What can we learn from circulating tumour cells in lung cancer – biomarkers, mouse models, drug resistance and heterogeneity


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Caroline Dive1,
1Cancer Research UK Manchester Institute, Manchester, UK

Abstract

Two paradigms exist for circulating tumour cells (CTCs) in lung cancer. In small cell lung cancer (SCLC), CTCs detected by the EpCAM dependent CellSearch platform are prevalent, CTC number is prognostic ('cut off' >50 CTCs in 7.5ml blood), dynamic range (up to 1000s CTCs in 7.5ml blood) is suitable for use as a pharmacodynamic biomarker and CTC-based predictive biomarker assays are feasible. In non small cell lung cancer (NSCLC), CTCs are more difficult to find, CellSearch detected CTCs are prognostic ('cut off' >5 CTCs in 7.5ml blood) but their clinical utility is less clear. Yet marker independent NSCLC CTC enrichment based on size identifies considerably more CTCs and reveals heterogeneity in epithelial-mesenchymal transition (EMT) phenotypes. What CTCs offer is full genome and transcriptome analysis at the single CTC level, cellular protein based biomarkers and the ability to build CTC derived mouse models (that we term CTC derived patient explants [CDX]). We developed 11 CDX where CTCs were enriched at baseline from chemosensitive or chemorefractory SCLC patients and for some patients a second model was derived at patient progression. These are being exploited to search for new drug targets, to test novel drugs and explore drug resistance mechanisms. Notably, we derived a CDX from a NSCLC patient whose CellSearch epithelial CTC count was zero and ~80% CTCs captured on filters were mesenchymal. Current SCLC CTC analysis is focusing on whole genome and exome sequencing of matched longitudinal analysis of baseline and relapse CTC samples to identify genetic changes associated with therapy resistance. Studies underway are aimed at providing mRNA and genomic DNA analysis from the same CTC sample to establish direct linkage between mutational changes and emergent mRNA profiles and pathways to gain insights into mechanisms underpinning treatment responses.

Full authorship

 

Caroline Dive1, Ged Brady1, Christopher Morrow1, Crispin Miller1 & Fiona Blackhall2,3

1Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, UK

2Institute of Cancer Sciences, University of Manchester, UK

3Christie Hospital Foundation NHS Trust, Manchester, UK

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