Gene expression profiles in circulating tumor cells to predict prognosis in metastatic breast cancer patients

Bianca Mostert, Anieta Sieuwerts, Jaco Kraan, Joan Vries, Petra Spoel, A van Galen, DJ Peeters, LY Dirix, Caroline Seynaeve, Agnes Jager, FE Jongh, P Hamberg, JML Stouthard, DFS Kehrer, Maxime Look, Marcel Smid, Jan willem Gratama, John Foekens, John Martens, Stefan Sleijfer

Research output: Contribution to journalArticleAcademicpeer-review

43 Citations (Scopus)


Background: A circulating tumor cell (CTC) count is an established prognostic factor in metastatic breast cancer (MBC). Besides enumeration, CTC characterization promises to improve outcome prediction and treatment guidance. Having shown the feasibility of quantifying clinically relevant mRNA transcripts in CTCs, we determined the prognostic value of CTC gene expression in MBC. Patients and methods: CTCs were isolated and enumerated from blood of 197 MBC patients who were about to start first-line systemic therapy. Of these, 180 were assessable for quantification of mRNA expression by RT-qPCR in relation to time-to-treatment failure (TTF). A prognostic CTC gene profile was generated by leave-one-out cross validation in a 103 patient discovery set and validated in 77 patients. Additionally, all 180 patients were randomly divided into two equal sets to discover and validate a second prognostic profile. Results: CTC count predicted for TTF at baseline {>= 5 versus <5 CTCs/7.5 ml blood, hazard ratio (HR) 2.92 [95% confidence interval (CI) 1.71-4.95] P < 0.0001}. A 16-gene CTC profile was generated in the first discovery set, which identified patients with death or TTF < 9 months versus those with a better outcome. In multivariate analysis, the 16-gene profile was the only factor associated with TTF [HR 3.15 (95% CI 1.35-7.33) P 0.008]. Validation of this profile in the independent patient set pointed into the same direction, but was not statistically significant. A newly generated 8-gene profile showed similarly favorable test characteristics as the 16-gene profile, but did not significantly pass validation either. Conclusion: A 16-gene CTC profile was identified, which provided prognostic value on top of CTC count in MBC patients. However, validation of this profile in an independent cohort, nor of a second profile, reached statistical significance, underscoring the need to further fine-tune the still promising approach of CTC characterization.
Original languageUndefined/Unknown
Pages (from-to)510-516
Number of pages7
JournalAnnals of Oncology
Issue number3
Publication statusPublished - 2015

Cite this