title: Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer.
abstract: In most patients with small-cell lung cancer (SCLC)-a metastatic, aggressive disease-the condition is initially chemosensitive but then relapses with acquired chemoresistance. In a minority of patients, however, relapse occurs within 3 months of initial treatment; in these cases, disease is defined as chemorefractory. The molecular mechanisms that differentiate chemosensitive from chemorefractory disease are currently unknown. To identify genetic features that distinguish chemosensitive from chemorefractory disease, we examined copy-number aberrations (CNAs) in circulating tumor cells (CTCs) from pretreatment SCLC blood samples. After analysis of 88 CTCs isolated from 13 patients (training set), we generated a CNA-based classifier that we validated in 18 additional patients (testing set, 112 CTC samples) and in six SCLC patient-derived CTC explant tumors. The classifier correctly assigned 83.3% of the cases as chemorefractory or chemosensitive. Furthermore, a significant difference was observed in progression-free survival (PFS) (Kaplan-Meier P value = 0.0166) between patients designated as chemorefractory or chemosensitive by using the baseline CNA classifier. Notably, CTC CNA profiles obtained at relapse from five patients with initially chemosensitive disease did not switch to a chemorefractory CNA profile, which suggests that the genetic basis for initial chemoresistance differs from that underlying acquired chemoresistance.
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Carter
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Rothwell
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mesquita
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Smowton
authors.affiliation: Computational Biology Support Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Fabiola
authors.identifier: 0000-0001-9609-5638
authors.initials: F
authors.lastname: Fernandez-Gutierrez
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burt
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Antonello
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Morris
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Priest
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Mathew
authors.initials: M
authors.lastname: Carter
authors.affiliation: Computational Biology Support Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.|RNA Biology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Crispin
authors.initials: C
authors.lastname: Miller
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hughes
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.|Cancer Research UK Lung Cancer Centre of Excellence, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.|Cancer Research UK Lung Cancer Centre of Excellence, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Ged
authors.initials: G
authors.lastname: Brady
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D056915:DNA Copy Number Variations / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D011379:Prognosis; D017422:Sequence Analysis, DNA; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm