Cerebrospinal Fluid based liquid biopsy to inform diagnosis and management of Leptomeningeal Metastases in EGFR-Mutant Lung Cancer – A Case Report
Main Article Content
Abstract
Leptomeningeal disease (LMD) in advanced non-small cell lung cancer (NSCLC) carries a poor prognosis and is challenging to diagnose without invasive biopsy. Traditional cerebrospinal fluid (CSF) cytology considered the gold standard in diagnosis is only 33% sensitive and often requires patients to undergo multiple lumbar punctures to receive an accurate diagnosis. Innovative technologies that utilize cerebrospinal fluid (CSF) based liquid biopsy have facilitated the detection of tumor derived DNA as a surrogate for cytology, at a much earlier time period than imaging would indicate a definitive diagnosis. This study presents a 47-year-old male diagnosed with non-small cell lung cancer who presented with an increase in intraocular pressure. Subsequent testing using the Belay Summit™ test revealed an EGFR T790M mutation in the CSF. Following the detection of this variant, the patient received treatment with osimertinib (Tagrisso®), which proved beneficial for his condition.
Keywords:
Lung cancer, Leptomeningeal disease, CNS metastasis, genomic testing, CSF
Article Details
How to Cite
YOUSSEF, Michael et al.
Cerebrospinal Fluid based liquid biopsy to inform diagnosis and management of Leptomeningeal Metastases in EGFR-Mutant Lung Cancer – A Case Report.
Medical Research Archives, [S.l.], v. 13, n. 6, june 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6680>. Date accessed: 15 july 2025.
doi: https://doi.org/10.18103/mra.v13i6.6680.
Section
Case Reports
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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30. Mair R, Mouliere F. Cell-free DNA technologies for the analysis of brain cancer. Br J Cancer. Feb 2022;126(3):371-378. doi:10.1038/s41416-021-01594-5
31. Malhotra J, Muddasani R, Fricke J, et al. Clinical Utility of a Circulating Tumor Cell-Based Cerebrospinal Fluid Assay in the Diagnosis and Molecular Analysis of Leptomeningeal Disease in Patients With Advanced Non-Small Cell Lung Cancer. JCO Precis Oncol. Dec 2024;8:e2400373. doi:10.1200/PO-24-00373
2. Ostrom QT, Wright CH, Barnholtz-Sloan JS. Brain metastases: epidemiology. Handb Clin Neurol. 2018;149:27-42. doi:10.1016/B978-0-12-811161-1.00002-5
3. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. Oct 19 2017; 19(11):1511-1521. doi:10.1093/neuonc/nox077
4. Roughley A, Damonte E, Taylor-Stokes G, Rider A, Munk VC. Impact of Brain Metastases on Quality of Life and Estimated Life Expectancy in Patients with Advanced Non-Small Cell Lung Cancer. Value Health. Nov 2014;17(7):A650. doi:10.1016/j.j val.2014.08.2364
5. Gou Q, Gou Q, Gan X, Xie Y. Novel therapeutic strategies for rare mutations in non-small cell lung cancer. Sci Rep. May 5 2024;14(1):10317. doi:10.103 8/s41598-024-61087-2
6. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. Feb 16 2017;376(7):629-640. doi:10.1056/NEJMoa1612674
7. Li YS, Jiang BY, Yang JJ, et al. Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations. J Thorac Oncol. Nov 2016;11(11):1962-1969. doi:10.1016/j.jtho.2016.06.029
8. Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. Jan 2018;19(1):e43-e55. doi:10.1016/S1470-2045(17)30689-7
9. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. Jul 2012; 77(1):134-9. doi:10.1016/j.lungcan.2012.03.002
10. Murtuza A, Bulbul A, Shen JP, et al. Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer. Cancer Res. Feb 15 2019;79(4):689-698. doi:10.1158/0008-5472.CAN-18-1281
11. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. Jan 11 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
12. Yang JCH, Kim SW, Kim DW, et al. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol. Feb 20 2020;38(6):538-547. doi:10.120 0/JCO.19.00457
13. Chamberlain M, Junck L, Brandsma D, et al. Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol. Apr 1 2017;19(4): 484-492. doi:10.1093/neuonc/now183
14. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. May 4 2010;74(18):1449-54. doi:10.1212/WNL.0b013e3181dc1a69
15. Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer. Feb 15 1998;82(4):733-9. doi:10.1002/(sici)1097-0142(199 80215)82:4<733::aid-cncr17>3.0.co;2-z
16. Pentsova EI, Shah RH, Tang J, et al. Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid. J Clin Oncol. Jul 10 2016;34(20):2404-15. doi:10.1200/JCO.2016.66.6487
17. Wang Y, Douville C, Cohen JD, et al. Detection of rare mutations, copy number alterations, and methylation in the same template DNA molecules. Proc Natl Acad Sci U S A. Apr 11 2023;120(15): e2220704120. doi:10.1073/pnas.2220704120
18. Nie Q.; Schilter KF.; Hernandez KA JJ, R.; Acevedo, A., Larson, A.; Domagala, BA.; Vo, SA.; Khurana, S.; Mitchell, K.; Ellis, D.; Muhammedov, B.; Wang, Y.; Douville, C.; Coe, B.; Bettegowda, C.; Reddi HV. Analytical Validation and Clinical Sensitivity of the Belay Summit™ assay for the detection of DNA variants in cerebrospinal fluid of primary and metastatic CNS cancer. Journal of Molecular Diagnostics. 2025;
19. Eck MJ, Yun CH. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta. Mar 2010;1804(3):559-66. doi:10.1016/j.bbapap.2009.12.010
20. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. Apr 15 2013;19(8):2240-7. doi:10.1158/1078-0432.CCR-12-2246
21. Ma C, Wei S, Song Y. T790M and acquired resistance of EGFR TKI: a literature review of clinical reports. J Thorac Dis. Mar 2011;3(1):10-8. doi:10.3978/j.issn.2072-1439.2010.12.02
22. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. Feb 12 2008;105(6):2070-5. doi:10.1073/pnas.0709662105
23. Shah R, Lester JF. Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations. Clin Lung Cancer. May 2020;21(3):e216-e228. doi:10.1016/j.cllc.2019.12.003
24. Levy BP, Rao P, Becker DJ, Becker K. Attacking a Moving Target: Understanding Resistance and Managing Progression in EGFR-Positive Lung Cancer Patients Treated With Tyrosine Kinase Inhibitors. Oncology (Williston Park). Jul 2016;30(7):601-12.
25. Tanaka K, Nosaki K, Otsubo K, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Oncotarget. Sep 15 2017;8(40):68123-68130. doi:10.18632/onc otarget.19243
26. Kobayashi Y, Fujino T, Nishino M, et al. EGFR T790M and C797S Mutations as Mechanisms of Acquired Resistance to Dacomitinib. J Thorac Oncol. May 2018;13(5):727-731. doi:10.1016/j.jtho.2 018.01.009
27. Janne PA, Planchard D, Kobayashi K, et al. CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. Mar 1 2024;42(7):808-820. doi:10.1200/JCO.23.02219
28. Wu YL, Ahn MJ, Garassino MC, et al. CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). J Clin Oncol. Sep 10 2018;36(26):2702-2709. doi:10.1200/JCO.2018.77.9363
29. De Mattos-Arruda L, Mayor R, Ng CKY, et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. Nov 10 2015;6:8839. doi:10.1038/ncomms9839
30. Mair R, Mouliere F. Cell-free DNA technologies for the analysis of brain cancer. Br J Cancer. Feb 2022;126(3):371-378. doi:10.1038/s41416-021-01594-5
31. Malhotra J, Muddasani R, Fricke J, et al. Clinical Utility of a Circulating Tumor Cell-Based Cerebrospinal Fluid Assay in the Diagnosis and Molecular Analysis of Leptomeningeal Disease in Patients With Advanced Non-Small Cell Lung Cancer. JCO Precis Oncol. Dec 2024;8:e2400373. doi:10.1200/PO-24-00373