Top

Clinical and Translational Oncology

Published in:

01-03-2017 | Research Article

Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs

Authors: S. Chen, J. Zhao, L. Cui, Y. Liu

Published in: Clinical and Translational Oncology | Issue 3/2017

Abstract

Purpose

Changes in EGFR profiles of non small cell lung cancer (NSCLC) patients correlates to clinical outcome. Extracting quality tumor tissue remains a challenge for molecular profiling. Our study aims to ascertain the clinical relevance of urinary cell free DNA as an alternative tumor material source.

Methods

150 patients with activating EGFR mutation and received EGFR-TKIs were recruited to participate in the serial monitoring study. Matched primary tumor samples were taken together with blood and urine specimens before the initiation of TKIs. The EGFR mutation testing was performed and quantified using ddPCR. For serial time point measurements, urine and blood samples were extracted at 1-month intervals for duration of 9 months.

Results

Urinary ctDNA yielded a close agreement of 88 % on EGFR mutation status when compared to primary tissue at baseline. Almost all samples detected via urine specimens were uncovered in plasma samples. Analysis of urinary cell free DNA at different time points showed a strong correlation to treatment efficacy. Interestingly, a secondary EGFR mutation T790M was detected for 53 % of the patients during monitoring. The results were corroborated with the plasma ctDNA analysis. The T790M+ group had a reduced median survival when compared to the wildtype group.

Conclusion

Urinary cell free DNA may be a potential alternative to conventional primary tissue based EGFR mutation testing. Our findings showed that the assay sensitivity was comparable to results from blood plasma. Urinary samples being noninvasive and readily available have clinical utility for monitoring of EGFR TKI treatment.

Available only for authorised users

Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. doi:10.1126/science.1099314.CrossRefPubMed

Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42. doi:10.1016/S1470-2045(11)70184-X.CrossRefPubMed

Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81. doi:10.1038/nrc2088.CrossRefPubMed

Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Am Assoc Cancer Res. 2013;19(8):2240–7.

Chouaid C, Dujon C, Do P, Monnet I, Madroszyk A, Le Caer H, et al. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01). Lung Cancer. 2014;86(2):170–3. doi:10.1016/j.lungcan.2014.08.016.CrossRefPubMed

Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–84. doi:10.1038/nrclinonc.2013.110.CrossRefPubMed

Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61(1):112–23.CrossRefPubMed

Douillard J-Y, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol. 2014;9(9):1345–53. doi:10.1097/JTO.0000000000000263.CrossRefPubMedPubMedCentral

Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O’Connell A, Messineo MM, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):1698–705.CrossRefPubMedPubMedCentral

10.

Bai H, Mao L, Wang HS, Zhao J, Yang L, An TT, et al. Epidermal growth factor receptor mutations in plasma dna samples predict tumor response in chinese patients with stages IIIB to IV non-small-cell lung cancer. J Clin Oncol. 2009;27(16):2653–9.CrossRefPubMed

11.

Kimura H, Suminoe M, Kasahara K, Sone T, Araya T, Tamori S, et al. Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA). Br J Cancer. 2007;97(6):778–84. doi:10.1038/sj.bjc.6603949.CrossRefPubMedPubMedCentral

12.

Richardson AL, Iglehart JD. BEAMing up personalized medicine: mutation detection in blood. Clin Cancer Res. 2012;18(12):3209–11. doi:10.1158/1078-0432.CCR-12-0871.CrossRefPubMedPubMedCentral

13.

Fischbach FT, Dunning MB. A manual of laboratory and diagnostic tests. Philadelphia: Lippincott Williams & Wilkins; 2009.

14.

Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology. 1983;148(3):839–43. doi:10.1148/radiology.148.3.6878708.CrossRefPubMed

15.

Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):S24–31. doi:10.1038/onc.2009.198.CrossRefPubMedPubMedCentral

16.

Jekunen AP. Role of rebiopsy in relapsed non-small cell lung cancer for directing oncology treatments. J Oncol. 2015;2015:11. doi:10.1155/2015/809835.CrossRef

17.

Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–990. http://www.nature.com/nm/journal/v14/n9/suppinfo/nm.1789_S1.html.

18.

Szpechcinski A, Chorostowska-Wynimko J, Struniawski R, Kupis W, Rudzinski P, Langfort R, et al. Cell-free DNA levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease. Br J Cancer. 2015;113(3):476–83. doi:10.1038/bjc.2015.225.CrossRefPubMedPubMedCentral

19.

Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50.PubMed

20.

Casadio V, Calistri D, Salvi S, Gunelli R, Carretta E, Amadori D, et al. Urine cell-free DNA integrity as a marker for early prostate cancer diagnosis: a pilot study. BioMed Res Int. 2013;2013:5. doi:10.1155/2013/270457.CrossRef

21.

Utting M, Werner W, Dahse R, Schubert J, Junker K. Microsatellite analysis of free tumor DNA in urine, serum, and plasma of patients. Am Assoc Cancer Res. 2002;8(1):35–40.

22.

Su Y-H, Wang M, Brenner DE, Norton PA, Block TM. Detection of mutated K-ras DNA in urine, plasma, and serum of patients with colorectal carcinoma or adenomatous polyps. Ann N Y Acad Sci. 2008;1137(1):197–206. doi:10.1196/annals.1448.027.CrossRefPubMedPubMedCentral

23.

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. doi:10.1056/NEJMoa040938.CrossRefPubMed

24.

Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73. doi:10.1371/journal.pmed.0020073.CrossRefPubMedPubMedCentral

25.

Liao B-C, Lin C-C. Yang JC-H. Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015;27(2):94–101. doi:10.1097/cco.0000000000000164.CrossRefPubMed

26.

Zheng D, Ye X, Zhang MZ, Sun Y, Wang JY, Ni J et al. Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci Rep. 2016;6:20913. doi:10.1038/srep20913. http://www.nature.com/articles/srep20913-supplementary-information.

27.

Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3(90):90ra59. doi:10.1126/scitranslmed.3002356.CrossRefPubMedPubMedCentral

28.

Lee Y, Lee GK, Lee Y-S, Zhang W, Hwang J-A, Nam B-H, et al. Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations. Cancer. 2014;120(14):2090–8. doi:10.1002/cncr.28711.CrossRefPubMed

29.

Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90.CrossRefPubMed

30.

Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786–92. doi:10.1056/NEJMoa044238.CrossRefPubMed

31.

Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366–77. doi:10.1056/NEJMoa0800668.CrossRefPubMedPubMedCentral

Title: Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs
Authors: S. Chen
J. Zhao
L. Cui
Y. Liu
Publication date: 01-03-2017
Publisher: Springer International Publishing
Published in: Clinical and Translational Oncology / Issue 3/2017
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-016-1534-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2017

Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery

Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?

New clinical trials regulation in Spain: analysis of royal decree 1090/2015

Clinical behavior of solitary fibrous tumor: a retrospective review of 30 patients

Intermittent versus continuous androgen deprivation therapy to biochemical recurrence after external beam radiotherapy: a phase 3 GICOR study

European edition of the NCCN clinical practice guidelines: relevance of the translation and adaptation into Spanish

Keynote webinar | Spotlight on antibody–drug conjugates in cancer