Molecular analysis of circulating tumour cells identifies distinct profiles in treatment naïve chemosensitive and chemofractory small cell lung cancer patients

Ged Brady1

1Cancer Research Uk Manchester Institute, Manchester, UK

Abstract

Background

Small cell lung cancer (SCLC) is an aggressive, highly metastatic, neuroendocrine tumour with dismal prognosis with limited therapy options beyond platinum-based chemotherapy. Most SCLC patients respond to chemotherapy but relapse within months and ~20% are initially chemorefractory. Serial biopsy in SCLC is challenging whereas the molecular analysis of SCLC circulating tumour cells (CTCs) offers a minimally invasive opportunity to study drug resistance mechanisms, evaluate CTC heterogeneity and reveal new drug targets1.

Approach

To monitor tumour genetics over time, we applied single cell whole genome amplification and next generation sequencing (NGS) to CTCs isolated by DEPArray© from SCLC patients prior to chemotherapy and, for those who responded to treatment, CTCs were also examined at relapse.  Low coverage whole genome sequencing (WGS) of CTCs was used to investigate genome wide patterns of copy number alterations (CNA) and focussed NGS used to identify key mutational changes.

Results

Characteristic specific TP53 mutations and distinct CNA patterns were identified in all patients examined with inter-tumour heterogeneity enabling accurate unsupervised clustering of CTCs from each patient. Intra-tumour heterogeneity determined through a comparison of CTCs from each patient varied between patients and initial data indicates this may be linked with disease outcome.  A CTC based CNA classifier has been developed and is currently undergoing evaluation as predictive biomarker for response to platinum-based chemotherapy.  Further work is aimed at refining the CNA signature and extending these observations to a larger patient cohort and the examination of relapse samples.

Conclusion

These data highlight the utility of CTC to explore drug resistance, monitor tumour evolution and stratify patients with differential responses to chemotherapy for entry to future clinical trials of targeted treatments.

References
1. Hodgkinson, C.L., et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med 20, 897-903 (2014).