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 (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 15, 2018

Published In

Volume / Issue

  • 24 / 6

Start / End Page

  • 1486 - 1499

PubMed ID

  • 29311117

Pubmed Central ID

  • PMC5856614

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-17-2312

Language

  • eng

Conference Location

  • United States