Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Osimertinib Quantitative and Gene Variation Analyses in Cerebrospinal Fluid and Plasma of a Non-small Cell Lung Cancer Patient with Leptomeningeal Metastases

Author(s): Yuanyuan Song, Peng Liu, Yu Huang, Yanfang Guan, Xiaohong Han* and Yuankai Shi*

Volume 19, Issue 8, 2019

Page: [666 - 673] Pages: 8

DOI: 10.2174/1568009618666181017114111

Price: $65

conference banner
Abstract

Background: Leptomeningeal metastases (LM) are much more frequent in patients of non-small lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) shows promising efficacy for LM.

Objective: The aim of this study was to analyze the concentration of osimertinib and gene variation of circulating tumor DNA (ctDNA) in human plasma and cerebrospinal fluid (CSF). Furthermore, we explored whether ctDNA in CSF might be used as a biomarker to predict and monitor therapeutic responses.

Methods: The dynamic paired CSF and blood samples were collected from the NSCLC patient with LM acquired EGFR-TKI resistance. A method based on ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) was developed and validated for detecting osimertinib in CSF and plasma samples. Gene variations of ctDNA were tested by next-generation sequencing with a panel of 1021 genes.

Results: The concentrations of osimertinib in CSF were significantly lower than that in plasma (penetration rate was 1.47%). Mutations included mTOR, EGFR, CHECK1, ABCC11, and TP53 were explored in ctDNA from plasma and CSF samples. The detected mutation rate of CSF samples was higher than that of plasma samples (50% vs. 25%). Our data further revealed that the variations allele frequency (VAF) and molecular tumor burden index (mTBI) of ctDNA derived from CSF exhibited the negative correlation with efficacy of treatment.

Conclusion: ctDNA from CSF might be a useful biomarker for monitoring the efficacy of treatment and an effective complement to nuclear magnetic resonance imaging (MRI) for LM.

Keywords: Leptomeningeal metastases, Non-small cell lung cancer, Osimertinib, UPLC-MS/MS, Next-generation sequencing, Cerebrospinal fluid, Plasma.

« Previous Next »
Graphical Abstract

[1]
Popper, H.H. Progression and metastasis of lung cancer. Cancer Metastasis Rev., 2016, 35(1), 75-91.
[2]
Yamanaka, R. Medical management of brain metastases from lung cancer. Oncol. Rep., 2009, 22(6), 1269-1276.
[3]
Li, Y.S.; Jiang, B.Y.; Yang, J.J.; Tu, H.Y.; Zhou, Q.; Guo, W.B.; Yan, H.H.; Wu, Y.L. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J. Thorac. Oncol., 2016, 11(11), 1962-1969.
[4]
Wu, Y.L.; Zhou, C.; Cheng, Y.; Lu, S.; Chen, G.Y.; Huang, C.; Huang, Y.S.; Yan, H.H.; Ren, S.; Liu, Y.; Yang, J.J. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: A phase II study (CTONG-0803). Ann. Oncol., 2013, 24(4), 993-999.
[5]
Kobayashi, S.; Boggon, T.J.; Dayaram, T.; Janne, P.A.; Kocher, O.; Meyerson, M.; Johnson, B.E.; Eck, M.J.; Tenen, D.G.; Halmos, B. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N. Engl. J. Med., 2005, 352(8), 786-792.
[6]
Cross, D.A.; Ashton, S.E.; Ghiorghiu, S.; Eberlein, C.; Nebhan, C.A.; Spitzler, P.J.; Orme, J.P.; Finlay, M.R.; Ward, R.A.; Mellor, M.J.; Hughes, G.; Rahi, A.; Jacobs, V.N.; Red Brewer, M.; Ichihara, E.; Sun, J.; Jin, H.; Ballard, P.; Al-Kadhimi, K.; Rowlinson, R.; Klinowska, T.; Richmond, G.H.; Cantarini, M.; Kim, D.W.; Ranson, M.R.; Pao, W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov., 2014, 4(9), 1046-1061.
[7]
Ballard, P.; Yates, J.W.; Yang, Z.; Kim, D.W.; Yang, J.C.; Cantarini, M.; Pickup, K.; Jordan, A.; Hickey, M.; Grist, M.; Box, M.; Johnstrom, P.; Varnas, K.; Malmquist, J.; Thress, K.S.; Janne, P.A.; Cross, D. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin. Cancer Res., 2016, 22(20), 5130-5140.
[8]
Cordova, C.; Chi, A.S.; Chachoua, A.; Kondziolka, D.; Silverman, J.S.; Shepherd, T.M.; Jain, R.; Snuderl, M. Osimertinib dose escalation induces regression of progressive EGFR T790M-mutant leptomeningeal lung adenocarcinoma. J. Thorac. Oncol., 2017, 12(11), e188-e190.
[9]
Nanjo, S.; Ebi, H.; Arai, S.; Takeuchi, S.; Yamada, T.; Mochizuki, S.; Okada, Y.; Nakada, M.; Murakami, T.; Yano, S. High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells. Oncotarget, 2016, 7(4), 3847-3856.
[10]
Mok, T.S.; Wu, Y.L.; Ahn, M.J.; Garassino, M.C.; Kim, H.R.; Ramalingam, S.S.; Shepherd, F.A.; He, Y.; Akamatsu, H.; Theelen, W.S.; Lee, C.K.; Sebastian, M.; Templeton, A.; Mann, H.; Marotti, M.; Ghiorghiu, S.; Papadimitrakopoulou, V.A.; Investigators, A. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med., 2017, 376(7), 629-640.
[11]
Planchard, D.; Brown, K.H.; Kim, D.W.; Kim, S.W.; Ohe, Y.; Felip, E.; Leese, P.; Cantarini, M.; Vishwanathan, K.; Janne, P.A.; Ranson, M.; Dickinson, P.A. Osimertinib western and asian clinical pharmacokinetics in patients and healthy volunteers: Implications for formulation, dose, and dosing frequency in pivotal clinical studies. Cancer Chemother. Pharmacol., 2016, 77(4), 767-776.
[12]
Rood, J.J.M.; van Bussel, M.T.J.; Schellens, J.H.M.; Beijnen, J.H.; Sparidans, R.W. Liquid chromatography-tandem mass spectrometric assay for the T790M mutant EGFR inhibitor osimertinib (AZD9291) in human plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2016, 1031, 80-85.
[13]
Xiong, S.; Deng, Z.; Sun, P.; Mu, Y.; Xue, M. Development and validation of a rapid and sensitive LC-MS/MS method for the pharmacokinetic study of osimertinib in rats. J. AOAC Int., 2017, 100(6), 1771-1775.
[14]
De Mattos-Arruda, L.; Weigelt, B.; Cortes, J.; Won, H.H.; Ng, C.K.; Nuciforo, P.; Bidard, F.C.; Aura, C.; Saura, C.; Peg, V.; Piscuoglio, S.; Oliveira, M.; Smolders, Y.; Patel, P.; Norton, L.; Tabernero, J.; Berger, M.F.; Seoane, J.; Reis-Filho, J.S. Capturing intra-tumour genetic heterogeneity by de novo mutation profiling of circulating cell-free tumour DNA: A proof-of- principle. Ann. Oncol., 2014, 25(9), 1729-1735.
[15]
De Mattos-Arruda, L.; Mayor, R.; Ng, C.K.; Weigelt, B.; Martínez-Ricarte, F.; Torrejon, D.; Oliveira, M.; Arias, A.; Raventos, C.; Tang, J.; Guerini-Rocco, E.; Martínez-Sáez, E.; Lois, S.; Marín, O.; de la Cruz, X.; Piscuoglio, S.; Towers, R.; Vivancos, A.; Peg, V. Ramon, y. Cajal. S.; Carles, J.; Rodon, J.; González-Cao, M.; Tabernero, J.; Felip, E.; Sahuquillo, J.; Berger, M.F.; Cortes, J.; Reis-Filho, J.S.; Seoane, J. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat. Commun., 2015, 6, 8839.
[16]
Pentsova, E.I.; Shah, R.H.; Tang, J.; Boire, A.; You, D.; Briggs, S.; Omuro, A.; Lin, X.; Fleisher, M.; Grommes, C.; Panageas, K.S.; Meng, F.; Selcuklu, S.D.; Ogilvie, S.; Distefano, N.; Shagabayeva, L.; Rosenblum, M.; DeAngelis, L.M.; Viale, A.; Mellinghoff, I.K.; Berger, M.F. Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J. Clin. Oncol., 2016, 34(20), 2404-2415.
[17]
Guidance for Industry, Bioanalytical Method Validation, U.S. Department of Health and Human Services, Food and Drug Administration,. 2013.https://www.fda.gov/downloads/drugs/guidances/ucm368107.pdf
[18]
Yang, H.; Yang, X.; Zhang, Y.; Liu, X.; Deng, Q.; Zhao, M.; Xu, X.; He, J. Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure. Target. Oncol., 2015, 10(1), 135-140.
[19]
Zhao, J.; Chen, M.; Zhong, W.; Zhang, L.; Li, L.; Xiao, Y.; Nie, L.; Hu, P.; Wang, M. Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin. Lung Cancer, 2013, 14(2), 188-193.
[20]
Grommes, C.; Oxnard, G.R.; Kris, M.G.; Miller, V.A.; Pao, W.; Holodny, A.I.; Clarke, J.L.; Lassman, A.B. ‘Pulsatile’ high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Onco., 2011, 13(12), 1364-1369.
[21]
Li, Y.S.; Jiang, B.Y.; Yang, J.J.; Zhang, X.C.; Zhang, Z.; Ye, J.Y.; Zhong, W.Z.; Tu, H.Y.; Chen, H.J.; Wang, Z.; Xu, C.R.; Wang, B.C.; Du, H.J.; Chuai, S.; Han-Zhang, H.; Su, J.; Zhou, Q.; Yang, X.N.; Guo, W.B.; Yan, H.H.; Liu, Y.H.; Yan, L.X.; Huang, B.; Zheng, M.M.; Wu, Y.L. Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small cell lung cancer: A new medium of liquid biopsy. Ann. Oncol., 2018, 29(4), 945-952.
[22]
Lin, Y.; Wang, X.; Jin, H. EGFR-TKI resistance in NSCLC patients: mechanisms and strategies. Am. J. Cancer Res., 2014, 4(5), 411-435.
[23]
Turke, A.B.; Zejnullahu, K.; Wu, Y.L.; Song, Y.; Dias-Santagata, D.; Lifshits, E.; Toschi, L.; Rogers, A.; Mok, T.; Sequist, L.; Lindeman, N.I.; Murphy, C.; Akhavanfard, S.; Yeap, B.Y.; Xiao, Y.; Capelletti, M.; Iafrate, A.J.; Lee, C.; Christensen, J.G.; Engelman, J.A.; Jänne, P.A. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell, 2010, 17(1), 77-88.
[24]
Bean, J.; Brennan, C.; Shih, J.Y.; Riely, G.; Viale, A.; Wang, L.; Chitale, D.; Motoi, N.; Szoke, J.; Broderick, S.; Balak, M.; Chang, W.C.; Yu, C.J.; Gazdar, A.; Pass, H.; Rusch, V.; Gerald, W.; Huang, S.F.; Yang, P.C.; Miller, V.; Ladanyi, M.; Yang, C.H.; Pao, W. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumours with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA, 2007, 104(52), 20932-20937.
[25]
Wullschleger, S.; Loewith, R.; Hall, M.N. TOR signaling in growth and metabolism. Cell, 2006, 124(3), 471-484.
[26]
Karachaliou, N.; Codony-Servat, J.; Teixidó, C.; Pilotto, S.; Drozdowskyj, A.; Codony-Servat, C.; Giménez-Capitán, A.; Molina-Vila, M.A.; Bertrán-Alamillo, J. Gervais. R.; Massuti, B.; Morán, T.; Majem, M.; Felip, E.; Carcereny, E.; García-Campelo, R.; Viteri, S.; González-Cao, M.; Morales-Espinosa, D.; Verlicchi, A.; Crisetti, E.; Chaib, I.; Santarpia, M.; Luis Ramírez, J.; Bosch-Barrera, J.; Felipe Cardona, A.; de, Marinis. F.; López-Vivanco, G.; Miguel Sánchez, J.; Vergnenegre, A.; Sánchez Hernández, J.J.; Sperduti, I.; Bria, E.; Rosell, R. BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer. Sci. Rep., 2015, 5, 17499.
[27]
Fei, S.J.; Zhang, X.C.; Dong, S.; Cheng, H.; Zhang, Y.F.; Huang, L.; Zhou, H.Y.; Xie, Z.; Chen, Z.H.; Wu, Y.L. Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells. PLoS One, 2013, 8(7)e69104
[28]
Uemura, T.; Oguri, T.; Ozasa, H.; Takakuwa, O.; Miyazaki, M.; Maeno, K.; Sato, S.; Ueda, R. ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci., 2010, 101(11), 2404-2410.
[29]
Oguri, T.; Bessho, Y.; Achiwa, H.; Ozasa, H.; Maeno, K.; Maeda, H.; Sato, S.; Ueda, R. MRP8/ABCC11 directly confers resistance to 5-fluorouracil. Mol. Cancer Ther., 2007, 6(1), 122-127.

Rights & Permissions Print Cite
Article Metrics
128
9
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy