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12-02-2016 | Hepatocellular carcinoma | Article

Organic Cation Transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment

Journal: BMC Cancer

Authors: Daniel Grimm, Jonas Lieb, Veronika Weyer, Johanna Vollmar, Felix Darstein, Anja Lautem, Maria Hoppe-Lotichius, Sandra Koch, Arno Schad, Jörn M. Schattenberg, Marcus A. Wörns, Arndt Weinmann, Peter R. Galle, Tim Zimmermann

Publisher: BioMed Central

Abstract

Background

The polyspecific organ cation transporter 1 (OCT1) is one of the most important active influx pumps for drugs like the kinase inhibitor sorafenib. The aim of this retrospective study was the definition of the role of intratumoral OCT1 mRNA expression in hepatocellular carcinoma (HCC) as a biomarker in systemic treatment with sorafenib.

Methods

OCT1 mRNA expression levels were determined in biopsies from 60 primary human HCC by real time PCR. The data was retrospectively correlated with clinical parameters.

Results

Intratumoral OCT1 mRNA expression is a significant positive prognostic factor for patients treated with sorafenib according to Cox regression analysis (HR 0.653, 95 %-CI 0.430-0.992; p = 0.046). Under treatment with sorafenib, a survival benefit could be shown using the lower quartile of intratumoral OCT1 expression as a cut-off. Macrovascular invasion (MVI) was slightly more frequent in patients with low OCT1 mRNA expression (p = 0.037). Treatment-induced AFP response was not associated with intratumoral OCT1 mRNA expression levels (p = 0.633).

Conclusions

This study indicates a promising role for intratumoral OCT1 mRNA expression as a prognostic biomarker in therapeutic algorithms in HCC. Further prospective studies are warranted on this topic.

El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76. doi:10.1053/j.gastro.2007.04.061.CrossRefPubMed

EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43. doi:10.1016/j.jhep.2011.12.001.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.CrossRefPubMed

Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol. 2012;56(3):686–95. doi:10.1016/j.jhep.2011.07.031.CrossRefPubMed

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. doi:10.1056/NEJMoa0708857.CrossRefPubMed

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. doi:10.1016/s1470-2045(08)70285-7.CrossRefPubMed

Camma C, Cabibbo G, Petta S, Enea M, Iavarone M, Grieco A, et al. Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma. Hepatology (Baltimore, Md). 2013;57(3):1046–54. doi:10.1002/hep.26221.CrossRef

Carr BI, Carroll S, Muszbek N, Gondek K. Economic evaluation of sorafenib in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol. 2010;25(11):1739–46. doi:10.1111/j.1440-1746.2010.06404.x.CrossRefPubMed

Shao YY, Hsu CH, Cheng AL. Predictive Biomarkers of Antiangiogenic Therapy for Advanced Hepatocellular Carcinoma: Where Are We? Liver cancer. 2013;2(2):93–107. doi:10.1159/000343845.PubMedCentralCrossRefPubMed

10.

Heise M, Lautem A, Knapstein J, Schattenberg JM, Hoppe-Lotichius M, Foltys D, et al. Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer. 2012;12:109. doi:10.1186/1471-2407-12-109.PubMedCentralCrossRefPubMed

11.

Lozano E, Herraez E, Briz O, Robledo VS, Hernandez-Iglesias J, Gonzalez-Hernandez A, et al. Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. BioMed Res Int. 2013;2013:692071. doi:10.1155/2013/692071.PubMedCentralCrossRefPubMed

12.

Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther. 2011;10(3):531–9. doi:10.1158/1535-7163.mct-10-0731.PubMedCentralCrossRefPubMed

13.

Herraez E, Lozano E, Macias RI, Vaquero J, Bujanda L, Banales JM et al. The expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology (Baltimore, Md). 2013. doi:10.1002/hep.26425.

14.

Nardinelli L, Sanabani SS, Didone A, Ferreira Pde B, Serpa M, Novaes MM, et al. Pretherapeutic expression of the hOCT1 gene predicts a complete molecular response to imatinib mesylate in chronic-phase chronic myeloid leukemia. Acta Haematol. 2012;127(4):228–34. doi:10.1159/000336610.CrossRefPubMed

15.

Chan SL, Mo FK, Johnson PJ, Hui EP, Ma BB, Ho WM, et al. New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol. 2009;27(3):446–52. doi:10.1200/jco.2008.18.8151.CrossRefPubMed

16.

Personeni N, Bozzarelli S, Pressiani T, Rimassa L, Tronconi MC, Sclafani F, et al. Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2012;57(1):101–7. doi:10.1016/j.jhep.2012.02.016.CrossRefPubMed

17.

Lautem A, Heise M, Grasel A, Hoppe-Lotichius M, Weiler N, Foltys D, et al. Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma. Int J Oncol. 2013;42(4):1297–304.PubMed

18.

Bazeos A, Marin D, Reid AG, Gerrard G, Milojkovic D, May PC, et al. hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia. Leukemia. 2010;24(6):1243–5.CrossRefPubMed

19.

Giannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S, et al. The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia. Blood. 2013;121(4):628–37.CrossRefPubMed

20.

Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, et al. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009;15(14):4750–8.CrossRefPubMed

21.

Maffioli M, Camos M, Gaya A, Hernandez-Boluda JC, Alvarez-Larran A, Domingo A, et al. Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia. Leuk Res. 2011;35(8):1014–9.CrossRefPubMed

22.

Weinmann A, Koch S, Niederle IM, Schulze-Bergkamen H, Konig J, Hoppe-Lotichius M, et al. Trends in Epidemiology, Treatment, and Survival of Hepatocellular Carcinoma Patients Between 1998 and 2009: An Analysis of 1066 Cases of a German HCC Registry. J Clin Gastroenterol. 2013. doi:10.1097/MCG.0b013e3182a8a793.

23.

Rich N, Singal AG. Hepatocellular carcinoma tumour markers: current role and expectations. Best Pract Res Clin Gastroenterol. 2014;28(5):843–53. doi:10.1016/j.bpg.2014.07.018.CrossRefPubMed

24.

Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 2013;43(2):147–54. doi:10.1111/j.1872-034X.2012.01113.x.PubMedCentralCrossRefPubMed

25.

Cucchetti A, Trevisani F, Pecorelli A, Erroi V, Farinati F, Ciccarese F et al. Estimation of lead-time bias and its impact on the outcome of surveillance for the early diagnosis of hepatocellular carcinoma. J Hepatol. 2014. doi:10.1016/j.jhep.2014.03.037.

26.

Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487–97. doi:10.1056/NEJMra050100.CrossRefPubMed