Utility of circulating tumour cells in drug development for lung cancer


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Caroline Dive
Paterson Institute for Cancer Research, Manchester, UK

Abstract

CTC analysis should be particularly useful in cancer types such as lung cancer where obtaining tumour biopsies poses significant challenge, particularly pre and post therapy. CTCs are identified based on EpCam and cytokeratin expression and absence of CD45 (a white blood cell (wbc) marker) using CellSearch technology (Veridex).

In chemo-naive Small Cell Lung Cancer (SCLC) patients (n=50), CTCs were detected in 86% patients (median 28, range 0-44896). CTC number (#) increased with disease stage and was highest in patients with liver metastases. The median survival for patients with CTC# >300 was 134 days and 443 days where CTC# was <2.  Immunofluorescent detection of CD56 (a neuro-endocrine marker) in SCLC CTCs was heterogeneous but consistent with expression in primary tumours. CTC# was pharmacodynamic, decreasing after one cycle of etoposide/platinum chemotherapy. Bcl-2, an anti-apoptotic drug target, is amplified in ~40% SCLC patients and was detectable in SCLC CTCs using fluorescence in situ-hybridisation; potentially, Bcl-2 amplification will predict sensitivity to Bcl-2 targeted drugs. CTC# and % apoptotic CTCs (analysed by nuclear morphology) are now being applied as pharmacodynamic biomarkers in early clinical trials of pro-apoptotic drugs.

In Non-Small Cell Lung Cancer (NSCLC) patients (n=87), CTCs were detected in 30% patients with advanced stage disease and a CTC# of >5 in 7.5ml blood predicts for a worse progression free and overall survival. Dynamic changes in CTC# were observed after standard chemotherapy suggesting that CTC# may be useful in early prediction of response to investigational drugs. Immunohistochemistry has been optimised to characterise NSCLC CTCs using ISET technology that isolates CTCs by size and morphology. Thyroid transcription factor 1 (TTF1, a routinely used diagnostic marker for NSCLC) expression is used to confirm the identity of NSCLC CTCs.

Overall, our data suggest that CTC analysis is a powerful addition to the biomarker portfolio for drug development in lung cancer.