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Circulating tumors cells as biomarkers: progress toward biomarker qualification.

ABSTRACT: Personalized cancer medicine requires the development of tumor-specific biomarkers to optimize selection of targeted therapies and to better assess response to therapy. Current efforts in several tumor types have shown that patients in whom circulating tumor cells (CTCs) are detected have an inferior prognosis relative to those in whom CTCs are not detected and that the elimination or decrease of CTCs following treatment is associated with improved clinical outcomes. Technological advances in the detection, isolation, capture, and characterization of CTCs from phlebotomy samples obtained in a routine clinical practice setting have enabled the evaluation of different CTC biomarkers. Unmet needs in cancer diagnosis and treatment where CTC biomarkers have been studied include determining prognosis, assessing the effects of treatment, and as a source of tumor for the biologic identification and characterization of determinants to predict sensitivity to one form of treatment versus another and to understand mechanisms of treatment resistance.At present, there is no single definition of a CTC and no single CTC "biomarker." Rather, multiple assays (tests) are in development for CTC biomarkers. However, before the role of any biomarker in medical decision making can be determined, it is essential that the assays used to measure the biomarker are analytically validated in a sequence of trials to generate the evidence to support the biomarker's use in the given context of use. It is against this background that this review focuses on the process of developing CTC biomarker assays, with the objective of outlining the necessary steps to qualify specific CTC tests for medical decision making in clinical practice or drug development. The potential for point-of-care tests is clear.

SUBMITTER: Danila DC

PROVIDER: S-EPMC3985131 | biostudies-literature | 2011 Nov-Dec

REPOSITORIES: biostudies-literature

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Circulating tumors cells as biomarkers: progress toward biomarker qualification.

Danila Daniel C DC Pantel Klaus K Fleisher Martin M Scher Howard I HI

Cancer journal (Sudbury, Mass.) 20111101 6

Personalized cancer medicine requires the development of tumor-specific biomarkers to optimize selection of targeted therapies and to better assess response to therapy. Current efforts in several tumor types have shown that patients in whom circulating tumor cells (CTCs) are detected have an inferior prognosis relative to those in whom CTCs are not detected and that the elimination or decrease of CTCs following treatment is associated with improved clinical outcomes. Technological advances in th ...[more]

PMID: 22157288

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Project description:Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard.Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs. We report similar performance for the various platforms tested in capturing CTCs, and find that capture efficiency is dependent on the level of EpCAM expression. We demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, qRT-PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence (IF). We quantify cell surface expression of EGFR in metastatic lung cancer patient samples. In addition, we determined HER2 status by IF and FISH in CTCs from metastatic breast cancer patients. In the majority of patients (89%) we found concordance with HER2 status from patient tumor tissue, though in a subset of patients (11%), HER2 status in CTCs differed from that observed in the primary tumor. Surprisingly, we found CTC counts to be higher in ER+ patients in comparison to HER2+ and triple negative patients, which could be explained by low EpCAM expression and a more mesenchymal phenotype of tumors belonging to the basal-like molecular subtype of breast cancer.Our data suggests that molecular characterization from captured CTCs is possible and can potentially provide real-time information on biomarker status. In this regard, CTCs hold significant promise as a source of tumor material to facilitate clinical biomarker evaluation. However, limitations exist from a purely EpCAM based capture system and addition of antibodies to mesenchymal markers could further improve CTC capture efficiency to enable routine biomarker analysis from CTCs.

Project description:We report an integrated pipeline for efficient serum glycoprotein biomarker candidate discovery and qualification that may be used to facilitate cancer diagnosis and management. The discovery phase used semi-automated lectin magnetic bead array (LeMBA)-coupled tandem mass spectrometry with a dedicated data-housing and analysis pipeline; GlycoSelector (http://glycoselector.di.uq.edu.au). The qualification phase used lectin magnetic bead array-multiple reaction monitoring-mass spectrometry incorporating an interactive web-interface, Shiny mixOmics (http://mixomics-projects.di.uq.edu.au/Shiny), for univariate and multivariate statistical analysis. Relative quantitation was performed by referencing to a spiked-in glycoprotein, chicken ovalbumin. We applied this workflow to identify diagnostic biomarkers for esophageal adenocarcinoma (EAC), a life threatening malignancy with poor prognosis in the advanced setting. EAC develops from metaplastic condition Barrett's esophagus (BE). Currently diagnosis and monitoring of at-risk patients is through endoscopy and biopsy, which is expensive and requires hospital admission. Hence there is a clinical need for a noninvasive diagnostic biomarker of EAC. In total 89 patient samples from healthy controls, and patients with BE or EAC were screened in discovery and qualification stages. Of the 246 glycoforms measured in the qualification stage, 40 glycoforms (as measured by lectin affinity) qualified as candidate serum markers. The top candidate for distinguishing healthy from BE patients' group was Narcissus pseudonarcissus lectin (NPL)-reactive Apolipoprotein B-100 (p value = 0.0231; AUROC = 0.71); BE versus EAC, Aleuria aurantia lectin (AAL)-reactive complement component C9 (p value = 0.0001; AUROC = 0.85); healthy versus EAC, Erythroagglutinin Phaseolus vulgaris (EPHA)-reactive gelsolin (p value = 0.0014; AUROC = 0.80). A panel of 8 glycoforms showed an improved AUROC of 0.94 to discriminate EAC from BE. Two biomarker candidates were independently verified by lectin magnetic bead array-immunoblotting, confirming the validity of the relative quantitation approach. Thus, we have identified candidate biomarkers, which, following large-scale clinical evaluation, can be developed into diagnostic blood tests. A key feature of the pipeline is the potential for rapid translation of the candidate biomarkers to lectin-immunoassays.

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Circulating tumors cells as biomarkers: progress toward biomarker qualification.

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Circulating tumors cells as biomarkers: progress toward biomarker qualification.

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