Prognostic Value of Disseminated Tumor Cells in Unresectable Pancreatic Ductal Adenocarcinoma: a Prospective Observational Study

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2022 Jun 6

PMID 35659265

Authors

Oddmund Nordgard

Morten Lapin

Kjersti Tjensvoll

Satu Oltedal

Karin Hestnes Edland

Nicolay Bore Neverdahl

Dmitrij Fostenes

Herish Garresori

Nils Glenjen

Rune Smaaland

Bjornar Gilje

Affiliations

Soon will be listed here.

Abstract

Background: Although pancreatic ductal adenocarcinoma (PDAC) rarely metastasizes to the skeleton, disseminated tumor cells have been detected in bone marrow samples from patients with this disease. The prognostic value of such findings is currently unclear. Thus, the current study aimed to clarify the prognostic information associated with disseminated tumor cell detection in samples from patients with PDAC.

Methods: Bone marrow aspirates were obtained from 48 patients with locally advanced (n = 11) or metastatic (n = 37) PDAC, before and after 2 months of chemotherapy. Disseminated tumor cells were detected with an mRNA panel and quantitative reverse transcription PCR. We used the highest levels measured in healthy bone marrow (n = 30) as a threshold to define the positive detection of disseminated tumor cells. Progression-free and overall survival were analyzed with Kaplan-Meier and Cox proportional hazards regression analyses.

Results: Disseminated tumor cells were detected in 15/48 (31%) bone marrow samples obtained before starting chemotherapy and in 8/25 (32%) samples obtained during chemotherapy. Patients with disseminated tumor cells detected before therapy had significantly shorter progression-free (p = 0.03; HR = 2.0) and overall survival (p = 0.03; HR = 2.0), compared to those without disseminated tumor cells in the bone marrow. When restricting disseminated tumor cell detection to keratins KRT7 and KRT8, the prognostic information was substantially stronger (p = 1 × 10; HR = 22, and p = 2 × 10; HR = 7.7, respectively). The multivariable Cox regression analysis demonstrated that disseminated tumor cell detection prior to treatment had independent prognostic value. In contrast, disseminated tumor cells detected during treatment did not have prognostic value.

Conclusions: Disseminated tumor cells detected before commencing chemotherapy had prognostic value in patients with inoperable PDAC.

Citing Articles

Keratin 8 Is an Inflammation-Induced and Prognosis-Related Marker for Pancreatic Adenocarcinoma.

Xiong F, Guo T, Wang X, Wu G, Liu W, Wang Q Dis Markers. 2022; 2022:8159537.

PMID: 35958278 PMC: 9359862. DOI: 10.1155/2022/8159537.

References

Soeth E, Grigoleit U, Moellmann B, Roder C, Schniewind B, Kremer B . Detection of tumor cell dissemination in pancreatic ductal carcinoma patients by CK 20 RT-PCR indicates poor survival. J Cancer Res Clin Oncol. 2005; 131(10):669-76. DOI: 10.1007/s00432-005-0008-1. View

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

Uhlen M, Karlsson M, Zhong W, Tebani A, Pou C, Mikes J . A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science. 2019; 366(6472). DOI: 10.1126/science.aax9198. View

Synnestvedt M, Borgen E, Wist E, Wiedswang G, Weyde K, Risberg T . Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study. BMC Cancer. 2012; 12:616. PMC: 3576235. DOI: 10.1186/1471-2407-12-616. View

Benoy I, Elst H, Philips M, Wuyts H, van Dam P, Scharpe S . Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer. 2006; 94(5):672-80. PMC: 2361203. DOI: 10.1038/sj.bjc.6602985. View

Waseem A, Karsten U, Leigh I, Purkis P, Waseem N, Lane E . Conformational changes in the rod domain of human keratin 8 following heterotypic association with keratin 18 and its implication for filament stability. Biochemistry. 2004; 43(5):1283-95. DOI: 10.1021/bi035072s. View

Tjensvoll K, Oltedal S, Farmen R, Shammas F, Heikkila R, Kvaloy J . Disseminated tumor cells in bone marrow assessed by TWIST1, cytokeratin 19, and mammaglobin A mRNA predict clinical outcome in operable breast cancer patients. Clin Breast Cancer. 2010; 10(5):378-84. DOI: 10.3816/CBC.2010.n.050. View

Muralidhar V, Nipp R, Mamon H, Punglia R, Hong T, Ferrone C . Association Between Very Small Tumor Size and Decreased Overall Survival in Node-Positive Pancreatic Cancer. Ann Surg Oncol. 2018; 25(13):4027-4034. DOI: 10.1245/s10434-018-6832-8. View

Stephenson D, Nahm C, Chua T, Gill A, Mittal A, Reuver P . Circulating and disseminated tumor cells in pancreatic cancer and their role in patient prognosis: a systematic review and meta-analysis. Oncotarget. 2018; 8(63):107223-107236. PMC: 5739809. DOI: 10.18632/oncotarget.19928. View

10.

Uhlen M, Zhang C, Lee S, Sjostedt E, Fagerberg L, Bidkhori G . A pathology atlas of the human cancer transcriptome. Science. 2017; 357(6352). DOI: 10.1126/science.aan2507. View

11.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

12.

Thorban S, Roder J, Pantel K, Siewert J . Epithelial tumour cells in bone marrow of patients with pancreatic carcinoma detected by immunocytochemical staining. Eur J Cancer. 1996; 32A(2):363-5. DOI: 10.1016/0959-8049(95)00586-2. View

13.

Roder J, Thorban S, Pantel K, Siewert J . Micrometastases in bone marrow: prognostic indicators for pancreatic cancer. World J Surg. 1999; 23(9):888-91. DOI: 10.1007/s002689900594. View

14.

Mackay T, van Erning F, van der Geest L, de Groot J, Haj Mohammad N, Lemmens V . Association between primary origin (head, body and tail) of metastasised pancreatic ductal adenocarcinoma and oncologic outcome: A population-based analysis. Eur J Cancer. 2018; 106:99-105. DOI: 10.1016/j.ejca.2018.10.008. View

15.

Hugenschmidt H, Labori K, Brunborg C, Verbeke C, Thomas Seeberg L, Schirmer C . Cytokeratin-positive cells in the bone marrow from patients with pancreatic, periampullary malignancy and benign pancreatic disease show no prognostic information. BMC Cancer. 2020; 20(1):1107. PMC: 7667773. DOI: 10.1186/s12885-020-07510-z. View

16.

Soeth E, Vogel I, Roder C, Juhl H, Marxsen J, Kruger U . Comparative analysis of bone marrow and venous blood isolates from gastrointestinal cancer patients for the detection of disseminated tumor cells using reverse transcription PCR. Cancer Res. 1997; 57(15):3106-10. View

17.

Zhang Y, Weinberg R . Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018; 12(4):361-373. PMC: 6186394. DOI: 10.1007/s11684-018-0656-6. View

18.

Farmen R, Nordgard O, Gilje B, Shammas F, Kvaloy J, Oltedal S . Bone marrow cytokeratin 19 mRNA level is an independent predictor of relapse-free survival in operable breast cancer patients. Breast Cancer Res Treat. 2007; 108(2):251-8. DOI: 10.1007/s10549-007-9592-x. View

19.

Ma B, Wells A, Clark A . The pan-therapeutic resistance of disseminated tumor cells: Role of phenotypic plasticity and the metastatic microenvironment. Semin Cancer Biol. 2019; 60:138-147. PMC: 6992520. DOI: 10.1016/j.semcancer.2019.07.021. View

20.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View