Determination of copper and other trace elements in serum samples from patients with biliary tract cancers: prospective noninterventional nonrandomized clinical study protocol

Rebersek, Martina; Hribernik, Nezka; Markovic, Katarina; Markovic, Stefan; Valentinuzzi, Katja Ursic; Cemazar, Maja; Zuliani, Tea; Milacic, Radmila; Scancar, Janez

doi:10.2478/raon-2024-0026

Abstract

Background

Biliary tract cancers (BTCs) are usually diagnosed at an advanced stage, when the disease is incurable. Currently used tumor biomarkers have limited diagnostic value for BTCs, so there is an urgent need for sensitive and specific biomarkers for their earlier diagnosis. Deregulation of the homeostasis of trace elements is involved in the carcinogenesis of different cancers, including BTCs. The objective of the study is to determine/compare the total concentrations of copper (Cu), zinc (Zn) and iron (Fe) and the proportions of free Cu and Cu bound to ceruloplasmin (Cp) and the isotopic ratio of ⁶⁵Cu/⁶³Cu in serum samples from healthy volunteers and cancer patients using inductively coupled plasma-mass spectrometry-based methods (ICP-MS).

Patients and methods

In this prospective, noninterventional, nonrandomized study 20 patients and 20 healthy volunteers will be enrolled to identify serum Cu, Zn and Fe levels, Cu isotopic fractionation as a predictive biomarker of response to systemic therapy of BTCs, which will be evaluated by computed tomography. Newly developed analytical methods based on ICP-MS will be applied to metal-based biomarker research in oncology.

Conclusions

In the study the comparison of the total concentration of selected trace elements, the proportion of free Cu and Cu bound to Cp and the isotopic ratio of ⁶⁵Cu/⁶³Cu in serum samples from healthy volunteers and cancer patients will be conducted to provide the foundation for the development of a BTC cancer screening methodology and the data on their usability as a potential predictive biomarker for BTCs of response to systemic therapy.

References

Bertuccio P, Malvezzi M, Carioli G, Hashim D, Boffetta P, El-Serag HB, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol 2019; 71: 104–14. doi: 10.1016/j.jhep.2019.03.013
Open DOI Search in Google Scholar Back to article
Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet 2021; 397: 428–44. doi: 10.1016/S0140-6736(21)00153-7
Open DOI Search in Google Scholar Back to article
Vogel A, Bridgewater J, Edeline J, Kelley RK, Klümpen HJ, Malka D, et al; ESMO Guidelines Committee. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34: 127–40. doi: 10.1016/j.annonc.2022.10.506
Open DOI Search in Google Scholar Back to article
National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Biliary tract cancers. V 3. [online]. 2023. [cited 2024 Feb 18]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
Search in Google Scholar Back to article
Cancer in Slovenia 2020. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Slovenian Cancer Registry; 2023.
Search in Google Scholar Back to article
Đokic M, Stupan U, Licen S, Trotovsek B. Residual disease in lymph nodes has no influence on survival in patients with incidental gallbladder cancer − institution experience with literature review. Radiol Oncol 2021; 56: 208–15. doi: 10.2478/raon-2021-0048
Open DOI Search in Google Scholar Back to article
Fostea RM, Fontana E, Torga G, Arkenau HT. Recent progress in the systemic treatment of advanced/metastatic cholangiocarcinoma. Cancers 2020; 12: 2599. doi: 10.3390/cancers12092599
Open DOI Search in Google Scholar Back to article
Mirallas O, López-Valbuena D, García-Illescas D, Fabregat-Franco C, Verdaguer H, Tabernero, et al. Advances in the systemic treatment of therapeutic approaches in biliary tract cancer. ESMO Open 2022;7: 100503. doi: 10.1016/j.esmoop.2022.100503
Open DOI Search in Google Scholar Back to article
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–81. doi: 10.1056/NEJMoa0908721
Open DOI Search in Google Scholar Back to article
Oh DY, He AR, Qin S, Chen T, Okusaka T, Arndt Vogel, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid 2022; 1: EVID 0a2200015. doi: 10.1056/EVIDoa2200015
Open DOI Search in Google Scholar Back to article
Ferreira CR, Gahl WA. Disorders of metal metabolism. Transl Sci Rare Dis 2017; 2: 101–39. doi: 10.3233/TRD-170015
Open DOI Search in Google Scholar Back to article
Morales M, Xue X. Targeting iron metabolism in cancer therapy. Theranostics 2021; 11: 8412–29. doi: 10.7150/thno.59092
Open DOI Search in Google Scholar Back to article
Stojsavljević, A, Vujotić L, Rovčanin B, Borković-Mitić S, Gavrović-Jankulović, Manojlović D. Assessment of trace metal alterations in the blood, cerebrospinal fluid and tissue samples of patients with malignant brain tumors. Sci Rep 2020; 10: 3816. doi: 10.1038/s41598-020-60774-0
Open DOI Search in Google Scholar Back to article
Lelièvre P, Sancey L, Coll JL, Deniaud A, Busser B. The multifaceted roles of copper in cancer: A trace metal element with dysregulated metabolism, but also a target or a bullet for therapy. Cancers 2020; 12: 3594. doi: 10.3390/cancers12123594
Open DOI Search in Google Scholar Back to article
Chen F, Han B, Meng Y, Han Y, Liu B, Zhang B, et al. Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer. Aging 2021; 13: 20438–67. doi: 10.18632/aging.203427
Open DOI Search in Google Scholar Back to article
Wang B, Wang XP. Does ceruloplasmin defend against neurodegenerative diseases? Curr Neuropharmacol 2019; 17: 539–49. doi: 10.2174/1570159X16666180508113025
Open DOI Search in Google Scholar Back to article
Linder MC. Ceruloplasmin and other copper binding components of blood plasma and their functions: an update. Metallomics 2016; 8: 887–905. doi: 10.1039/c6mt00103c
Open DOI Search in Google Scholar Back to article
Mukae Y, Ito H, Miyata Y, Araki K, Matsuda T, Aibara N, et al. Ceruloplasmin levels in cancer tissues and urine are significant biomarkers of pathological features and outcome in bladder cancer. Anticancer Res 2021; 41: 3815–23. doi: 10.21873/anticanres.15174
Open DOI Search in Google Scholar Back to article
Sogabe M, Kojima S, Kaya T, Tomioka A, Kaji H, Sato T, et al. Sensitive new assay system for serum wisteria floribunda agglutinin-reactive ceruloplasmin that distinguishes ovarian clear cell carcinoma from endometrioma. Anal Chem 2022; 94: 2476–84. doi: 10.1021/acs.analchem.1c04302
Open DOI Search in Google Scholar Back to article
Michalczyk K, Cymbaluk-Płoska A. The role of zinc and copper in gynecological malignancies. Nutrients 2020; 12: 3732. doi: 10.3390/nu12123732
Open DOI Search in Google Scholar Back to article
Woimant F, Djebrani-Oussedik N, Poujois A. New tools for Wilson’s disease diagnosis: exchangeablecopper fractio. Ann Transl Med 2019; 7(Suppl 2): S70. doi: 10.21037/atm.2019
Open DOI Search in Google Scholar Back to article
WHO Guidelines Review Committee, Nutrition and Food Safety (NFS). WHO guideline on use of ferritin concentrations to assess iron status in individuals and populations [Internet]. Geneva: World Health Organization 2020. [cited 2024 Jan 15]. Available at: https://www.who.int/publications/i/item/9789240000124. PMID: 33909381
Search in Google Scholar Back to article
Lossow K, Schwarz M, Kipp AP. Are trace element concentrations suitable biomarkers for the diagnosis of cancer? Redox Biol 2021; 42: 101900. doi: 10.1016/j.redox.2021.101900
Open DOI Search in Google Scholar Back to article
Chen F, Han B, Meng Y, Han Y, Liu B, Zhang B, et al. Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer. Aging 2021; 13: 20438–67. doi: 10.18632/aging.203427
Open DOI Search in Google Scholar Back to article
Balter V, Nogueira da Costa A, Bondanese VP, Jaouen K, Lamboux A, et al. Natural variations of copper and sulfur stable isotopes in blood of hepatocellular carcinoma patients. Proc Natl Acad Sci U S A 2015; 112: 982–5. doi: 10.1073/pnas.1415151112
Open DOI Search in Google Scholar Back to article
Hastuti AAMB, Costas-Rodríguez M, Matsunaga A, Ichinose T, Hagiwara S, Shimura M, et al. Cu and Zn isotope ratio variations in plasma for survival prediction in hematological malignancy cases. Sci Rep 2020; 10: 16389. doi: 10.1038/s41598-020-71764-7
Open DOI Search in Google Scholar Back to article
Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, et al. Connecting copper and cancer: from transition metal signaling to metalloplasia. Nat Rev Cancer 2022; 22: 102–13. doi: 10.1038/s41568-021-00417-2
Open DOI Search in Google Scholar Back to article
Wang J, Zhao H, Xu Z, Cheng X. Zinc dysregulation in cancers and its potential as a therapeutic target. Cancer Biol Med 2020; 17: 612–25. doi: 10.20892/j.issn.2095-3941.2020.0106
Open DOI Search in Google Scholar Back to article
Krężel A, Maret W. The biological inorganic chemistry of zinc ions. Arch Biochem Biophys 2016; 611: 3–19. doi: 10.1016/j.abb.2016.04.010
Open DOI Search in Google Scholar Back to article
Infusino I, Valente C, Dolci A, Panteghini M. Standardization of ceruloplasmin measurements is still an issue despite the availability of a common reference material. Anal Bioanal Chem 2009; 397: 521–5. doi: 10.1007/s00216-009-3248-0
Open DOI Search in Google Scholar Back to article
Quarles CD, Macke M Jr, Michalke B, Zischka H, Karst U, Sullivan P, et al. LC-ICP-MS method for the determination of “extractable copper” in serum. Metallomics 2020; 12: 1348–55. doi: 10.1039/d0mt00132e
Open DOI Search in Google Scholar Back to article
Neselioglu S, Ergin M, Erel O. A new kinetic, automated assay to determine the ferroxidase activity of ceruloplasmin. Anal Sci 2017; 33: 1339–44. doi: 10.2116/analsci.33.1339
Open DOI Search in Google Scholar Back to article
Solovyev N, Ala A, Schilsky M, Mills C, Willis, K, Harrington C F. Biomedical copper speciation in relation to Wilson’s disease using strong anion exchange chromatography coupled to triple quadrupole inductively coupled plasma-mass spectrometry. Anal. Chim Acta 2020; 1098: 27–36. doi: 10.1016/j.aca.2019.11.033
Open DOI Search in Google Scholar Back to article
Bernevic B, El-Khatib AH, Jakubowski N, Weller MG. Online immunocapture ICP-MS for the determination of the metalloprotein ceruloplasmin in human serum. BMC Res Notes 2018; 11: doi:10.1186/s13104-018-3324-7
Open DOI Search in Google Scholar Back to article
Marković K, Milačič R, Vidmar J, Marković S, Uršič K, Nikšić Žakelj M, et al. Monolithic chromatography on conjoint liquid chromatography columns for speciation of platinum-based chemotherapeutics in serum of cancer patients. J Trace Elem Med Biol 2020; 57: 28–39. doi: 10.1016/j.jtemb.2019.09.011
Open DOI Search in Google Scholar Back to article
Marković K, Milačič R, Marković S, Kladnik J, Turel I, Ščančar J. Binding kinetics of ruthenium pyrithione chemotherapeutic candidates to human serum proteins studied by HPLC-ICP-MS. Molecules 2020; 25: 1512–3. doi: cules25071512
Search in Google Scholar Back to article
Martinčič A, Čemažar M, Serša G, Kovač V, Milačič R, Ščančar J. A novel method for speciation of Pt in human serum incubated with cisplatin, oxaliplatin and carboplatin by conjoint liquid chromatography on monolithic disks with UV and ICP-MS detection. Talanta 2013; 116: 141–8, doi: 10.1016/j.talanta.2013.05.016
Open DOI Search in Google Scholar Back to article
Martinčič A, Milačič R, Vidmar J, Turel I, Keppler BK, Ščančar J. New method for the speciation of Ru-based chemotherapeutics in human serum by conjoint liquid chromatography on affinity and anion-exchange monolithic disks. J Chromatogr A 2014; 1371: 168–76. doi: 10.1016/j.chroma.2014.10.054
Open DOI Search in Google Scholar Back to article
Marković K, Cemazar M, Sersa G, Milačič R, Ščančar J. Speciation of copper in human serum using conjoint liquid chromatography on short-bed monolithic disks with UV and post column ID-ICP-MS detection. J Anal At Spectrom 2022; 37: 1675–86. doi: 10.1039/D2JA00161F
Open DOI Search in Google Scholar Back to article
Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1-Update and clarification: from the RECIST committee. Eur J Cancer 2016; 62:132–7. doi: 10.1016/j.ejca.2016.03.081
Open DOI Search in Google Scholar Back to article
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017; 18: e143–e52. doi: 10.1016/S1470-2045(17)30074-8. Erratum in: Lancet Oncol 2019; 20: e242.
Open DOI Search in Google Scholar Back to article
National Cancer Institute (NCI). NCI common terminology criteria for adverse events (CTCAE). Version 5.0.2021. [cited 2024 Feb 18]. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x11.pdf
Search in Google Scholar Back to article

Determination of copper and other trace elements in serum samples from patients with biliary tract cancers: prospective noninterventional nonrandomized clinical study protocol

Abstract

Background

Patients and methods

Conclusions

Paradigm

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