart JB. Current and future molecular testing in NSCLC, what can we expect from new sequencing technologies? J Clin Med. 2018;7(6):144. https://doi.org/10.3390/jcm7060144

7. 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. https://doi.org/10.1038/modpathol.2014.107

8. Chen F, Clark DP, Hawkins AL, et al. A break-apart fluorescence in situ hybridization assay for detecting RET translocations in papillary thyroid carcinoma. Cancer Genet Cytogenet. 2007;178(2):128-134. https://doi.org/10.1016/j.cancergencyto.2007.07.006

9. Musholt TJ, Staubitz JI, Cámara RJ, et al. Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques - a molecular and clinical analysis. Eur J Surg Oncol. 2019;45(6):1018-1024. https://doi.org/10.1016/j.ejso.2018.11.009

10. Go H, Jung YJ, Kang HW, et al. Diagnostic method for the detection of KIF5B-RET transformation in lung adenocarcinoma. Lung Cancer. 2013;82(1):44-50. https://doi.org/10.1016/j.lungcan.2013.07.009

11. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non–small cell lung cancer. J Thorac Oncol. 2018;13(1):27-45. https://doi.org/10.1016/j.jtho.2017.10.021

12. Rebelo S, Domingues R, Catarino AL, et al. Immunostaining and RT-PCR: different approaches to search for RET rearrangements in patients with papillary thyroid carcinoma. Int J Oncol. 2003;23(4)1025-1032. https://doi.org/10.3892/ijo.23.4.1025

13. Cerilli LA, Mills SE, Rumpel CA, et al. Interpretation of RET immunostaining in follicular lesions of the thyroid. Am J Clin Pathol. 2002;118(2):186-193. https://doi.org/10.1309/53UC-4U88-RRTN-H33G

14. Bolón-Canedo V, Alonso-Betanzos A, López-de-Ullibarri I, Cao R. Challenges and future trends for microarray analysis. Methods Mol Biol. 2019;1986:283-293. https://doi.org/10.1007/978-1-4939-9442-7_14

15. Drilon A, Wang L, Arcila ME, et al. Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res. 2015;21(16):3631-3639. https://doi.org/10.1158/1078-0432.CCR-14-2683

16. Khoo C, Rogers TM, Fellowes A, et al. Molecular methods for somatic mutation testing in lung adenocarcinoma: EGFR and beyond. Transl Lung Cancer Res. 2015;4(2):126-141. https://doi.org/10.3978/j.issn.2218-6751.2015.01.10

17. Vaughn CP, Costa JL, Feilotter HE, et al. Simultaneous detection of lung fusions using a multiplex RT-PCR next generation sequencing-based approach: a multi-institutional research study. BMC Cancer. 2018;18(1):828. https://doi.org/10.1186/s12885-018-4736-4

18. 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. https://doi.org/10.1007/s00428-014-1589-3

19. Hou H, Yang X, Zhang J, et al. Discovery of targetable genetic alterations in advanced non-small cell lung cancer using a next-generation sequencing-based circulating tumor DNA assay. Sci Rep. 2017;7(6):14605. https://doi.org/10.1038/s41598-017-14962-0

20. Villaflor V, Won B, Nagy R, et al. Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer. Oncotarget. 2016;7(41):66880-66891. https://doi.org/10.18632/oncotarget.11801

21. Vnencak-Jones CL, Berger MF, Pao W. Types of molecular tumor testing. My Cancer Genome. 2020. Updated February 3, 2020. Accessed February 12, 2020. https://www.mycancergenome.org/content/molecular-medicine/types-of-molecular-tumor-testing/

22. Yu Y, Dong L, Li D, et al. Targeted DNA sequencing detects mutations related to susceptibility among familial non-medullary thyroid cancer. Sci Rep. 2015;5:16129. https://doi.org/10.1038/srep16129

23. Davies KD, Le AT, Sheren J, et al. Comparison of molecular testing modalities for detection of ROS1 rearrangements in a cohort of positive patient samples. J Thorac Oncol. 2018;13(10):1474-1482. https://doi.org/10.1016/j.jtho.2018.05.041

24. Lih CJ, Harrington RD, Sims DJ, et al. Analytical validation of the next-generation sequencing assay for a nationwide signal-finding clinical trial: molecular analysis for therapy choice clinical trial. J Mol Diagn. 2017;19(2):313-327. https://doi.org/10.1016/j.jmoldx.2016.10.007

25. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358. https://doi.org/10.1016/j.jtho.2017.12.001

26. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. https://doi.org/10.5858/arpa.2017-0388-CP

27. Zhang T, Lu Y, Ye Q, et al. An evaluation and recommendation of the optimal methodologies to detect RET gene rearrangements in papillary thyroid carcinoma. Genes Chromosomes Cancer. 2015;54(3):168-176. https://doi.org/10.1002/gcc.22229

28. Caria P, Dettori T, Frau DV, et al. Assessing RET/PTC in thyroid nodule fine-needle aspirates: the FISH point of view. Endocr Relat Cancer. 2013;20(4):527-536. https://doi.org/10.1530/ERC-13-0157

29. Colato C, Vicentini C, Cantara S, et al. Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements. Eur J Endocrinol. 2015;172(5):571-582. https://doi.org/10.1530/EJE-14-0930

30. Tsuta K, Kohno T, Yoshida A, et al. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 2014;110(6):1571-1578. https://doi.org/10.1038/bjc.2014.36

31. Kim SW, Roh J, Park CS. Immunohistochemistry for pathologists: protocols, pitfalls, and tips. J Pathol Transl Med. 2016;50(6):411-418. https://doi.org/10.4132/jptm.2016.08.08

32. 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 guideline, go online to NCCN.org.

33. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv192-iv237. http://dx.doi.org/10.1093/annonc/mdy275. Published correction appears in Ann Oncol. 2019;30(5):863-870. http://dx.doi.org/10.1093/annonc/mdy474

34. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline for Thyroid Carcinoma V.1.2020. © National Comprehensive Cancer Network, Inc 2020. Accessed June 19, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.

35. Medullary thyroid cancer. American Thyroid Association. Accessed February 12, 2020. https://www.thyroid.org/medullary-thyroid-cancer/

36. Wells SA Jr., Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. http://dx.doi.org/10.1089/thy.2014.0335

37. Nishino M, Nikiforova M. Update on molecular testing for cytologically indeterminate thyroid nodules Arch Pathol Lab Med. 2018;142(4):446-457. https://doi.org/10.5858/arpa.2017-0174-RA

38. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1-33. https://doi.org/10.1089/thy.2015.0020

39. Pacini F, Castagna MG, Brilli L, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl 7):110-119. https://doi.org/10.1093/annonc/mds230

Glossary

ALK = anaplastic lymphoma kinase 

AMP = Association for Molecular Pathology

BRAF = B-rapidly accelerated fibrosarcoma

CAP = College of American Pathologists

ctDNA = circulating tumor DNA

EGFR = epidermal growth factor receptor

FNA = fine needle aspiration

IASLC = International Association for the Study of Lung Cancer

MEN = multiple endocrine neoplasia

MET = MET proto-oncogene

MTC = medullary thyroid cancer

NCCN = National Comprehensive Cancer Network

NTRK = neurotrophic tropomyosin receptor kinase

NGS = next-generation sequencing

RET = rearranged during transfection

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: September 01, 2020


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