Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance).


Journal Article

Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2-5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1-ERBB2-, 48% ESR1+ERBB2-, and 27% ERBB2+ Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486-99. ©2018 AACR.

Full Text

Duke Authors

Cited Authors

  • Magbanua, MJM; Rugo, HS; Wolf, DM; Hauranieh, L; Roy, R; Pendyala, P; Sosa, EV; Scott, JH; Lee, JS; Pitcher, B; Hyslop, T; Barry, WT; Isakoff, SJ; Dickler, M; Van't Veer, L; Park, JW

Published Date

  • March 2018

Published In

Volume / Issue

  • 24 / 6

Start / End Page

  • 1486 - 1499

PubMed ID

  • 29311117

Pubmed Central ID

  • 29311117

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.ccr-17-2312


  • eng