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Nat Med. 2017 Jan;23(1):114-119. doi: 10.1038/nm.4239. Epub 2016 Nov 21.

Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer.

Author information

1
Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
2
Computational Biology Support Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
3
Faculty of Life Sciences, University of Manchester, Manchester, UK.
4
RNA Biology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
5
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK.
6
Institute of Cancer Sciences, University of Manchester, Manchester, UK.
7
Cancer Research UK Lung Cancer Centre of Excellence, CRUK Manchester Institute, University of Manchester, Manchester, UK.

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.

Comment in

PMID:
27869802
DOI:
10.1038/nm.4239
[Indexed for MEDLINE]

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