Clinical relevance of EMT and stem-like gene expression in circulating tumor cells of metastatic colorectal cancer patients

• Published in: The pharmacogenomics journal Vol. 18; no. 1; pp. 29 - 34
• Main Authors: Ning, Y, Zhang, W, Hanna, D L, Yang, D, Okazaki, S, Berger, M D, Miyamoto, Y, Suenaga, M, Schirripa, M, El-Khoueiry, A, Lenz, H-J
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2018
• Subjects: Adult; Aged; Aged, 80 and over; AKT protein; AKT2 protein; Biomarkers, Tumor - genetics; Blood circulation; Cancer metastasis; Care and treatment; CD45 antigen; Clinical trials; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; Epithelial-Mesenchymal Transition - genetics; Female; Gene expression; Gene Expression - genetics; Genetic aspects; Humans; Male; Mesenchyme; Metastases; Metastasis; Middle Aged; Neoplastic Cells, Circulating - metabolism; Physiological aspects; Prognosis; Progression-Free Survival; Regression analysis; Stem cells; Survivin; Tumor cells; United States
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2016.62

Using approved methods, circulating tumor cells (CTCs) are only isolated from blood in 30%-50% of metastatic colorectal cancer (mCRC) patients. We previously validated a technique to isolate circulating tumor cells (CTCs) in a cohort of mCRC patients by combining immunomagnetic enrichment of EpCAM /CD45 cells with qRT-PCR amplification of CK20 and survivin expression. Here, we examined the prognostic utility of CTC epithelial-mesenchymal transition (EMT) and stem cell gene expression. An 8 ml blood sample was collected from 78 consecutive mCRC patients before treatment with investigational and standard chemotherapeutics. The mRNA expression of EMT (PI3Kα, Akt-2, Twist1) and stem cell (ALDH1) markers was measured. Associations between CTC gene expression and progression-free survival (PFS) and overall survival (OS) were determined using Cox regression models. Among patients without CK20 or survivin-expressing CTCs (n=17), 55% had expression of ALDH1, PI3Kα and/or Akt-2. Patients with positive CTC Akt-2 expression had a significantly shorter median PFS (3.0 versus 4.0 months) compared with those without CTC Akt-2 expression in univariable (hazard ratio (HR)=1.61; log-rank P=0.034) and multivariable analyses (HR=1.70; adjusted P=0.041). In univariable analysis, CTC ALDH1 expression was associated with shorter OS (10.0 versus 38.6 months; HR=2.04, P=0.021). Patients with CTCs expressing ALDH1, PI3Kα and/or Akt-2 had a significantly inferior PFS (3.0 versus 7.7 months; HR=1.88, P=0.015) and OS (10.0 versus 26.8+ months; HR=2.25, P=0.050) in univariable, but not multivariable, analysis. CTC Akt-2 expression may serve as a clinically useful prognostic marker in mCRC patients and warrants further evaluation in prospective trials.