. Diagnostic value and therapeutic efficacy of serum levels of Pro-Gastrin-releasing peptide precursor (ProGRP) and neuron-specific enolase (NSE) small cell lung cancer
serum levels of Pro-Gastrin-releasing peptide precursor (ProGRP) and neuron-specific enolase (NSE
Abstract
Background: One of the most prevalent malignant tumors in China is primary lung cancer. This condition can be broadly categorized into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is a type of neuroendocrine tumor highly malignant, undifferentiated, and prone to metastasis. In its early stages, SCLC typically does not present with noticeable symptoms. It is usually diagnosed when the disease has progressed to the middle or late stage. Therefore, early diagnosis is pivotal for enhancing the outcome of SCLC. Pro-Gastrin-releasing peptide precursor (ProGRP) and neuron-specific enolase (NSE) are tumor markers recommended by guidelines for SCLC. This study investigates the diagnostic value and efficacy of ProGRP and NSE serum levels in the context of SCLC, with the intention of providing more valuable references for SCLC diagnosis.
Objective: The purpose of this research is to probe the diagnostic value and therapeutic efficacy of serum levels of ProGRP and NSE in SCLC, with the aim of enhancing the level of clinical diagnosis.
Methods: A total of 84 SCLC patients who were admitted to our hospital from December 2022 to March 2024 were included in the SCLC group. The NSCLC group consisted of 45 patients diagnosed with NSCLC, while the benign lung disease group consisted of 57 patients diagnosed with non-cancerous lung conditions. Furthermore, the healthy control group comprised 60 healthy individuals. The serum levels of ProGRP and NSE were compared across all four groups. Moreover, the concentrations of ProGRP and NSE were compared between patients diagnosed with limited-stage and extensive-stage SCLC. The sensitivity and specificity of serum ProGRP and NSE levels for diagnosing SCLC were analyzed via ROC curve analysis. The critical value of the ROC curve was adopted as the grouping standard, and the clinical efficacy of different levels of serum ProGRP and NSE in SCLC patients was compared. Finally, the correlation between serum ProGRP and NSE levels and age, gender, smoking history, staging, distant metastasis, and tumor diameter in SCLC patients was evaluated.
Results: The concentrations of serum ProGRP and NSE were observed in different groups. The findings confirmed that the SCLC group exhibited considerably elevated levels of serum ProGRP and NSE in comparison to the healthy control group, benign lung disease group, and NSCLC group, with the variance regarded as substantially significant (P<0.05). ProGRP and NSE values were found to be higher in limited-stage SCLC compared to extensive-stage SCLC, and the difference between the groups held remarkable statistical significance (P<0.05). The ROC curve displayed that the critical value of ProGRP for diagnosing SCLC was 136.49pg/mL, the area under the curve (AUC) was 0.869, the sensitivity attained 80.00%, and the specificity reached 84.87%, indicating a diagnostic efficacy better than that of NSE (P<0.05). Additionally, following two cycles of chemotherapy, the low-level ProGRP group exhibited a superior therapeutic effect compared to the high-level ProGRP group (P<0.05), but the two groups did not manifest remarkable statistical difference in terms of PFS (P>0.05). No statistically meaningful variance was detected in PFS and therapeutic effect between the low-level NSE group and the high-level NSE group (P>0.05). Subsequent to further analysis of the correlation between serum ProGRP and NSE levels and age, gender, smoking history, staging, and so on, it was unraveled that their levels did not significantly correlate with the patient’s age, gender or smoking history (P>0.05) but were evidently associated with staging. ProGRP and NSE levels were discovered to be higher in extensive-stage SCLC when compared to limited-stage SCLC. Moreover, in SCLC patients with lymph node metastasis and a tumor diameter ≥ 5 cm, the serum levels of ProGRP and NSE were higher than in patients without lymph node metastasis and with a tumor diameter < 5 cm, and the difference was considered statistically meaningful (P<0.05).
Conclusion: The levels of tumor markers ProGRP and NSE are of paramount significance for the clinical diagnosis and staging of SCLC patients. ProGRP is a more specific and sensitive tumor marker for SCLC than NSE and can be employed as an auxiliary diagnostic tool for SCLC. Thus, it is worth promoting ProGRP in a clinical setting.
References
[1]van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011 Nov 12;378(9804):1741-55. doi: 10.1016/S0140-6736(11)60165-7. Epub 2011 May 10. PMID: 21565397.
[2]Wang Y, Zou S, Zhao Z, Liu P, Ke C, Xu S. New insights into small-cell lung cancer development and therapy. Cell Biol Int. 2020 Aug;44(8):1564-1576. doi: 10.1002/cbin.11359. Epub 2020 Apr 18. PMID: 32281704.
[3]Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018 Jan 24;553(7689):446-454. doi: 10.1038/nature25183. PMID: 29364287.
[4]Zugazagoitia J, Paz-Ares L. Extensive-Stage Small-Cell Lung Cancer: First-Line and Second-Line Treatment Options. J Clin Oncol. 2022 Feb 20;40(6):671-680. doi: 10.1200/JCO.21.01881. Epub 2022 Jan 5. PMID: 34985925.
[5]Ganti AKP, Loo BW, Bassetti M, Blakely C, Chiang A, D'Amico TA,et al. Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021 Dec;19(12):1441-1464. doi: 10.6004/jnccn.2021.0058. PMID: 34902832.
[6]Bernhardt EB, Jalal SI. Small Cell Lung Cancer. Cancer Treat Res. 2016;170:301-22. doi: 10.1007/978-3-319-40389-2_14. PMID: 27535400.
[7]Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017 Dec;17(12):725-737. doi: 10.1038/nrc.2017.87. Epub 2017 Oct 27. Erratum in: Nat Rev Cancer. 2017 Nov 10;: PMID: 29077690.
[8]Kiseli M, Caglar GS, Yarci Gursoy A, Tasci T, Candar T, Akincioglu E,et al. Pro-Gastrin Releasing Peptide: A New Serum Marker for Endometrioid Adenocarcinoma. Gynecol Obstet Invest. 2018;83(6):540-545. doi: 10.1159/000488854. Epub 2018 Jun 13. PMID: 29898448.
[9]Fang L, Huang Z, Lin Y, Fu J, Liang X, Liu F. Clinical Application of Pro-Gastrin-Releasing Peptide. Clin Lab. 2018 Jul 1;64(7):1259-1268. doi: 10.7754/Clin.Lab.2018.180316. PMID: 30146822.
[10]Ueland T, Gullestad L, Kou L, Aukrust P, Anand IS, Broughton MN, McMurray JJ, van Veldhuisen DJ, Warren DJ, Bolstad N. Pro-gastrin-releasing peptide and outcome in patients with heart failure and anaemia: results from the RED-HF study. ESC Heart Fail. 2018 Dec;5(6):1052-1059. doi: 10.1002/ehf2.12312. Epub 2018 Aug 25. PMID: 30145817.
[11]Isgrò MA, Bottoni P, Scatena R. Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects. Adv Exp Med Biol. 2015;867:125-43. doi: 10.1007/978-94-017-7215-0_9. PMID: 26530364.
[12]Haque A, Ray SK, Cox A, Banik NL. Neuron specific enolase: a promising therapeutic target in acute spinal cord injury. Metab Brain Dis. 2016 Jun;31(3):487-95. doi: 10.1007/s11011-016-9801-6. Epub 2016 Feb 5. PMID: 26847611.
[13]Xu CM, Luo YL, Li S, Li ZX, Jiang L, Zhang GX, Owusu L, Chen HL. Multifunctional neuron-specific enolase: its role in lung diseases. Biosci Rep. 2019 Nov 29;39(11):BSR20192
[14]Chen KN. [Small Cell Lung Cancer and TNM Staging]. Zhongguo Fei Ai Za Zhi. 2016 Jun 20;19(6):409-12. Chinese. doi: 10.3779/j.issn.1009-3419.2016.06.22. PMID: 27335307.
[15]Avasarala SK, Rickman OB. Endobronchial Therapies for Diagnosis, Staging, and Treatment of Lung Cancer. Surg Clin North Am. 2022 Jun;102(3):393-412. doi: 10.1016/j.suc.2022.01.004. Epub 2022 Apr 21. PMID: 35671763.
[16]Conforti F, Pala L, Vivanet G, Corti C, Catania C, Maiettini D, Varano G, Di Venosa B, Curigliano G, Salvini P, Berardi R, Ballatore Z, De Pas TM. High-dose continuous-infusion ifosfamide in advanced thymic epithelial Tumors: A TYME network study. Lung Cancer. 2023 Feb;176:98-102. doi: 10.1016/j.lungcan.2023.01.004. Epub 2023 Jan 7. PMID: 36630822.
[17]Tran S, Bielle F. WHO 2021 and beyond: new types, molecular markers and tools for brain tumor classification. Curr Opin Oncol. 2022 Nov 1;34(6):670-675. doi: 10.1097/CCO.0000000000000903. Epub 2022 Sep 12. PMID: 36093875.
[18]Wang WZ, Shulman A, Amann JM, Carbone DP, Tsichlis PN. Small cell lung cancer: Subtypes and therapeutic implications. Semin Cancer Biol. 2022 Nov;86(Pt 2):543-554. doi: 10.1016/j.semcancer.2022.04.001. Epub 2022 Apr 6. PMID: 35398266.
[19]Takada M, Kusunoki Y, Masuda N, Matui K, Yana T, Ushijima S, Iida K, Tamura K, Komiya T, Kawase I, Kikui N, Morino H, Fukuoka M. Pro-gastrin-releasing peptide (31-98) as a tumour marker of small-cell lung cancer: comparative evaluation with neuron-specific enolase. Br J Cancer. 1996 May;73(10):1227-32. doi: 10.1038/bjc.1996.235. PMID: 8630283.
[20]Ischia J, Patel O, Sethi K, Nordlund MS, Bolton D, Shulkes A, Baldwin GS. Identification of binding sites for C-terminal pro-gastrin-releasing peptide (GRP)-derived peptides in renal cell carcinoma: a potential target for future therapy. BJU Int. 2015 May;115(5):829-38. doi: 10.1111/bju.12886. Epub 2015 Jan 26. PMID: 25130393.
[21]Echeverría-Palacio CM, Agut T, Arnaez J, Valls A, Reyne M, Garcia-Alix A. Neuron-Specific Enolase in Cerebrospinal Fluid Predicts Brain Injury After Sudden Unexpected Postnatal Collapse. Pediatr Neurol. 2019 Dec;101:71-77. doi: 10.1016/j.pediatrneurol.2019.02.020. Epub 2019 Mar 5. PMID: 31023601.
[22]Topuzova MP, Alekseeva TM, Panina EB, Vavilova TV, Kovzelev PD, Portik OA, Skoromets AA. Vozmozhnost' ispol'zovaniia neĭron-spetsificheskoĭ enolazy kak biomarkera v ostrom periode insul'ta [The possibility of using neuron-specific enolase as a biomarker in the acute period of stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(8. Vyp. 2):53-62. Russian. doi: 10.17116/jnevro201911908253. PMID: 31825363.
[23]Sosnin DY, Gal'kovich KR, Khovaeva YB, Gil'manov AZ. Comparative Content of Neuron-Specific Enolase in Human Blood Serum and Seminal Plasma. Bull Exp Biol Med. 2022 Jul;173(3):298-301. doi: 10.1007/s10517-022-05537-9. Epub 2022 Jul 18. PMID: 35844024.
[24]Kamata K, Uchida M, Takeuchi Y, Takahashi E, Sato N, Miyake Y, Okubo M, Kodama T, Yamaguchi K. Increased serum concentrations of pro-gastrin-releasing peptide in patients with renal dysfunction. Nephrol Dial Transplant. 1996 Jul;11(7):1267-70. PMID: 8672021.
[25]Dong J, Tong S, Shi X, Wang C, Xiao X, Ji W,.et al. Progastrin-Releasing Peptide Precursor and Neuron-Specific Enolase Predict the Efficacy of First-Line Treatment with Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors Among Non-Small-Cell Lung Cancer Patients Harboring EGFR Mutations. Cancer Manag Res. 2021 Jan 5;12:13607-13616. doi: 10.2147/CMAR.S285121. PMID: 33447080.
[26]Wójcik E, Kulpa JK, Sas-Korczyńska B, Korzeniowski S, Jakubowicz J. ProGRP and NSE in therapy monitoring in patients with small cell lung cancer. Anticancer Res. 2008 Sep-Oct;28(5B):3027-33. PMID: 19031951.
[27]Winther B, Moi P, Paus E, Reubsaet JL. Targeted determination of the early stage SCLC specific biomarker pro-gastrin-releasing peptide (ProGRP) at clinical concentration levels in human serum using LC-MS. J Sep Sci. 2007 Nov;30(16):2638-46. doi: 10.1002/jssc.200700221. PMID: 17874417.
[28]Rossetti C, Abdel Qader A, Halvorsen TG, Sellergren B, Reubsaet L. Antibody-free biomarker determination: exploring molecularly imprinted polymers for pro-gastrin releasing peptide. Anal Chem. 2014 Dec 16;86(24):12291-8. doi: 10.1021/ac503559c. Epub 2014 Nov 26. PMID: 25397409.
[29]Marangos PJ, Schmechel DE. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci. 1987;10:269-95. doi: 10.1146/annurev.ne.10.030187.001413. PMID: 3551759.
[30]Endo T, Hasegawa T, Tezuka Y, Kanai Y, Otani S, Yamamoto S, Tetsuka K, Sato Y, Endo S, Sohara Y. [Atypical pulmonary carcinoid tumor with abnormal elevation of serum gastrin-releasing peptide precursor: report of a case]. Kyobu Geka. 2008 Oct;61(11):993-5. Japanese. PMID: 18939440.
[31]Okusaka T, Eguchi K, Kasai T, Kurata T, Yamamoto N, Ohe Y, Tamura T, Shinkai T, Saijo N. Serum levels of pro-gastrin-releasing peptide for follow-up of patients with small cell lung cancer. Clin Cancer Res. 1997 Jan;3(1):123-7. PMID: 9815547.
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