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Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment

2016-07-13 14:46:14

Science Advances; 13 July 2016: DOI:10.1126/sciadv.1600274

Bee Luan Khoo, Gianluca Grenci, Tengyang Jing, Ying Bena Lim, Soo Chin Lee, Jean Paul Thiery, Jongyoon Han,and Chwee Teck Lim



Abstract


The lack of a robust anticancer drug screening system to monitor patients during treatment delays realization of personalized treatment. We demonstrate an efficient approach to evaluate drug response using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. Custom microfabricated tapered microwells were integrated with microfluidics to allow robust formation of CTC clusters without pre-enrichment and subsequent drug screening in situ. Rapid feedback after 2 weeks promotes immediate intervention upon detection of drug resistance or tolerance. The procedure was clinically validated with blood samples (n = 73) from 55 patients with early-stage, newly diagnosed, locally advanced, or refractory metastatic breast cancer. Twenty-four of these samples were used for drug evaluation. Cluster formation potential correlated inversely with increased drug concentration and therapeutic treatment. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment.



Introduction


Progression of anticancer drug development into actual clinical utility remains hindered by the inherent heterogeneity of cancer. Furthermore, tumor biopsies often fail to reflect the complete cancer gene expression profile. Current imaging techniques for cancer evaluation [for example, computed tomography (CT) scan] also suffer from technical limitations, which lead to false-negative findings. These limitations affect the development of prognostic assays in aiding the development of robust drug regimens. At present, several drug screening systems available for cancer cell lines are often designed for use with multiwell plates or robotics. However, the translational relevance of cell lines is often in question because prolonged culture and multiple passages lead to phenotypes that are no longer representative of the original tumor in terms of the cell’s epigenetics and gene expression.



In the past few years, several methods of in vitro cultures of circulating tumor cells (CTCs) were established. CTCs are primary cancer cells that originate from either primary or secondary tumors. Their enumeration had led to the finding that, at least in metastatic patients, their prevalence correlates with shorter overall survival. Previous attempts at CTC expansion led to the establishment of cell lines derived from CTCs of breast, colon, and prostate cancer patients. These cell lines were usually established after months in culture, requiring pre-enrichment procedures such as affinity binding, fluorescence-activated cell sorting, or negative selection. The efficiency in obtaining CTC cultures using these methods was also low (<20%), and the need for pre-enrichment with each method resulted in a loss of CTCs.



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