hPG80 (Circulating Progastrin), a Novel Blood-Based Biomarker for Detection of Poorly Differentiated Neuroendocrine Carcinoma and Well Differentiated Neuroendocrine Tumors

Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Léa Payen, Younes Mahi, Berengere Vire, Madison Sands, B Mark Evers, Dominique Joubert, Lowell Anthony, Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Léa Payen, Younes Mahi, Berengere Vire, Madison Sands, B Mark Evers, Dominique Joubert, Lowell Anthony

Abstract

Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. Plasma hPG80 was quantified from 95 stage IV NEN patients, using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in two cohorts of healthy donor controls aged 50-80 (n = 252) and 18-25 (n = 137). Median hPG80 in NENs patients was 5.54 pM compared to 1.5 pM for the 50-80 controls and 0.29 pM the 18-25 cohort (p < 0.0001). Subgroup analysis revealed median hPG80 levels significantly higher than for either control cohort in neuroendocrine carcinoma (NEC; n = 25) and neuroendocrine tumors (NET; n = 70) including the small-cell lung cancer (SCLC) sub-cohort (n = 13). Diagnostic accuracy, estimated by AUCs, was high for NENs, as well as both sub-groups (NEC/NET) when compared to the younger and older control groups. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low- and high-grade NENs; further study is warranted. A prospective multi-center trial is ongoing in NET to evaluate hPG80 as a means of monitoring disease (NCT04750954).

Keywords: blood-based diagnostic biomarker; circulating progastrin; hPG80; neuroendocrine carcinoma; neuroendocrine neoplasms; neuroendocrine tumors; small-cell carcinoma.

Conflict of interest statement

The employees of ECS Progastrin are A.P., Y.M., B.V. and D.J. Those with no competing interest are J.K., S.A., L.P., M.S., B.M.E. and L.A.

Figures

Figure 1
Figure 1
Diagnostic performance of hPG80 in (A) NENs, NEC and NET patient cohorts, (B) by tumor grade, (C) by tumor site as compared to the 18–25-year-old and 50–80-year-old.
Figure 2
Figure 2
Diagnostic accuracy, estimated by the Receiver Operator Characteristic (ROC) Area Under the Curve (AUC)s, is 0.89 for all NENs (A), 0.92 for NECs (B), and 0.87 for NETs (C) when compared to the young 18–25 y control group (square); for the older 50–80 y cohort, the values were 0.75 for all NENs (A), 0.75 for NECs (B), and 0.74 for NETs (C) (triangles).
Figure 3
Figure 3
Sensitivity of hPG80 in the all-patient (neuroendocrine neoplasm) cohorts with a specificity set at 90% as compared to (A) 18–25 y control group and (B) 50–80 y control group.

References

    1. Chauhan A., Kohn E., Del Rivero J. Neuroendocrine Tumors-Less Well Known, Often Misunderstood, and Rapidly Growing in Incidence. JAMA Oncol. 2020;6:21–22. doi: 10.1001/jamaoncol.2019.4568.
    1. Dasari A., Shen C., Halperin D., Zhao B., Zhou S., Xu Y., Shih T., Yao J.C. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients with Neuroendocrine Tumors in the United States. JAMA Oncol. 2017;3:1335–1342. doi: 10.1001/jamaoncol.2017.0589.
    1. Oberg K., Modlin I.M., De Herder W., Pavel M., Klimstra D., Frilling A., Metz D.C., Heaney A., Kwekkeboom D., Strosberg J., et al. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol. 2015;16:e435–e446. doi: 10.1016/S1470-2045(15)00186-2.
    1. Rehfeld J.F., Zhu X., Norrbom C., Bundgaard J.R., Johnsen A.H., Nielsen J.E., Vikesaa J., Stein J., Dey A., Steiner D.F., et al. Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17. Biochem. J. 2008;415:35–43. doi: 10.1042/BJ20080881.
    1. Varro A., Voronina S., Dockray G.J. Pathways of processing of the gastrin precursor in rat antral mucosa. J. Clin. Investig. 1995;95:1642–1649. doi: 10.1172/JCI117839.
    1. Siddheshwar R.K., Gray J.C., Kelly S.B. Plasma levels of progastrin but not amidated gastrin or glycine extended gastrin are elevated in patients with colorectal carcinoma. Gut. 2001;48:47–52. doi: 10.1136/gut.48.1.47.
    1. Kohli M., Tan W., Vire B., Liaud P., Blairvacq M., Berthier F., Rouison D., Garnier G., Payen L., Cousin T., et al. Prognostic Value of Plasma hPG80 (Circulating Progastrin) in Metastatic Renal Cell Carcinoma. Cancers. 2021;13:375. doi: 10.3390/cancers13030375.
    1. You B., Mercier F., Assenat E., Langlois-Jacques C., Glehen O., Soule J., Payen L., Kepenekian V., Dupuy M., Belouin F., et al. The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients. EBioMedicine. 2019;51:102574. doi: 10.1016/j.ebiom.2019.11.035.
    1. Prieur A., Cappellini M., Habif G., Lefranc M.P., Mazard T., Morency E., Pascussi J.M., Flaceliere M., Cahuzac N., Vire B., et al. Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer. Clin. Cancer Res. 2017;23:5267–5280. doi: 10.1158/1078-0432.CCR-17-0533.
    1. Kim J.T., Li J., Jang E.R., Gulhati P., Rychahou P.G., Napier D.L., Wang C., Weiss H.L., Lee E.Y., Anthony L., et al. Deregulation of Wnt/beta-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors. Carcinogenesis. 2013;34:953–961. doi: 10.1093/carcin/bgt018.
    1. Giraud J., Failla L.M., Pascussi J.M., Lagerqvist E.L., Ollier J., Finetti P., Bertucci F., Ya C., Gasmi I., Bourgaux J.F., et al. Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells. Cancer Res. 2016;76:3618–3628. doi: 10.1158/0008-5472.CAN-15-1497.
    1. Hollande F., Lee D.J., Choquet A., Roche S., Baldwin G.S. Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells. J. Cell Sci. 2003;116:1187–1197. doi: 10.1242/jcs.00321.
    1. Pannequin J., Delaunay N., Buchert M., Surrel F., Bourgaux J.F., Ryan J., Boireau S., Coelho J., Pélegrin A., Singh P., et al. β-Catenin/Tcf-4 Inhibition after Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors. Gastroenterology. 2007;133:1554–1568. doi: 10.1053/j.gastro.2007.08.023.
    1. Singh P., Owlia A., Varro A., Dai B., Rajaraman S., Wood T. Gastrin gene expression is required for the proliferation and tumorigenicity of human colon cancer cells. Cancer Res. 1996;56:4111–4115.
    1. White M.C., Holman D.M., Boehm J.E., Peipins L.A., Grossman M., Henley S.J. Age and cancer risk: A potentially modifiable relationship. Am. J. Prev. Med. 2014;46:S7–S15. doi: 10.1016/j.amepre.2013.10.029.
    1. Cappellini M., Flaceliere M., Saywell V., Soule J., Blanc E., Belouin F., Ortiz E., Canterel-Thouennon L., Poupeau S., Tigrett S., et al. A novel method to detect hPG80 (human circulating progastrin) in the blood. Anal. Methods. 2021;13:4468–4477. doi: 10.1039/D1AY00986A.
    1. Rindi G., Klimstra D.S., Abedi-Ardekani B., Asa S.L., Bosman F.T., Brambilla E., Busam K.J., de Krijger R.R., Dietel M., El-Naggar A.K., et al. A common classification framework for neuroendocrine neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod. Pathol. 2018;31:1770–1786. doi: 10.1038/s41379-018-0110-y.
    1. Oronsky B., Ma P.C., Morgensztern D., Carter C.A. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia. 2017;19:991–1002. doi: 10.1016/j.neo.2017.09.002.
    1. Herrera-Martinez A.D., Hofland L.J., Galvez Moreno M.A., Castano J.P., de Herder W.W., Feelders R.A. Neuroendocrine neoplasms: Current and potential diagnostic, predictive and prognostic markers. Endocr. Relat. Cancer. 2019;26:R157–R179. doi: 10.1530/ERC-18-0354.
    1. Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J. Gastrointest. Oncol. 2020;12:791–807. doi: 10.4251/wjgo.v12.i8.791.
    1. Modlin I.M., Gustafsson B.I., Moss S.F., Pavel M., Tsolakis A.V., Kidd M. Chromogranin A—Biological function and clinical utility in neuro endocrine tumor disease. Ann. Surg. Oncol. 2010;17:2427–2443. doi: 10.1245/s10434-010-1006-3.
    1. Walenkamp A., Crespo G., Fierro Maya F., Fossmark R., Igaz P., Rinke A., Tamagno G., Vitale G., Oberg K., Meyer T. Hallmarks of gastrointestinal neuroendocrine tumours: Implications for treatment. Endocr. Relat. Cancer. 2014;21:R445–R460. doi: 10.1530/ERC-14-0106.
    1. Malczewska A., Kos-Kudla B., Kidd M., Drozdov I., Bodei L., Matar S., Oberg K., Modlin I.M. The clinical applications of a multigene liquid biopsy (NETest) in neuroendocrine tumors. Adv. Med. Sci. 2020;65:18–29. doi: 10.1016/j.advms.2019.10.002.
    1. Ma Z.Y., Gong Y.F., Zhuang H.K., Zhou Z.X., Huang S.Z., Zou Y.P., Huang B.W., Sun Z.H., Zhang C.Z., Tang Y.Q., et al. Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management. World J. Gastroenterol. 2020;26:2305–2322. doi: 10.3748/wjg.v26.i19.2305.
    1. Nusse R., Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017;169:985–999. doi: 10.1016/j.cell.2017.05.016.
    1. Jiang X., Cao Y., Li F., Su Y., Li Y., Peng Y., Cheng Y., Zhang C., Wang W., Ning G. Targeting beta-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours. Nat. Commun. 2014;5:5809. doi: 10.1038/ncomms6809.
    1. Cao Y., Zhou W., Li L., Wang J., Gao Z., Jiang Y., Jiang X., Shan A., Bailey M.H., Huang K.L., et al. Pan-cancer analysis of somatic mutations across 21 neuroendocrine tumor types. Cell Res. 2018;28:601–604. doi: 10.1038/s41422-018-0019-5.
    1. Koh T.J., Chen D. Gastrin as a growth factor in the gastrointestinal tract. Regul. Pept. 2000;93:37–44. doi: 10.1016/S0167-0115(00)00176-2.

Source: PubMed

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