title: Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy.
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.
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Hou
authors.forename: Alastair
authors.initials: A
authors.lastname: Greystoke
authors.forename: Lee
authors.initials: L
authors.lastname: Lancashire
authors.forename: Jeff
authors.initials: J
authors.lastname: Cummings
authors.forename: Tim
authors.initials: T
authors.lastname: Ward
authors.forename: Ruth
authors.initials: R
authors.lastname: Board
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
authors.forename: Sarah
authors.initials: S
authors.lastname: Hughes
authors.forename: Matthew
authors.initials: M
authors.lastname: Krebs
authors.forename: Andrew
authors.initials: A
authors.lastname: Hughes
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Blackhall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000097:blood / Q000276:immunology*; D002986:Clinical Trials as Topic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis; D012698:Serologic Tests; D055752:Small Cell Lung Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor