Promise and limits of the CellSearch platform for evaluating pharmacodynamics in circulating tumor cells.
Circulating tumor cells (CTCs), which are captured from blood with anti-epithelial cell adhesion molecule (EpCAM) antibodies, have established prognostic value in specific epithelial cancers, but less is known about their utility for assessing patient response to molecularly targeted agents via measurement of pharmacodynamic (PD) endpoints. We discuss the use of CellSearch (Janssen Diagnostics, LLC, Raritan, NJ) CTC isolation technology for monitoring PD response in early phase trials. We present representative data from three clinical trials with the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) suggesting that CTCs can be used to measure PD effects. However, while often leading to hypothesis-generating information, our experience points to the difficulty in obtaining sufficient EpCAM-expressing CTCs from patients with advanced disease to reach statistically significant conclusions about PD effects from each trial. Overall, the level of phenotypic heterogeneity observed in specimens from patients with advanced carcinomas suggests caution in the use of cell-surface differentiation marker-based methods for isolating CTCs.
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Lihua
L
Wang
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Priya
P
Balasubramanian
Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Alice P
AP
Chen
Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Shivaani
S
Kummar
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Yvonne A
YA
Evrard
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD. Electronic address: kindersr@mail.nih.gov.
Robert J
RJ
Kinders
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002986:Clinical Trials as Topic; D003520:Cyclophosphamide / Q000008:administration & dosage; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D009360:Neoplastic Cells, Circulating / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015203:Reproducibility of Results; D012984:Software; D013048:Specimen Handling / Q000379:methods*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D000071858:Epithelial Cell Adhesion Molecule; C521013:veliparib; D000077146:Irinotecan; D003520:Cyclophosphamide; D002166:Camptothecin
Assay validation; CTCs; Pharmacodynamics; Surrogate endpoint
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