Circulating tumor cells as potential biomarkers in bladder cancer

Ajjai Alva*, Terence Friedlander, Melanie Clark, Tamara Huebner, Stephanie Daignault, Maha Hussain, Cheryl Lee, Khaled Hafez, Brent Hollenbeck, Alon Weizer, Gayatri Premasekharan, Tony Tran, Christine Fu, Cristian Ionescu-Zanetti, Michael Schwartz, Andrea Fan, Pamela Paris

*Corresponding author for this work

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Purpose We explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing. Materials and Methods A total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFlux™ System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing. Results Median circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low - fewer than 10, medium - 11 to 30 and high - greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch® showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity. Conclusions This study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells.

Original languageEnglish (US)
Pages (from-to)790-798
Number of pages9
JournalJournal of Urology
Volume194
Issue number3
DOIs
StatePublished - Sep 1 2015

Keywords

  • circulating
  • genomics
  • molecular
  • neoadjuvant therapy
  • neoplastic cells
  • pathology
  • urinary bladder neoplasms

ASJC Scopus subject areas

  • Urology

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    Alva, A., Friedlander, T., Clark, M., Huebner, T., Daignault, S., Hussain, M., Lee, C., Hafez, K., Hollenbeck, B., Weizer, A., Premasekharan, G., Tran, T., Fu, C., Ionescu-Zanetti, C., Schwartz, M., Fan, A., & Paris, P. (2015). Circulating tumor cells as potential biomarkers in bladder cancer. Journal of Urology, 194(3), 790-798. https://doi.org/10.1016/j.juro.2015.02.2951