Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Carcinoma

Introduction Circulating Tumor Cells (CTC) have been studied in various solid tumors but clinical utility of CTC in Small Cell Lung Cancer (SCLC) remains to be demonstrated. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics. Patients and methods CTC-CPC is a monocentric prospective non-interventional study including treatment-naïve newly diagnosed SCLC. CD56+CTC were isolated from whole blood samples, at diagnosis and relapse after first-line treatment. Whole-exome-sequencing (WES) was performed on isolated CTC, matched PBMC (peripheral blood mononuclear cells) and tumor biopsies for genomic characterization, mutational signature classification and biological altered pathways identification. CTC Derived Xenografts were generated. Results Phenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. WES of CD56+CTC and matched tumor biopsy reveal genomic alteration frequently impaired in SCLC. At diagnosis CD56+CTC were characterized by a high mutation load, a distinct mutational profile and a unique genomic signature according BioInfoMiner web platform, compared to match tumors biopsies. In addition to classical pathways altered in SCLC, we found new biological processes specifically affected in CD56+CTC at diagnosis: sumoylation and transcriptional regulation by AP-2 and RUNX2. High numeration of CD56+CTC (>7/ml) at diagnosis was associated with ES-SCLC. Finally, comparing genomic features of diagnosis and relapse CD56+CTC, we identify altered oncogenic pathways (e.g. DLL3 or MAPK pathway) that might seed disease relapse. Conclusions We report a versatile method of CD56+CTC detection in SCLC. Numeration of CD56+CTC at diagnosis is correlated with disease extension. Isolated CD56+CTC conserve tumorigenic properties and show a distinct mutational profile. We report a minimal gene set as a unique signature of CD56+CTC and identify new affected biological pathways enriched in EpCAM-independent isolated CTC in SCLC. Highlights – Isolation of CD56+CTC using an immunofluorescence-based EpCAM-independent method at diagnosis is feasible in SCLC – CD56+CTC are characterized by a high mutation load and a unique genomic signature – Above classical pathways altered in SCLC, new biological processes specifically altered in CD56+CTC can be identified. – High numeration of CD56+CTC at diagnosis is associated with ES-SCLC. – Studying CD56+CTC at progression helps understand somatic evolution and elaborate strategies overcoming treatment resistance