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Erschienen in: Annals of Surgical Oncology 4/2018

13.02.2018 | Pancreatic Tumors

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

verfasst von: Colin M. Court, MD, Jacob S. Ankeny, MD, Shonan Sho, MD, Paul Winograd, MD, Shuang Hou, PhD, Min Song, MD, Zev A. Wainberg, MD, Mark D. Girgis, MD, Thomas G. Graeber, PhD, Vatche G. Agopian, MD, Hsian-Rong Tseng, PhD, James S. Tomlinson, MD, PhD

Erschienen in: Annals of Surgical Oncology | Ausgabe 4/2018

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Abstract

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, p < 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 cut-off 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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Literatur
1.
2.
Zurück zum Zitat Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.CrossRef Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.CrossRef
3.
Zurück zum Zitat Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.CrossRefPubMedPubMedCentral Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Shubert CR, Bergquist JR, Groeschl RT, Habermann EB, Wilson PM, Truty MJ, et al. Overall survival is increased among stage III pancreatic adenocarcinoma patients receiving neoadjuvant chemotherapy compared to surgery first and adjuvant chemotherapy: an intention to treat analysis of the National Cancer Database. Surgery. 2016;160(4):1080–96.CrossRefPubMed Shubert CR, Bergquist JR, Groeschl RT, Habermann EB, Wilson PM, Truty MJ, et al. Overall survival is increased among stage III pancreatic adenocarcinoma patients receiving neoadjuvant chemotherapy compared to surgery first and adjuvant chemotherapy: an intention to treat analysis of the National Cancer Database. Surgery. 2016;160(4):1080–96.CrossRefPubMed
5.
Zurück zum Zitat Riediger H, Keck T, Wellner U, zur Hausen A, Adam U, Hopt UT, et al. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest 2009;13(7):1337–44.CrossRef Riediger H, Keck T, Wellner U, zur Hausen A, Adam U, Hopt UT, et al. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest 2009;13(7):1337–44.CrossRef
7.
Zurück zum Zitat Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–6904.CrossRefPubMed Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–6904.CrossRefPubMed
8.
Zurück zum Zitat Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623–31.CrossRefPubMed Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623–31.CrossRefPubMed
9.
Zurück zum Zitat Court CM, Ankeny JS, Sho S, Hou S, Li Q, Hsieh C, et al. Reality of single circulating tumor cell sequencing for molecular diagnostics in pancreatic cancer. J Mol Diagn. 2016;18(5):688–96.CrossRefPubMedPubMedCentral Court CM, Ankeny JS, Sho S, Hou S, Li Q, Hsieh C, et al. Reality of single circulating tumor cell sequencing for molecular diagnostics in pancreatic cancer. J Mol Diagn. 2016;18(5):688–96.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Ankeny JS, Court CM, Hou S, Li Q, Song M, Wu D, et al. Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. Br J Cancer 2016;114(12):1367–75.CrossRefPubMedPubMedCentral Ankeny JS, Court CM, Hou S, Li Q, Song M, Wu D, et al. Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. Br J Cancer 2016;114(12):1367–75.CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Amin M, Edge S, Greene F. AJCC cancer staging manual. 8th ed. Cham: Springer; 2017.CrossRef Amin M, Edge S, Greene F. AJCC cancer staging manual. 8th ed. Cham: Springer; 2017.CrossRef
12.
Zurück zum Zitat Lu YT, Zhao L, Shen Q, Garcia MA, Wu D, Hou S, et al. NanoVelcro Chip for CTC enumeration in prostate cancer patients. Methods. 2013;64(2):144–52.CrossRefPubMed Lu YT, Zhao L, Shen Q, Garcia MA, Wu D, Hou S, et al. NanoVelcro Chip for CTC enumeration in prostate cancer patients. Methods. 2013;64(2):144–52.CrossRefPubMed
13.
Zurück zum Zitat Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE 2012;7(12):e51862.CrossRefPubMedPubMedCentral Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE 2012;7(12):e51862.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol. 2015;12(6):319–34.CrossRefPubMed Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol. 2015;12(6):319–34.CrossRefPubMed
15.
Zurück zum Zitat Donahue TR, Isacoff WH, Hines OJ, Tomlinson JS, Farrell JJ, Bhat YM, et al. Downstaging chemotherapy and alteration in the classic computed tomography/magnetic resonance imaging signs of vascular involvement in patients with pancreaticobiliary malignant tumors: influence on patient selection for surgery. Arch Surg. 2011;146(7):836–43.CrossRefPubMed Donahue TR, Isacoff WH, Hines OJ, Tomlinson JS, Farrell JJ, Bhat YM, et al. Downstaging chemotherapy and alteration in the classic computed tomography/magnetic resonance imaging signs of vascular involvement in patients with pancreaticobiliary malignant tumors: influence on patient selection for surgery. Arch Surg. 2011;146(7):836–43.CrossRefPubMed
16.
Zurück zum Zitat Khoja L, Backen A, Sloane R, Menasce L, Ryder D, Krebs M, et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer. 2012;106(3):508–16.CrossRefPubMed Khoja L, Backen A, Sloane R, Menasce L, Ryder D, Krebs M, et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer. 2012;106(3):508–16.CrossRefPubMed
17.
Zurück zum Zitat Bidard FC, Huguet F, Louvet C, Mineur L, Bouche O, Chibaudel B, et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann Oncol. 2013;24(8):2057–61.CrossRefPubMed Bidard FC, Huguet F, Louvet C, Mineur L, Bouche O, Chibaudel B, et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann Oncol. 2013;24(8):2057–61.CrossRefPubMed
18.
Zurück zum Zitat Hoffmann K, Kerner C, Wilfert W, Mueller M, Thiery J, Hauss J, et al. Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients. World J Gastroenterol. 2007;13(2):257–63.CrossRefPubMedPubMedCentral Hoffmann K, Kerner C, Wilfert W, Mueller M, Thiery J, Hauss J, et al. Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients. World J Gastroenterol. 2007;13(2):257–63.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat de Albuquerque A, Kubisch I, Breier G, Stamminger G, Fersis N, Eichler A, et al. Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology. 2012;82(1):3–10.CrossRefPubMed de Albuquerque A, Kubisch I, Breier G, Stamminger G, Fersis N, Eichler A, et al. Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology. 2012;82(1):3–10.CrossRefPubMed
20.
Zurück zum Zitat Poruk KE, Blackford AL, Weiss MJ, Cameron JL, He J, Goggins M, et al. Circulating tumor cells expressing markers of tumor-initiating cells predict poor survival and cancer recurrence in patients with pancreatic ductal adenocarcinoma. Clin Cancer Res. 2017;23(11):2681–90.CrossRefPubMed Poruk KE, Blackford AL, Weiss MJ, Cameron JL, He J, Goggins M, et al. Circulating tumor cells expressing markers of tumor-initiating cells predict poor survival and cancer recurrence in patients with pancreatic ductal adenocarcinoma. Clin Cancer Res. 2017;23(11):2681–90.CrossRefPubMed
21.
Zurück zum Zitat Kamande JW, Hupert ML, Witek MA, Wang H, Torphy RJ, Dharmasiri U, et al. Modular microsystem for the isolation, enumeration, and phenotyping of circulating tumor cells in patients with pancreatic cancer. Anal Chem. 2013;85(19):9092–9100.CrossRefPubMed Kamande JW, Hupert ML, Witek MA, Wang H, Torphy RJ, Dharmasiri U, et al. Modular microsystem for the isolation, enumeration, and phenotyping of circulating tumor cells in patients with pancreatic cancer. Anal Chem. 2013;85(19):9092–9100.CrossRefPubMed
22.
Zurück zum Zitat Court CM, Ankeny JS, Hou S, Tseng HR, Tomlinson JS. Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis. Expert Rev Mol Diagn. 2015;15(11):1491–1504.CrossRefPubMedPubMedCentral Court CM, Ankeny JS, Hou S, Tseng HR, Tomlinson JS. Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis. Expert Rev Mol Diagn. 2015;15(11):1491–1504.CrossRefPubMedPubMedCentral
Metadaten
Titel
Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer
verfasst von
Colin M. Court, MD
Jacob S. Ankeny, MD
Shonan Sho, MD
Paul Winograd, MD
Shuang Hou, PhD
Min Song, MD
Zev A. Wainberg, MD
Mark D. Girgis, MD
Thomas G. Graeber, PhD
Vatche G. Agopian, MD
Hsian-Rong Tseng, PhD
James S. Tomlinson, MD, PhD
Publikationsdatum
13.02.2018
Verlag
Springer International Publishing
Erschienen in
Annals of Surgical Oncology / Ausgabe 4/2018
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-017-6290-8

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