B Mostert1, A M Sieuwerts2, J Kraan1, J Bolt-de Vries1, P van der Spoel1, A van Galen1, D J Peeters3, L Y Dirix3, C M Seynaeve1, A Jager1, F E de Jongh4, P Hamberg5, J M L Stouthard6, D F S Kehrer7, M P Look1, M Smid1, J W Gratama1, J A Foekens1, J W M Martens2, S Sleijfer8. 1. Department of Medical Oncology. 2. Department of Medical Oncology Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands. 3. Translational Cancer Research Unit, Center for Oncological Research, GZA Hospitals Sint-Augustinus and University of Antwerp, Antwerp, Belgium. 4. Ikazia Hospital, Rotterdam. 5. Sint Franciscus Gasthuis, Rotterdam. 6. Maasstad Hospital, Rotterdam. 7. Department of Internal Medicine, IJsselland Hospital, Capelle aan den IJssel, The Netherlands. 8. Department of Medical Oncology Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands s.sleijfer@erasmusmc.nl.
Abstract
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.
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 MBCpatients 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 MBCpatients. 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.
Authors: Mark Jesus M Magbanua; 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; John W Park Journal: Clin Cancer Res Date: 2018-01-08 Impact factor: 12.531
Authors: Esther A Reijm; Anieta M Sieuwerts; Marcel Smid; Joan Bolt-de Vries; Bianca Mostert; Wendy Onstenk; Dieter Peeters; Luc Y Dirix; Caroline M Seynaeve; Agnes Jager; Felix E de Jongh; Paul Hamberg; Anne van Galen; Jaco Kraan; Maurice P H M Jansen; Jan W Gratama; John A Foekens; John W M Martens; Els M J J Berns; Stefan Sleijfer Journal: BMC Cancer Date: 2016-02-18 Impact factor: 4.430
Authors: William M Strauss; Chris Carter; Jill Simmons; Erich Klem; Nathan Goodman; Behrad Vahidi; Juan Romero; Michael Masterman-Smith; Ruth O'Regan; Keerthi Gogineni; Lee Schwartzberg; Laura K Austin; Paul W Dempsey; Massimo Cristofanilli Journal: Oncotarget Date: 2016-05-03
Authors: I E de Kruijff; A M Sieuwerts; N Beije; W J C Prager-van der Smissen; L Angus; C M Beaufort; M N Van; E Oomen-de Hoop; A Jager; P Hamberg; F E de Jongh; J Kraan; J W M Martens; S Sleijfer Journal: Front Oncol Date: 2021-06-25 Impact factor: 6.244