Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer

Ankeny, Jacob S.; Court, Colin M.; Hou, Shuang; Li, Q; Song, Min; Wu, Danni; Chen, Jie‐Fu; Lee, T; Lin, Millicent; Sho, S; Rochefort, Matthew M.; Girgis, Mark D.; Yao, Jingwen; Wainberg, Zev A.; Muthusamy, V. Raman; Watson, Rabindra R.; Donahue, Timothy R.; Hines, Oscar J.; Reber, Howard A.; Graeber, Thomas G.; Tseng, Hsian‐Rong; Tomlinson, James S.

doi:10.1038/bjc.2016.121

Cited by 116 publications

(105 citation statements)

References 27 publications

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“…We enrolled patients at all stages of disease undergoing a variety of treatment modalities and determined how CTC enumeration correlated with clinicopathologic variables, surgical therapy, and survival outcomes. The current study builds on our previous investigation of CTCs as a diagnostic biomarker 10 by demonstrating the prognostic and predictive ability of CTCs for PDAC patients. We believe that our most significant finding was the predictive ability of CTCs for occult metastatic disease in the preoperative setting.…”

Section: Discussionmentioning

confidence: 87%

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Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer

et al. 2018

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Background Occult metastatic tumors, below imaging thresholds, are a limitation of staging systems that rely on cross-sectional imaging alone and are a cause of the routine understaging of pancreatic ductal adenocarcinomas (PDACs). We investigated circulating tumor cells (CTCs) as a preoperative predictor of occult metastatic disease and as a prognostic biomarker for PDAC patients. Experimental Design A total of 126 patients (100 with cancer, 26 with benign disease) were enrolled in our study and CTCs were identified and enumerated from 4 mL of venous blood using the microfluidic NanoVelcro assay. CTC enumeration was correlated with clinicopathologic variables and outcomes following both surgical and systemic therapies. Results CTCs were identified in 78% of PDAC patients and CTC counts correlated with increasing stage (ρ = 0.42, ρ < 0.001). Of the 53 patients taken for potentially curative surgery, 13 (24.5%) had occult metastatic disease intraoperatively. Patients with occult disease had significantly more CTCs than patients with local disease only (median 7 vs. 1 CTC, p < 0.0001). At a cutoff of three or more CTCs/4 mL, CTCs correctly identified patients with occult metastatic disease preoperatively (area under the receiver operating characteristic curve 0.82, 95% confidence interval (CI) 0.76–0.98, p < 0.0001). CTCs were a univariate predictor of recurrence-free survival following surgery [hazard ratio (HR) 2.36, 95% CI 1.17–4.78, p = 0.017], as well as an independent predictor of overall survival on multivariate analysis (HR 1.38, 95% CI 1.01–1.88, p = 0.040). Conclusions CTCs show promise as a prognostic biomarker for PDAC patients at all stages of disease being treated both medically and surgically. Furthermore, CTCs demonstrate potential as a preoperative biomarker for identifying patients at high risk of occult metastatic disease.

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Section: Discussionmentioning

confidence: 87%

“…9 We then used our PDAC CTC assay to show that CTCs are present in the majority of PDAC patients, but not patients with non-malignant pancreatic disease, and that CTCs may have utility as a diagnostic biomarker at the time of disease presentation. 10 …”

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confidence: 99%

Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer

et al. 2018

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“…The microfluidic nanovelcro chip showed a 75% sensitivity and 96.4% specificity for the diagnosis of primary pancreatic ductal adenocarcinoma, with 60.7%, 78.6%, and 96.3% detection in stages II, III, and IV, respectively; however, there was 0% detection in stage I disease (60). A size-based filtration microfluidic chip used to detect CTCs in lung cancer patients demonstrated a 73.3% sensitivity and 100% specificity, with a threshold for definition of lung cancer by CTC level set at 5.15 cells per mL (34).…”

Section: Diagnosticmentioning

confidence: 99%

Biophysical technologies for understanding circulating tumor cell biology and metastasis

Nieva

2017

Transl. Lung Cancer Res.

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An understanding of cancer evolution in lung cancer with its associated resistance to therapy can only be achieved with repeated sampling and analysis of the cancer. Given the high risks and costs associated with repeat physical biopsy, alternative technologies must be applied. Several modalities exist for analysis and re-analysis of cancer biology. Among them are the CellSearch platform, the CTC chip, and the highdefinition CTC platform. While the former is primarily able to provide prognosticating information in the form of CTC enumeration, the latter two have the advantage of serving as a platform to study tumor biology. Techniques for analysis of single cell genomics, as well as protein expression on a single cell basis provide scientists with the capacity to understand cancer cell populations as a collection of individual cells, rather than as an average of all cells. A multimodal combination of circulating tumor DNAs (ctDNAs), CTCs, proteomics, and CTC-derived xenografts (CDXs) to create computational models useful in diagnosis, prognostication, and predictiveness to treatment is likely the future of tailoring individualized cancer care.

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“…Prepared samples were injected through the device at the previously established optimal flow rate of 0.5 mL/hour and were then fixed using 100% ethanol. 15 …”

Section: Nanovelcro/lcm Ctc Chip Processingmentioning

confidence: 99%

Reality of Single Circulating Tumor Cell Sequencing for Molecular Diagnostics in Pancreatic Cancer

Court

Ankeny

Sho

et al. 2016

The Journal of Molecular Diagnostics

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To understand the potential and limitations of circulating tumor cell (CTC) sequencing for molecular diagnostics, we investigated the feasibility of identifying the ubiquitous KRAS mutation in single CTCs from pancreatic cancer (PC) patients. We used the NanoVelcro/laser capture microdissection CTC platform, combined with whole genome amplification and KRAS Sanger sequencing. We assessed both KRAS codon-12 coverage and the degree that allele dropout during whole genome amplification affected the detection of KRAS mutations from single CTCs. We isolated 385 single cells, 163 from PC cell lines and 222 from the blood of 12 PC patients, and obtained KRAS sequence coverage in 218 of 385 single cells (56.6%). For PC cell lines with known KRAS mutations, single mutations were detected in 67% of homozygous cells but only 37.4% of heterozygous single cells, demonstrating that both coverage and allele dropout are important causes of mutation detection failure from single cells. We could detect KRAS mutations in CTCs from 11 of 12 patients (92%) and 33 of 119 single CTCs sequenced, resulting in a KRAS mutation detection rate of 27.7%. Importantly, KRAS mutations were never found in the 103 white blood cells sequenced. Sequencing of groups of cells containing between 1 and 100 cells determined that at least 10 CTCs are likely required to reliably assess KRAS mutation status from CTCs. (J Mol Diagn 2016, 18: 688e696; http://dx

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Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer

Cited by 116 publications

References 27 publications

Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer

Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer

Biophysical technologies for understanding circulating tumor cell biology and metastasis

Reality of Single Circulating Tumor Cell Sequencing for Molecular Diagnostics in Pancreatic Cancer

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