Abstract
Purpose
Central nervous system (CNS) is the prevalent site for metastases in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-relapsed NSCLC patients. To understand the EGFR mutation status in paired cerebrospinal fluid (CSF) and plasma samples after EGFR-TKI treatment failure might be useful to guide the treatment of intra- and extracranial tumors in those patients.
Methods
Paired CSF and plasma samples were collected from seven NSCLC patients with CNS metastases after EGFR-TKI failure. EGFR mutations were tested by amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) methods. Gefitinib concentrations were evaluated by high-performance liquid chromatography–mass spectrometry (HPLC–MS/MS).
Results
EGFR mutations were detected in all seven CSF samples, including three of E19-Del, three of L858R and one of E19-Del&T790M by both methods. On the other hand, majority of the matched plasma samples (5/7) were negative for EGFR mutations by both methods. The other two plasma samples were positive for E19-Del&T790M by ddPCR, and one of them had undetectable T790M by ARMS. Gefitinib concentration in CSF was much lower than that in plasma (mean CSF/plasma ratio: 1.8 %).
Conclusions
After EGFR-TKI failure, majority of the NSCLC patients with CNS metastases remained positive detection of EGFR sensitive mutations in CSF, but much less detection in the matched plasma. Significantly low exposure of gefitinib in CSF might explain the intracranial protection of the EGFR sensitive mutation positive tumor cells.
This is a preview of subscription content, log in via an institution to check access.
References
Lee Y, Han JY, Kim HT, Yun T, Lee GK, Kim HY et al (2013) Impact of EGFR tyrosine kinase inhibitors versus chemotherapy on the development of leptomeningeal metastasis in never smokers with advanced adenocarcinoma of the lung. J Neurooncol 115:95–101
Langer CJ, Mehta MP (2005) Current management of brain metastases, with a focus on systemic options. J Clin Oncol 23:6207–6219
Lee YJ, Choi HJ, Kim SK, Chang J, Moon JW, Park IK et al (2010) Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer 116:1336–1343
Rhodes CH, Honsinger C, Sorenson GD (1994) Detection of tumor-derived DNA in cerebrospinal fluid. J Neuropathol Exp Neurol 53:364–368
Yang H, Cai L, Zhang Y, Tan H, Deng Q, Zhao M et al (2014) Sensitive detection of EGFR mutations in cerebrospinal fluid from lung adenocarcinoma patients with brain metastases. J Mol Diagn 16:558–563
Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT et al (2005) High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103:2344–2348
Ruppert AM, Beau-Faller M, Neuville A, Guerin E, Voegeli AC, Mennecier B et al (2009) EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up. Eur Respir J 33:436–440
Popat S, Hughes S, Papadopoulos P, Wilkins A, Moore S, Priest K et al (2007) Recurrent responses to non-small cell lung cancer brain metastases with erlotinib. Lung Cancer 56:135–137
Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D et al (2012) Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 4:162ra154
Zhu G, Ye X, Dong Z, Lu YC, Sun Y, Liu Y et al (2015) Highly sensitive droplet digital PCR method for detection of EGFR-activating mutations in plasma cell-free DNA from patients with advanced non-small cell lung cancer. J Mol Diagn 17:265–272
Zheng D, Ye X, Zhang MZ, Sun Y, Wang JY, Ni J et al (2016) Plasma EGFR T790 M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci Rep 6:20913
Jones HK, Stafford LE, Swaisland HC, Payne R (2002) A sensitive assay for ZD1839 (Iressa) in human plasma by liquid–liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in Phase I clinical trials. J Pharm Biomed Anal 29:221–228
Zhao J, Chen M, Zhong W, Zhang L, Li L, Xiao Y et al (2013) Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer 14:188–193
Camidge DR, Pao W, Sequis L (2014) V, Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 11:473–481
Sasaki S, Yoshioka Y, Ko R, Katsura Y, Namba Y, Shukuya T et al (2016) Diagnostic significance of cerebrospinal fluid EGFR mutation analysis for leptomeningeal metastasis in non-small-cell lung cancer patients harboring an active EGFR mutation following gefitinib therapy failure. Respir Investig 54(1):14–19
Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Nanjo S et al (2013) Rebiopsy of Non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790 M mutation-positive and mutation-negative populations. Cancer 119:4325–4332
Hata A, Katakami N, Yoshioka H, Kaji R, Masago K, Fujita S et al (2015) Spatiotemporal T790 M heterogeneity in individual patients with EGFR-mutant non-small-cell lung cancer after acquired resistance to EGFR-TKI. J Thorac Oncol 10(11):1553–1559
Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM et al (2006) Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 24:4517–4520
Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S et al (2009) Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol 4:1415–1419
Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R et al (2011) Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 3:90ra59
Acknowledgments
This work was supported by AstraZeneca. We acknowledge Changting Liu and Fuxiao Shen for sample management and Min Hu for manuscript reviewing.
Author contributions
JZ, XY and YS were responsible for the data collection and analysis and manuscript drafting. JZ, YX, MC and WZ were responsible for the provision of study material. ZY, GZ, YG and MW were responsible for the study design and administration. All authors have read and approved the final version.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
XY, YS, ZY, GZ and YG are employees of AstraZeneca during this study. YG holds stock in AstraZeneca. All other authors declare no conflicts of interest.
Additional information
Jing Zhao and Xin Ye contributed equally to the study.
Rights and permissions
About this article
Cite this article
Zhao, J., Ye, X., Xu, Y. et al. EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases. Cancer Chemother Pharmacol 78, 1305–1310 (2016). https://doi.org/10.1007/s00280-016-3155-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-016-3155-y