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

Background:Current diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) has important limitations and better biomarkers are needed to guide initial therapy. We investigated the performance of circulating tumour cells (CTCs) as an adjunctive biomarker at the time of disease presentation.Methods:Venous blood (VB) was collected prospectively from 100 consecutive, pre-treatment patients with PDAC. Utilising the microfluidic NanoVelcro CTC chip, samples were evaluated for the presence and number of CTCs. KRAS mutation analysis was used to compare the CTCs with primary tumour tissue. CTC enumeration data was then evaluated as a diagnostic and staging biomarker in the setting of PDAC.Results:We found 100% concordance for KRAS mutation subtype between primary tumour and CTCs in all five patients tested. Evaluation of CTCs as a diagnostic revealed the presence of CTCs in 54/72 patients with confirmed PDAC (sensitivity=75.0%, specificity=96.4%, area under the curve (AUROC)=0.867, 95% CI=0.798–0.935, and P<0.001). Furthermore, a cut-off of ⩾3 CTCs in 4 ml VB was able to discriminate between local/regional and metastatic disease (AUROC=0.885; 95% CI=0.800–0.969; and P<0.001).Conclusion:CTCs appear to function well as a biomarker for diagnosis and staging in PDAC.

[1]  S. Digumarthy,et al.  Isolation of rare circulating tumour cells in cancer patients by microchip technology , 2007, Nature.

[2]  T. Okumura,et al.  Incidence of Synchronous and Metachronous Pancreatic Carcinoma in 168 Patients with Branch Duct Intraductal Papillary Mucinous Neoplasm , 2010, Pancreatology.

[3]  Maximilian Reichert,et al.  EMT and Dissemination Precede Pancreatic Tumor Formation , 2012, Cell.

[4]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[5]  Channing J Der,et al.  KRAS: feeding pancreatic cancer proliferation. , 2014, Trends in biochemical sciences.

[6]  J. Cameron,et al.  Two thousand consecutive pancreaticoduodenectomies. , 2015, Journal of the American College of Surgeons.

[7]  Yi-Kuen Lee,et al.  Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. , 2011, Angewandte Chemie.

[8]  Irving Waxman,et al.  A multispecialty approach to the diagnosis and management of pancreatic cancer , 2000, American Journal of Gastroenterology.

[9]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[10]  C. Ko,et al.  Postoperative Complications Reduce Adjuvant Chemotherapy Use in Resectable Pancreatic Cancer , 2014, Annals of surgery.

[11]  Shuang Hou,et al.  Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases , 2015, Cancer.

[12]  Vikesh K. Singh,et al.  Unnecessary Tests and Procedures in Patients Presenting with Solid Tumors of the Pancreas , 2013, Journal of Gastrointestinal Surgery.

[13]  H. Tseng,et al.  Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis , 2015, Expert review of molecular diagnostics.

[14]  M. D'Angelica,et al.  Malignant Progression in IPMN: A Cohort Analysis of Patients Initially Selected for Resection or Observation , 2013, Annals of Surgical Oncology.

[15]  K. Lehmann,et al.  Pancreatic cancer: value of dual-phase helical CT in assessing resectability. , 1998, Radiology.

[16]  Polymer nanofiber-embedded microchips for detection, isolation, and molecular analysis of single circulating melanoma cells. , 2013, Angewandte Chemie.

[17]  J. Tomlinson,et al.  Targeting CEA in Pancreas Cancer Xenografts with a Mutated scFv-Fc Antibody Fragment , 2011, EJNMMI research.

[18]  Benjamin D. Smith,et al.  Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. , 2014, Cancer research.

[19]  Sridhar Ramaswamy,et al.  RNA sequencing of pancreatic circulating tumour cells implicates WNT signaling in metastasis , 2012, Nature.

[20]  F. Bidard,et al.  Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  S. Soper,et al.  Modular microsystem for the isolation, enumeration, and phenotyping of circulating tumor cells in patients with pancreatic cancer. , 2013, Analytical chemistry.

[22]  Alison Stopeck,et al.  Circulating tumor cells, disease progression, and survival in metastatic breast cancer. , 2004, The New England journal of medicine.

[23]  Timothy B Lannin,et al.  Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. , 2014, Gastroenterology.

[24]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[25]  L Khoja,et al.  A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker , 2011, British Journal of Cancer.

[26]  K. Pantel,et al.  Challenges in circulating tumour cell research , 2014, Nature Reviews Cancer.

[27]  F. Itokawa,et al.  Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result. , 2008, Journal of hepato-biliary-pancreatic surgery.

[28]  T. Imperiale,et al.  Optimal number of EUS-guided fine needle passes needed to obtain a correct diagnosis. , 2004, Gastrointestinal endoscopy.