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


Authors: Magbanua, M. J. M.; Rugo, H. S.; Wolf, D. M.; Hauranieh, L.; Roy, R.; Pendyala, P.; Sosa, E. V.; Scott, J. H.; Lee, J. S.; Pitcher, B.; Hyslop, T.; Barry, W. T.; Isakoff, S. J.; Dickler, M.; van't Veer, L.; Park, J. W.
Article Title: 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)
Abstract: 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, 25 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. 2018 AACR.
Keywords: gene-expression; prostate-cancer; growth; phase-iii trial; messenger-rna; stem-cell; number; cerebrospinal-fluid; factor receptor 2; mesenchymal transition markers
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 6
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-03-15
Start Page: 1486
End Page: 1499
Language: English
ACCESSION: WOS:000427627400025
DOI: 10.1158/1078-0432.ccr-17-2312
PROVIDER: wos
PMCID: PMC5856614
PUBMED: 29311117
Notes: Article -- Source: Wos
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MSK Authors
  1. Maura N Dickler
    237 Dickler