Abstract 3155: Investigating chemoresistance in small cell lung cancer through the molecular profiling of single circulating tumour cells

Abstract

Abstract Background Chemoresistance, both intrinsic and acquired, represents one of the greatest challenges in the management of Small Cell Lung Cancer (SCLC), contributing to the very poor survival seen in this disease. The investigation of SCLC, and particularly serially monitoring the development of changes associated with resistance, is hampered by the limited availability of tumour tissue for research. Circulating tumour cells (CTCs) in contrast, are abundant in this disease and represent a potential minimally invasive ‘liquid biopsy’ to study the molecular landscape of SCLC. Methods To investigate tumour genetics in SCLC CTCs were isolated from chemorefractory patients and chemoresponsive patients’ blood samples using the DEPArray©. Blood samples were collected prior to chemotherapy and again at progression with relapsed disease. Following single-cell whole genome amplification low coverage whole genome sequencing and whole exome sequencing (WES) of CTCs were used to investigate mutations and to generate genome-wide patterns of copy number alterations (CNA). Results Hallmark SCLC molecular abnormalities such as TP53 mutations and copy number loss in tumour suppressor genes such as RB1 (previously identified in bulk tumour profiling), were noted in the isolated SCLC CTCs. Distinct CNA profiles were found in the CTCs isolated from patients with chemorefractory disease compared to those isolated from patients with chemoresponsive disease. A potential signature based on differential copy number changes in 2183 loci between the two groups of patients’ CTCs was identified. When tested in an independent set of CTC-derived explants this signature achieved 100% accuracy in classifying patients with chemoresponsive disease. There were no profound differences in CNA pattern in the CTCs isolated from initially chemoresponsive patients when they had relapsed post chemotherapy when compared to the baseline samples. However, changes in the proportion of C>A transversions were identified by WES between baseline and relapse CTCs. Conclusions Our study highlights the utility of molecular profiling CTCs in the research of SCLC. The data presented confirm CTCs represent a novel medium for the investigation of chemoresistance. Citation Format: Louise R. Carter, Dominic G. Rothwell, HuiSun Leong, Yaoyong Li, Deborah J. Burt, Jenny Antonello, Cassandra Hodgkinson, Karen Morris, Lynsey Franklin, Crispin J. Miller, Fiona Blackhall, Caroline Dive, Ged Brady. Investigating chemoresistance in small cell lung cancer through the molecular profiling of single circulating tumour cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3155.