Circulating Tumor Cells: Application as a Biomarker for Molecular Characterization and Predictor of Survival in an All-Comer Solid Tumor Phase I Clinical Study

Abstract

PurposeClinical development of cancer drugs has a low success rate. Prognostic and predictive biomarkers using minimally invasive approaches hold promise for increasing the probability of success by enabling disease characterization, patient selection and early detection of drug treatment effect. Enumeration and molecular characterization of circulating tumor cells (CTC) may address some of these needs, and thus were evaluated for utility in a Phase I solid tumor clinical study.Experimental DesignBlood samples for CTC analysis were obtained from 24 cancer patients in a multi-center all-comer Phase I study of MEDI-575, a novel anti-PDGFRα antibody. Samples were taken at screening and analyzed for enumeration of CTC using the CellSearch® platform and for molecular characterization using a novel quantitative RT-PCR assay.ResultsFifty-nine percent of the patients showed at least 1 CTC per 7.5 ml of blood at baseline. Progression-free survival (PFS) and overall survival (OS) of patients with 0 CTCs at baseline were longer than PFS and Os for patients with 1-3 and >3 CTCs (8.8 versus 1.4 and 1.3 months PFS, P = 0.02; 9.0 vs 7.4 and 3.5 months OS, P = 0.20, respectively). Patients with 0 CTC showed a greater percentage of stable disease than the other 2 groups with 1-3 and >3 CTCs (57% vs 29% and 0%). The multimarker qRT-PCR method detected CTC in 40% of the patients, and 80% of these patients were positive for pre-selected drug target genes.ConclusionCTC enumeration of patients in an all-comer study is feasible and may allow for patient stratification for PFS and Os to evaluate the clinical response of investigational agents. Gene expression profiling of isolated CTC may provide a means for molecular characterization of selected tumor targets.

Dimethylnitrosamine-Induced Reduction in the Level of Poly-ADP-Ribosylation of Histone Proteins of Blood Lymphocytes - a Sensitive and Reliable Biomarker for Early Detection of Cancer

“…Early detection of cancer continues to be a formidable challenge to the scientific community and search for a suitable biomarker for use in mass screening of population is of utmost importance in our fight against cancer (Khan et al, 2012;Luna et al, 2012;van der Bilt et al 2012;Bao et al, 2013;Hensing and Salgia, 2013;Suradej et al, 2013;Wang et al, 2013;Behrens et al, 2014;Sigari et al, 2014). Constant efforts are being made worldwide to find an effective and reliable biomarker and a convenient assay for early detection of cancers, especially in its initiation stage, which is when a cell gets committed to transformation.…”

Phase I Dose-Escalation Study of MEDI-573, a Bispecific, Antiligand Monoclonal Antibody against IGFI and IGFII, in Patients with Advanced Solid Tumors

“…Methods were described previously (35), but this analysis used the CellSearch CXC Kit (Janssen Diagnostics). For evaluating CTCs as a prognostic marker for survival, patients were grouped by baseline CTC values of either less than 5 or 5 or more, as these cutoffs have been established as prognostic for breast cancer (36) and prostate cancer (37).…”

Cellules tumorales circulantes : pierre angulaire de la médecine personnalisée

“…Cette étape permettrait une caractérisation plus spécifique de ces cellules mais surtout d'identifier celles ayant les propriétés de cellules souches. Il a été également démontré que l'on pouvait caractériser leur ADN pour la recherche de mutations spécifiques (génomique), leur ARN pour l'expression des gènes (transcriptomique) et ceci par les techniques classiques ou de séquençage à haut débit [21]. Finalement, afin de démontrer le pouvoir tumorogénique des CTCs, ces dernières sont injectées à des souris immunodéficientes [22].…”

“…La détection des CTCs était un facteur indépen-dant de mauvais pronostique (survie sans récidive ; HR 1,88 ; survie globale ; HR 1,91). Ces résultats ont été confirmés dans des études indépendantes utilisant le même système [21].…”

“…Des cas isolés de détection de CTCs ont été décrit pour le cancer de l'endomètre [21]. En utilisant une signature moléculaire de 6 gènes (CCNE2, DKFZp762E1312, EMP2, MAL2, PPIC et SLC6A8), Obermayr et al ont pu mettre en évidence des CTCs dans les cancers du col et de l'endomètre [45].…”