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Molecular diagnostics for RET inhibition in NSCLC and thyroid cancers

Imaging in NSCLC with RET rearrangements

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Last updated:26th Nov 2021
Published:26th Nov 2021

Imaging Features and Patterns of Metastasis in Non-Small Cell Lung Cancer with RET Rearrangements

Digumarthy SR, Mendoza DP, Lin JJ, Rooney M, Do A, Chin E, et al. Cancers. 2020;12:693. doi:10.3390/cancers12030693.

  • RET fusions are present in up to 2% of all patients with NSCLC
  • RET fusions are more common in patients with adenocarcinoma histology and minimal or no smoking history
  • Primary RET+ tumours are more likely to be peripherally located
  • Patients with RET+ tumours have a higher frequency of brain metastases at initial diagnosis compared with ROS1+ NSCLC
  • Two RET-selective TKIs have demonstrated preliminary safety and efficacy in patients with RET+ NSCLC

 

Chromosomal rearrangements are important oncogenic fusion drivers in non-small cell lung cancer (NSCLC)1–3. Advanced NSCLC harbouring either anaplastic lymphoma kinase (ALK) or ROS1 gene fusions can be treated effectively with targeted tyrosine kinase inhibitors (TKIs).

Fusions involving the rearranged during transfection (RET) proto-oncogene occur in 1–2% of patients with NSCLC4–6, and are reported more commonly in patients with adenocarcinoma histology and minimal or no smoking history4,7. The presence of RET fusions is mutually exclusive with other oncogenic drivers.

Recently, two highly potent RET-selective TKIs (pralsetinib [BLU-667] and selpercatinib [LOXO-292]) have demonstrated preliminary safety and efficacy in patients with RET+ solid tumours, including advanced NSCLC8,9.

Previous studies suggest that distinct imaging features occur in NSCLC with specific driver mutations, including ALK and ROS1 fusions10–12. However, the radiological features of advanced RET+ NSCLC are less well characterised

In this single centre, retrospective study of 215 NSCLC patients harbouring a RET, ALK, or ROS1 gene fusion (RET+, N = 32; ALK+, N = 116; ROS1, N = 67), Digumarthy and colleagues assessed the imaging features of the primary tumour and metastatic patterns in adult patients with advanced RET+ NSCLC, in comparison with ALK+ and ROS1+ NSCLC.

Overall, patients with RET+ NSCLC were older at initial diagnosis (median 64 years) vs ALK+ or ROS1+ NSCLC (median 51 years and 54 years, respectively; P<0.05), with a higher frequency of neuroendocrine histology (RET: 12% vs ALK: 2% [P=0.025]; vs ROS1: 0% [P=0.010]).

Primary tumour size, density, and lobar location were not significantly different between the three patient groups, with RET+ tumours demonstrating a similar tendency for sclerotic rather than lytic bone metastases as reported previously for ALK+ and ROS1+ NSCLC10,13. However, radiological evaluation showed that primary RET+ tumours were significantly more likely to be peripherally located compared with ALK+ and ROS1+ tumours (RET: 69% vs ALK: 47% [P=0.029]; vs ROS1: 36% [P=0.003]).

RET_DigestNOV21_Fig1.png

Figure 1. Patterns of metastatic sites among patients with advanced RET, ALK, or ROS1 fusion-positive NSCLC. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; RET, rearrange during transfection; ROS1, ROS Proto-Oncogene 1. Comparisons of RET+ vs ALK+ and RET+ vs ROS1+ tumours were not statistically significant (P>0.05) unless otherwise highlighted.

Patients with RET+ tumours also had a significantly higher frequency of brain metastases at initial diagnosis compared with ROS1+ NSCLC; differences between RET+ and ALK+ patients were not statistically significant (Figure 1).

The incidence of lung, pleural, lymphangitic, or pericardial spread was comparable across the tumour subtypes – all patient groups had a high incidence of extrathoracic metastases (59–77% of patients).

Digumarthy and colleagues recommended that, in the absence of other well-validated targets, patients with clinical and imaging features suggestive of RET+ NSCLC are tested further to potentially expand effective treatment options.

In addition, although imaging features were not significantly different between primary tumour subtypes, the tendency towards peripheral location of primary RET+ tumours may have potential diagnostic implications.

RET+ NSCLC
- RET+ NSCLC shares several radiological features with ALK+ and ROS1+ NSCLC

- RET+ tumours are more likely to be peripheral in location, with a tendency for sclerotic bone metastases

- Molecular testing for RET fusions is advisable in the absence of EGFR, BRAF, ALK, or ROS1 alterations

References

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  2. Lin JJ, Shaw AT. Recent advances in targeting ROS1 in lung cancer. J Thorac Oncol. 2017;12:1611–1625.
  3. Lin JJ, Riely GJ, Shaw AT. Targeting ALK: Precision medicine takes on drug resistance. Cancer Discov. 2017;7:137–155.
  4. Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352–4359.
  5. Tsuta K, Kohno T, Yoshida A, Shimada Y, Asamura H, Furata K, et al. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 2014;110:1571–1578.
  6. Takeuchi K. Discovery stories of RET fusions in lung cancer: a mini-review. Front Physiol. 2019;10:216.
  7. Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, et al. Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry. J Clin Oncol. 2017;35:1403–1410.
  8. 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 Discov. 2018;8:836–849.
  9. Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M J, Gainor J, et al. New Eng J Med. 2020;383(9):813–824.
  10. Mendoza DP, Lin JJ, Rooney MM, Chen T, Sequist LV, Shaw AT, et al. Imaging features and metastatic patterns of advanced ALK-rearranged non-small cell lung cancer. Am J Roentgenol. 2020;214(4):766–774.
  11. Yoon HJ, Sohn I, Cho JH, Lee HY, Kim J-H, Choi Y-L, et al. Decoding tumor phenotypes for ALK, ROS1, and RET fusions in lung adenocarcinoma using a radiomics approach. Medicine (Baltimore). 2015;94:e1753.
  12. Park J, Kobayashi Y, Urayama KY, Yamaura H, Yatabe Y, Hida T. Imaging characteristics of driver mutations in EGFR, KRAS, and ALK among treatment-naïve patients with advanced lung adenocarcinoma. PLoS ONE. 2016;11:e0161081.
  13. Digumarthy SR, Mendoza DP, Lin JJ, Chen T, Rooney MM, Chin E, et al. Computed tomography imaging features and distribution of metastases in ROS1-rearranged non-small-cell lung cancer. Clin Lung Cancer. 2020;21:153–159.
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