Evaluation of Circulating Tumor Cells and Serological Cell Death Biomarkers in Small Cell Lung Cancer Patients Undergoing Chemotherapy

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2009 Jul 25

PMID 19628770

Citations 115

Authors

Jian-Mei Hou

Alastair Greystoke

Lee Lancashire

Jeff Cummings

Tim Ward

Ruth Board

Eitan Amir

Sarah Hughes

Matthew Krebs

Andrew Hughes

Malcolm Ranson

Paul Lorigan

Caroline Dive

Fiona H Blackhall

Affiliations

Soon will be listed here.

Abstract

Serological cell death biomarkers and circulating tumor cells (CTCs) have potential uses as tools for pharmacodynamic blood-based assays and their subsequent application to early clinical trials. In this study, we evaluated both the expression and clinical significance of CTCs and serological cell death biomarkers in patients with small cell lung cancer. Blood samples from 88 patients were assayed using enzyme-linked immunosorbent assays for various cytokeratin 18 products (eg, M65, cell death, M30, and apoptosis) as well as nucleosomal DNA. CTCs (per 7.5 ml of blood) were quantified using Veridex CellSearch technology. Before therapeutic treatment, cell death biomarkers were elevated in patients compared with controls. CTCs were detected in 86% of patients; additionally, CD56 was detectable in CTCs, confirming their neoplastic origin. M30 levels correlated with the percentage of apoptotic CTCs. M30, M65, lactate dehydrogenase, and CTC number were prognostic for patient survival as determined by univariate analysis. Using multivariate analysis, both lactate dehydrogenase and M65 levels remained significant. CTC number fell following chemotherapy, whereas levels of serological cell death biomarkers peaked at 48 hours and fell by day 22, mirroring the tumor response. A 48-hour rise in nucleosomal DNA and M30 levels was associated with early response and severe toxicity, respectively. Our results provide a rationale to include the use of serological biomarkers and CTCs in early clinical trials of new agents for small cell lung cancer.

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References

Bonner J, Sloan J, Rowland Jr K, Klee G, Kugler J, Mailliard J . Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer. Clin Cancer Res. 2000; 6(2):597-601. View

Brambilla E, Moro D, Gazzeri S, Brichon P, Nagy-Mignotte H, Morel F . Cytotoxic chemotherapy induces cell differentiation in small-cell lung carcinoma. J Clin Oncol. 1991; 9(1):50-61. DOI: 10.1200/JCO.1991.9.1.50. View

Murray N, Turrisi 3rd A . A review of first-line treatment for small-cell lung cancer. J Thorac Oncol. 2007; 1(3):270-8. DOI: 10.1016/s1556-0864(15)31579-3. View

Blackhall F, Shepherd F . Small cell lung cancer and targeted therapies. Curr Opin Oncol. 2007; 19(2):103-8. DOI: 10.1097/CCO.0b013e328011bec3. View

Wu C, Hao H, Li L, Zhou X, Guo Z, Zhang L . Preliminary investigation of the clinical significance of detecting circulating tumor cells enriched from lung cancer patients. J Thorac Oncol. 2008; 4(1):30-6. DOI: 10.1097/JTO.0b013e3181914125. View

Ueno T, Toi M, Biven K, Bando H, Ogawa T, Linder S . Measurement of an apoptotic product in the sera of breast cancer patients. Eur J Cancer. 2003; 39(6):769-74. DOI: 10.1016/s0959-8049(02)00865-1. View

Roth G, Krenn C, Brunner M, Moser B, Ploder M, Spittler A . Elevated serum levels of epithelial cell apoptosis-specific cytokeratin 18 neoepitope m30 in critically ill patients. Shock. 2004; 22(3):218-20. DOI: 10.1097/01.shk.0000136098.49672.0e. View

McShane L, Altman D, Sauerbrei W, Taube S, Gion M, Clark G . REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer. 2005; 41(12):1690-6. DOI: 10.1016/j.ejca.2005.03.032. View

Ulukaya E, Yilmaztepe A, Akgoz S, Linder S, Karadag M . The levels of caspase-cleaved cytokeratin 18 are elevated in serum from patients with lung cancer and helpful to predict the survival. Lung Cancer. 2007; 56(3):399-404. DOI: 10.1016/j.lungcan.2007.01.015. View

10.

de Haas E, di Pietro A, Simpson K, Meijer C, Suurmeijer A, Lancashire L . Clinical evaluation of M30 and M65 ELISA cell death assays as circulating biomarkers in a drug-sensitive tumor, testicular cancer. Neoplasia. 2008; 10(10):1041-8. PMC: 2546590. DOI: 10.1593/neo.08620. View

11.

Cohen S, Punt C, Iannotti N, Saidman B, Sabbath K, Gabrail N . Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(19):3213-21. DOI: 10.1200/JCO.2007.15.8923. View

12.

Olofsson M, Ueno T, Pan Y, Xu R, Cai F, van der Kuip H . Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Clin Cancer Res. 2007; 13(11):3198-206. DOI: 10.1158/1078-0432.CCR-07-0009. View

13.

Jorgensen L, Osterlind K, Genolla J, Gomm S, Hernandez J, Johnson P . Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres. Br J Cancer. 1996; 74(3):463-7. PMC: 2074633. DOI: 10.1038/bjc.1996.383. View

14.

Holdenrieder S, Stieber P . Apoptotic markers in cancer. Clin Biochem. 2004; 37(7):605-17. DOI: 10.1016/j.clinbiochem.2004.05.003. View

15.

Holdenrieder S, Stieber P, Bodenmuller H, Fertig G, Furst H, Schmeller N . Nucleosomes in serum as a marker for cell death. Clin Chem Lab Med. 2001; 39(7):596-605. DOI: 10.1515/CCLM.2001.095. View

16.

Taylor K, Micha D, Ranson M, Dive C . Recent advances in targeting regulators of apoptosis in cancer cells for therapeutic gain. Expert Opin Investig Drugs. 2006; 15(6):669-90. DOI: 10.1517/13543784.15.6.669. View

17.

Bremnes R, Sundstrom S, Aasebo U, Kaasa S, Hatlevoll R, Aamdal S . The value of prognostic factors in small cell lung cancer: results from a randomised multicenter study with minimum 5 year follow-up. Lung Cancer. 2003; 39(3):303-13. DOI: 10.1016/s0169-5002(02)00508-1. View

18.

de Bono J, Scher H, Montgomery R, Parker C, Miller M, Tissing H . Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008; 14(19):6302-9. DOI: 10.1158/1078-0432.CCR-08-0872. View

19.

Rupa J, de Bruine A, Gerbers A, Leers M, Nap M, Kessels A . Simultaneous detection of apoptosis and proliferation in colorectal carcinoma by multiparameter flow cytometry allows separation of high and low-turnover tumors with distinct clinical outcome. Cancer. 2003; 97(10):2404-11. DOI: 10.1002/cncr.11366. View

20.

Board R, Williams V, Knight L, Shaw J, Greystoke A, Ranson M . Isolation and extraction of circulating tumor DNA from patients with small cell lung cancer. Ann N Y Acad Sci. 2008; 1137:98-107. DOI: 10.1196/annals.1448.020. View