• Magbanua Mark Jesus M MJM Division of Hematology/Oncology, University of California at San Francisco, San Francisco, California. mark.magbanua@ucsf.edu john.park@ucsf.edu, Hope S Rugo, Denise M Wolf, Louai Hauranieh, Ritu Roy, Praveen Pendyala, Eduardo V Sosa, Janet H Scott, Jin Sun Lee, Brandelyn Pitcher, Terry Hyslop, William T Barry, Steven J Isakoff, Maura Dickler, Laura Van't Veer, and John W Park.
• Division of Hematology/Oncology, University of California at San Francisco, San Francisco, California. mark.magbanua@ucsf.edu john.park@ucsf.edu.
• Clin Cancer Res. 2018 Mar 15; 24 (6): 1486-1499.

AbstractPurpose: 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.©2018 American Association for Cancer Research.

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