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Molecular diagnostics for RET inhibition in NSCLC and thyroid cancers

Patient stratification

Read time: 50 mins
Last updated:10th Sep 2021
Published:10th Sep 2021

Why is patient stratification important for the treatment of RET-altered cancer?

  • Learn about common RET alterations in non-small cell lung cancer (NSCLC) and thyroid cancer
  • Discover the challenges in stratifying patients with RET-altered cancers
  • Listen to expert insights from specialist practitioners about how these challenges can be addressed

Importance of patient stratification for RET inhibition

In the following video Professor Fernando Lopez-Rios from San Pablo CEU University in Madrid, Spain, highlights the importance of molecular testing for rearranged during transfection (RET) gene fusions in non-small cell lung cancer (NSCLC) and thyroid cancers, and the real-world challenges of molecular testing.


Since its discovery in the 1980s, the altered RET gene has been detected in a variety of malignancies, including thyroid, lung, breast and colon cancer1.

RET alterations occur in approximately 2% of all human cancers2

Alterations in the RET gene occur via two main mechanisms: RET point mutations and RET rearrangements3. These alterations lead to the expression of an overactive RET protein that drives tumorigenesis1.

Mechanisms of RET alterations in cancer

Point mutations: Involve modification of the DNA sequence by the addition, deletion or substitution of a single nucleotide, which can change the amino acid sequence of the protein it encodes (Figure 1A)4.

RET point mutations can arise spontaneously, but they can also be inherited. They can occur in extracellular residues, leading to aberrant receptor dimerisation, or in the tyrosine kinase domain, leading to ligand-independent activation5

Gene rearrangements: Gene rearrangements involve formation of a hybrid gene through the fusion of two previously independent genes6.

RET fusions occur following incorrectly repaired double-strand breaks in DNA, which can be caused by oxidative stress or radiation7. Rearrangement of the RET gene leads to a fusion protein with a constitutively activated dimer (Figure 1B)8

RET_T2_Fig_1_Aug2021.png

Figure 1. Schematic representation of (A) a RET point mutation and (B) RET fusion (Adapted4,8,9). KIF5B, kinesin family member 5B; TK, tyrosine kinase; TM, transmembrane domain; RET, rearranged during transfection.

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RET alterations in NSCLC

In the following video Dr Alexander Drilon, a non-small cell lung cancer (NSCLC) expert, outlines how rearranged during transfection (RET) gene alteration status impacts on treatment decisions for patients with NSCLC.


The main types of RET alterations found in non-small cell lung cancer (NSCLC) are gene rearrangements, in the form of gene fusions. Somatic RET fusions occur in 1–2% of NSCLC patients, predominantly in patients with lung adenocarcinoma (Figure 2)1,5.

RET_T2_Fig_2_Aug2021.png

Figure 2. Prevalence of different driver oncogenes in lung adenocarcinoma patients from East Asia (Japan, Korea and China) and from America and Europe (Adapted17). ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1.

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RET alterations in thyroid cancer

Thyroid cancer comprises differing subtypes, many of which are associated with rearranged during transfection (RET) gene alterations1. Approximately 80% of thyroid cancer cases are papillary thyroid cancer (PTC), and <10–20% of these cases are driven by RET fusions (Figure 3)1,7. Common RET fusion partners in PTC are CCDC6 and NCOA4, which are found in approximately 90% of RET fusion-positive cases and lead to constitutively active RET proteins7.

RET_T2_Fig_3_AUG2021.png

Figure 3. Incidence of RET alterations in thyroid cancers (Adapted19). fMTC, familial medullary thyroid cancer; MTC medullary thyroid cancer; PTC, papillary thyroid cancer; sMTC, sporadic medullary thyroid cancer.

Medullary thyroid cancer (MTC) is a less common subtype of thyroid cancer than papillary thyroid cancer (PTC), accounting for 5–10% of all cases20. Approximately 75% of MTC cases are sporadic, but the remaining 25% of cases of MTC occur as part of a hereditary disorder known as multiple endocrine neoplasia type 2 (MEN2)1,20. MEN2 comprises two subtypes, MEN2A (95% of all MEN2 cases) and MEN2B (<5% of all MEN2 cases)1,21

MEN2 is a rare hereditary cancer syndrome driven by RET germline mutations, which is associated with tumours of the adrenal gland, thyroid and parathyroid1,21

Somatic RET point mutations are found in approximately 50% of patients with sporadic MTC, while germline activating RET point mutations are found in virtually all cases of MEN21,3.

Activating point mutations are the primary RET alterations in MTC1

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Emerging challenges in stratifying patients

Experts Dr Alexander Drilon and Professor Lori Wirth describe the challenges associated with stratifying patients for rearranged during transfection (RET) inhibition treatment in both thyroid cancer and non-small cell lung cancer (NSCLC).

Real-world challenges of thyroid cancer management: patient stratification and molecular testing for RET alterations

2

Experts Dr Alexander Drilon and Dr Lori Wirth describe the challenges associated with stratifying patients for rearranged during transfection (RET) inhibition treatment in both thyroid cancer and non-small cell lung cancer (NSCLC).

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References

  1. Salvatore D, Santoro M, Schlumberger M. The importance of the RET gene in thyroid cancer and therapeutic implications. Nature Reviews Endocrinology. 2021;17(5):296–306.
  2. Choudhury NJ, Drilon A. Decade in review: A new era for RET-rearranged lung cancers. Translational Lung Cancer Research. 2020;9(6):2571–2580.
  3. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, et al. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discovery. 2018;8(7):836–849.
  4. Genome.gov. Point mutation. https://www.genome.gov/genetics-glossary/Point-Mutation. Accessed 8 July 2021.
  5. Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discovery. 2020;10(4):498–505.
  6. Parker BC, Zhang W. Fusion genes in solid tumors: An emerging target for cancer diagnosis and treatment. Chinese Journal of Cancer. 2013;32(11):594–603.
  7. Santoro M, Moccia M, Federico G, Carlomagno F. Ret gene fusions in malignancies of the thyroid and other tissues. Genes. 2020;11(4). doi:10.3390/genes11040424.
  8. Gainor JF, Shaw AT. Novel Targets in Non‐Small Cell Lung Cancer: ROS1 and RET Fusions. The Oncologist. 2013;18(7):865–875.
  9. MedlinePlus Genetics. What kinds of gene variants are possible? https://medlineplus.gov/genetics/understanding/mutationsanddisorders/possiblemutations/. Accessed 27 August 2021.
  10. Selpercatinib. Highlights of Prescribing Information. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf.
  11. Pralsetinib. Highlights of Prescribing Information. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf. Accessed 27 August 2021.
  12. Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. New England Journal of Medicine. 2020;383(9):825–835.
  13. Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, et al. Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2020;383(9):813–824.
  14. Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. The Lancet Diabetes and Endocrinology. 2021;9(8):491–501.
  15. Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. The Lancet Oncology. 2021;22(7):959–969.
  16. NCCN. Clinical Practice Guidelines in Oncology for Thyroid Carcinoma. Version 1.2021. www.nccn.org. Accessed 31 August 2021.
  17. Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Translational Lung Cancer Research. 2015;4(2):156–164.
  18. Drusbosky LM, Rodriguez E, Dawar R, Ikpeazu C v. Therapeutic strategies in RET gene rearranged non-small cell lung cancer. Journal of Hematology and Oncology. 2021;14(1):1–8.
  19. Roskoski R, Sadeghi-Nejad A. Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers. Pharmacological Research. 2018;128:1–17.
  20. Santoro M, Carlomagno F. Central role of RET in thyroid cancer. Cold Spring Harbor Perspectives in Biology. 2013;5(12). doi:10.1101/cshperspect.a009233.
  21. Multiple Endocrine Neoplasia Type 2 - NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/multiple-endocrine-neoplasia-type/. Accessed 31 August 2021.
  22. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Medicine. 2020;12(1). doi:10.1186/s13073-019-0703-1.
  23. Keeling P, Clark J, Finucane S. Challenges in the clinical implementation of precision medicine companion diagnostics. Expert Review of Molecular Diagnostics. 2020;20(6):593–599.
  24. Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians’ attitudes about multiplex tumor genomic testing. Journal of Clinical Oncology. 2014;32(13):1317–1323.
  25. Freedman AN, Klabunde CN, Wiant K, Enewold L, Gray SW, Filipski KK, et al. Use of next-generation sequencing tests to guide cancer treatment: Results from a nationally representative survey of Oncologists in the United States. Journal of Clinical Oncology. 2018;36(15_suppl):6529–6529.
  1. Salvatore D, Santoro M, Schlumberger M. The importance of the RET gene in thyroid cancer and therapeutic implications. Nature Reviews Endocrinology. 2021;17(5):296–306.
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