The Prognostic Value of Cell-Free DNA in Advanced Non-Small-Cell Lung Cancer


Background: Cell-free DNA (cfDNA) holds promise as a tumor marker of clinical importance. We aimed to investigate the prognostic value of baseline cfDNA in non small-cell lung cancer (NSCLC). Material and Methods: During a three-year period, patients with newly diagnosed, previously untreated advanced NSCLC were included in a consecutive, prospective marker-trial. Plasma was isolated from a pre-treatment peripheral blood sample and the level of total cfDNA was measured by an in-house assay qPCR-method. The treatment comprised carboplatin (AUC 5) intravenously day 1), and vinorelbine (30 mg/m2 intravenously day 1 and 60 mg/m2 perorally day 8) q3w for a maximum of six cycles. The primary end-point was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate (ORR). Results: 245 patients were included and received a minimum of 1 cycle of chemotherapy (median 4). The median OS was 8.9 months, the median PFS by intention to treat 5.4 months and the ORR was 25%. The patients were divided into four groups based on quartiles of cfDNA and subsequently dichotomized by the 75th percentile revealing a significantly worse prognosis for patients in the upper 75th percentile (median OS 4.9 months) compared to patients with lower levels (10.0 months) (HR 2.1, 95%CI 1.4 - 3.1, p < 0.0001). A multivariate analysis confirmed the independent prognostic value of cfDNA. A subgroup analysis of patients with high cfDNA and poor performance status (PS = 2) identified a group of patients with even worse prognosis (median OS 2.0 versus 9.1 months, HR 3.6, 95%CI 1.4 - 9.2, p < 0.0001). Similar and significant results were found when comparing level of cfDNA and PFS. Conclusions: High pre-treatment level of cfDNA seems to have a strong prognostic impact in patients with newly diagnosed advanced NSCLC. Combined with PS it identifies a patient group with minimal or no benefit of chemotherapy.

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Nygaard, A. , Spindler, K. , Pallisgaard, N. , Andersen, R. and Jakobsen, A. (2013) The Prognostic Value of Cell-Free DNA in Advanced Non-Small-Cell Lung Cancer. Journal of Cancer Therapy, 4, 1-7. doi: 10.4236/jct.2013.48A001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] S. S. Hecht, “Tobacco Smoke Carcinogens and Lung Cancer,” Journal of the National Cancer Institute, Vol. 91, No. 14, 1999, pp. 1194-1210. doi:10.1093/jnci/91.14.1194
[2] L. A. Gorenstein and J. R. Sonett, “The Surgical Management of Stage I and Stage II Lung Cancer,” Surgical Oncology Clinics of North America, Vol. 20, No. 4, 2011, pp. 701-720. doi:10.1016/j.soc.2011.07.009
[3] E. M. Tan, P. H. Schur, R. I. Carr and H. G. Kunkel, “Deoxybonucleic Acid (DNA) and Antibodies to DNA in the Serum of Patients with Systemic Lupus Erythematosus,” Journal of Clinical Investigation, Vol. 45, No. 11, 1966, pp. 1732-1740. doi:10.1172/JCI105479
[4] S. A. Leon, B. Shapiro, D. M. Sklaroff and M. J. Yaros, “Free DNA in the Serum of Cancer Patients and the Effect of Therapy,” Cancer Research, Vol. 37, No. 3, 1977, pp. 646-650.
[5] C. Alix-Panabieres and K. Pantel, “Circulating Tumor Cells: Liquid Biopsy of Cancer,” Clinical Chemistry, Vol. 59, No. 1, 2013, pp. 110-118. doi:10.1373/clinchem.2012.194258
[6] M. Stroun, P. Maurice, V. Vasioukhin, J. Lyautey, C. Lederrey, F. Lefort, et al., “The Origin and Mechanism of Circulating DNA,” Annals of the New York Academy of Sciences, Vol. 906, 2000, pp. 161-168. doi:10.1111/j.1749-6632.2000.tb06608.x
[7] F. Diehl, M. Li, D. Dressman, Y. He, D. Shen, S. Szabo, et al., “Detection and Quantification of Mutations in the Plasma of Patients with Colorectal Tumors,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 45, 2005, pp. 16368-16373. doi:10.1073/pnas.0507904102
[8] H. Schwarzenbach, D. S. Hoon and K. Pantel, “Cell-Free Nucleic Acids as Biomarkers in Cancer Patients,” Nature Reviews Cancer, Vol. 11, No. 6, 2011, pp. 426-437. doi:10.1038/nrc3066
[9] P. Therasse, S. G. Arbuck, E. A. Eisenhauer, J. Wanders, R. S. Kaplan, L. Rubinstein, et al., “New Guidelines to Evaluate the Response to Treatment in Solid Tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada,” Journal of the National Cancer Institute, Vol. 92, No. 3, 2000, pp. 205-216. doi:10.1093/jnci/92.3.205
[10] K. L. Spindler, N. Pallisgaard, I. Vogelius and A. Jakobsen, “Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan,” Clinical Cancer Research, Vol. 18, No. 4, 2012, pp. 1177-1185. doi:10.1158/1078-0432.CCR-11-0564
[11] S. Kumar, R. Guleria, V. Singh, A. C. Bharti, A. Mohan and B.-C. Das, “Plasma DNA Level in Predicting Therapeutic Efficacy in Advanced Nonsmall Cell Lung Cancer,” European Respiratory Journal, Vol. 36, No. 4, 2010, pp. 885-892. doi:10.1183/09031936.00187909
[12] G. Pelosi, E. Schianchi, P. Dell’orto, G. Veronesi, L. Spaggiari, F. Pasini, et al., “Detecting Cell-Free Circulating hTERT mRNA in the Plasma May Identify a Subset of Nonsmall Cell Lung Cancer Patients,” Virchows Arch, Vol. 448, No. 1, 2006, pp. 7-15. doi:10.1007/s00428-005-0087-z
[13] C. Camps, R. Sirera, R. M. Bremnes, V. Rodenas, A. Blasco, M. J. Safont, et al., “Quantification in the Serum of the Catalytic Fraction of Reverse Telomerase: A Useful Prognostic Factor in Advanced Non-Small Cell Lung Cancer,” Anticancer Research, Vol. 26, No. 6C, 2006, pp. 4905-4909.
[14] R. Sirera, R. M. Bremnes, A. Cabrera, E. Jantus-Lewintre, E. Sanmartin, A. Blasco, et al., “Circulating DNA Is a Useful Prognostic Factor in Patients with Advanced NonSmall Cell Lung Cancer,” Journal of Thoracic Oncology, Vol. 6, No. 2, 2011, pp. 286-290. doi:10.1097/JTO.0b013e31820189a5
[15] R. M. Van den Berg, H. Brokx, A. Vesin, J. K. Field, C. Brambilla, C. J. Meijer, et al., “Prognostic Value of hTERT mRNA Expression in Surgical Samples of Lung Cancer Patients: The European Early Lung Cancer Project,” International Journal of Oncology, Vol. 37, No. 2, 2010, pp. 455-461.
[16] A. K. Pathak, M. Bhutani, S. Kumar, A. Mohan and R. Guleria, “Circulating Cell-Free DNA in Plasma/Serum of Lung Cancer Patients as a Potential Screening and Prognostic Tool,” Clinical Chemistry, Vol. 52, No. 10, 2006, pp. 1833-1842.
[17] O. Gautschi, C. Bigosch, B. Huegli, M. Jermann, A. Marx, E. Chasse, et al., “Circulating Deoxyribonucleic Acid as a Prognostic Marker in Non-Small-Cell Lung Cancer Patients Undergoing Chemotherapy,” Journal of Clinical Oncology, Vol. 22, No. 20, 2004, pp. 4157-4164. doi:10.1200/JCO.2004.11.123
[18] M. A. van der Drift, B. E. Hol, C H. Klaassen, C. F. Prinsen, Y. A. van Aarssen, R. Donders, et al., “Circulating DNA Is a Non-Invasive Prognostic Factor for Survival in Non-Small Cell Lung Cancer,” Lung Cancer, Vol. 68, No. 2, 2010, pp. 283-287. doi:10.1016/j.lungcan.2009.06.021
[19] G. J. Fournie, J. P. Courtin, F. Laval, J. J. Chale, J. P. Pourrat, M. C. Pujazon, et al., “Plasma DNA as a Marker of Cancerous Cell Death. Investigations in Patients Suffering from Lung Cancer and in Nude Mice Bearing Human Tumours,” Cancer Letters, Vol. 91, No. 2, 1995, pp. 221-227. doi:10.1016/0304-3835(95)03742-F
[20] M. D. Brundage, D. Davies and W. J. Mackillop, “Prognostic Factors in Non-Small Cell Lung Cancer: A Decade of Progress,” Chest, Vol. 122, No. 3, 2002, pp. 1037-1057. doi:10.1378/chest.122.3.1037

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