Skip to main content

Advertisement

SpringerLink
Log in

Resistin is associated with overall survival in non-small cell lung cancer patients during nivolumab treatment

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Since the role of resistin was evaluated only in patients with non-small cell lung cancer (NSCLC) not treated with immunotherapy, we aimed to evaluate levels of resistin during immunotherapy (nivolumab) and its prognostic role with regard to OS.

Methods/patients

From a cohort of 78 patients with advanced NSCLC enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 43 patients have been considered for this sub-analysis because of the availability of samples. Before and during nivolumab administration, clinical information and blood samples were collected and resistin, matrix metalloproteinase (MMP)-8, MMP-9, and myeloperoxidase were evaluated by enzyme-linked immunosorbent assay (ELISA).

Results

Median age was 71 with a prevalence of males and former smokers. Median resistin levels presented a peak at cycle 2 and then dropped down until the last cycle. Resistin correlated with all neutrophil degranulation products at cycle 1 (except for MMP-9) and at cycle 2 as well as with white blood cells and neutrophils. By a ROC curve analysis, a resistin value at cycle 2 of 19 ng/mL was tested as the best cut-off point for OS. Kaplan–Meier analysis demonstrated that patients above the resistin cut-off experienced a reduced OS (median OS 242.5 vs. 470 days, p = 0.0073), as confirmed by Cox proportional hazards regression analysis.

Conclusions

Resistin levels > 19 ng/mL at the time of the second cycle of nivolumab treatment independently predict a reduced OS in patients with advanced NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  2. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced non-squamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. https://doi.org/10.1056/NEJMoa1504627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Derosa G, Fogari E, D'Angelo A, Bianchi L, Bonaventura A, Romano D, et al. Adipocytokine levels in obese and non-obese subjects: an observational study. Inflammation. 2013;36(4):914–20. https://doi.org/10.1007/s10753-013-9620-4.

    Article  CAS  PubMed  Google Scholar 

  5. Liberale L, Bonaventura A, Vecchie A, Casula M, Dallegri F, Montecucco F, et al. The role of adipocytokines in coronary atherosclerosis. Curr Atheroscler Rep. 2017;19(2):10. https://doi.org/10.1007/s11883-017-0644-3.

    Article  CAS  PubMed  Google Scholar 

  6. Liberale L, Bertolotto M, Carbone F, Contini P, Wust P, Spinella G, et al. Resistin exerts a beneficial role in atherosclerotic plaque inflammation by inhibiting neutrophil migration. Int J Cardiol. 2018;272:13–9. https://doi.org/10.1016/j.ijcard.2018.07.112.

    Article  PubMed  Google Scholar 

  7. Gong WJ, Liu JY, Yin JY, Cui JJ, Xiao D, Zhuo W, et al. Resistin facilitates metastasis of lung adenocarcinoma through the TLR4/Src/EGFR/PI3K/NF-kappaB pathway. Cancer Sci. 2018;109(8):2391–400. https://doi.org/10.1111/cas.13704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kuo CH, Chen KF, Chou SH, Huang YF, Wu CY, Cheng DE, et al. Lung tumor-associated dendritic cell-derived resistin promoted cancer progression by increasing Wolf–Hirschhorn syndrome candidate 1/Twist pathway. Carcinogenesis. 2013;34(11):2600–9. https://doi.org/10.1093/carcin/bgt281.

    Article  CAS  PubMed  Google Scholar 

  9. Zhao CC, Chen J, Niu RF, Liu Y, Zhang CG. Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma. Oncol Rep. 2018;40(6):3392–404. https://doi.org/10.3892/or.2018.6736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Karapanagiotou EM, Tsochatzis EA, Dilana KD, Tourkantonis I, Gratsias I, Syrigos KN. The significance of leptin, adiponectin, and resistin serum levels in non-small cell lung cancer (NSCLC). Lung Cancer. 2008;61(3):391–7. https://doi.org/10.1016/j.lungcan.2008.01.018.

    Article  PubMed  Google Scholar 

  11. Sarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, et al. Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist. 2018;23(8):936–42. https://doi.org/10.1634/theoncologist.2017-0452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bonaventura A, Grossi F, Carbone F, Vecchie A, Minetti S, Bardi N, et al. Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study. Cancer Immunol Immunother CII. 2019;68(8):1351–8. https://doi.org/10.1007/s00262-019-02367-z.

    Article  CAS  PubMed  Google Scholar 

  13. Carbone F, Grossi F, Bonaventura A, Vecchie A, Minetti S, Bardi N, et al. Baseline serum levels of osteopontin predict clinical response to treatment with nivolumab in patients with non-small cell lung cancer. Clin Exp Metastasis. 2019;36(5):449–56. https://doi.org/10.1007/s10585-019-09984-z.

    Article  CAS  PubMed  Google Scholar 

  14. Bonaventura A, Liberale L, Carbone F, Vecchie A, Bonomi A, Scopinaro N, et al. Baseline neutrophil-to-lymphocyte ratio is associated with long-term T2D remission after metabolic surgery. Acta Diabetol. 2019. https://doi.org/10.1007/s00592-019-01345-2.

    Article  PubMed  Google Scholar 

  15. Bonaventura A, Carbone F, Liberale L, Mach F, Roth A, Burger F, et al. Platelet-to-lymphocyte ratio at the time of carotid endarterectomy is associated with acute coronary syndrome occurrence. J Cardiovasc Med (Hagerstown). 2019. https://doi.org/10.2459/JCM.0000000000000869.

    Article  Google Scholar 

  16. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liberale L, Bonaventura A, Carbone F, Bertolotto M, Contini P, Scopinaro N, et al. Early reduction of matrix metalloproteinase-8 serum levels is associated with leptin drop and predicts diabetes remission after bariatric surgery. Int J Cardiol. 2017;245:257–62. https://doi.org/10.1016/j.ijcard.2017.07.044.

    Article  PubMed  Google Scholar 

  18. Nicolas-Avila JA, Adrover JM, Hidalgo A. Neutrophils in homeostasis, immunity, and cancer. Immunity. 2017;46(1):15–28. https://doi.org/10.1016/j.immuni.2016.12.012.

    Article  CAS  PubMed  Google Scholar 

  19. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16(3):183–94. https://doi.org/10.1016/j.ccr.2009.06.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bonaventura A, Montecucco F, Dallegri F, Carbone F, Luscher TF, Camici GG, et al. Novel findings in neutrophil biology and their impact on cardiovascular disease. Cardiovasc Res. 2019. https://doi.org/10.1093/cvr/cvz084.

    Article  PubMed  Google Scholar 

  21. Kargl J, Busch SE, Yang GH, Kim KH, Hanke ML, Metz HE, et al. Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun. 2017;8:14381. https://doi.org/10.1038/ncomms14381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Peng B, Wang YH, Liu YM, Ma LX. Prognostic significance of the neutrophil to lymphocyte ratio in patients with non-small cell lung cancer: a systemic review and meta-analysis. Int J Clin Exp Med. 2015;8(3):3098–106.

    PubMed  PubMed Central  Google Scholar 

  23. Eruslanov EB. Phenotype and function of tumor-associated neutrophils and their subsets in early-stage human lung cancer. Cancer Immunol Immunother CII. 2017;66(8):997–1006. https://doi.org/10.1007/s00262-017-1976-0.

    Article  CAS  PubMed  Google Scholar 

  24. Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung cancer. 2017;111:176–81. https://doi.org/10.1016/j.lungcan.2017.07.024.

    Article  PubMed  Google Scholar 

Download references

Funding

This study has been supported by a grant from the Italian Ministry of Health to the Italian Cardiovascular Network (#2754291) and a Grant from the Fondazione CARIGE to Prof. Montecucco. Simona Coco is a PhD supported by a Grant from Italian Ministry of Health (Ricerca Corrente).

Author information

Author notes

  1. A. Bonaventura and F. Grossi have equally contributed as first authors.

  2. C. Genova and F. Montecucco have equally contributed as last authors.

Authors and Affiliations

  1. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy

    A. Bonaventura, F. Carbone, A. Vecchié, S. Minetti, N. Bardi, E. Elia, A. M. Ansaldo, D. Ferrara & F. Dallegri

  2. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1200 E Marshall St, Richmond, VA, 23298, USA

    A. Bonaventura & A. Vecchié

  3. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Medical Oncology, Milan, Italy

    F. Grossi

  4. IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy

    F. Carbone, F. Dallegri, C. Genova & F. Montecucco

  5. IRCCS Ospedale Policlinico San Martino, UOS Tumori Polmonari, Largo R. Benzi 10, 16132, Genoa, Italy

    E. Rijavec, M. G. Dal Bello, G. Rossi, M. Tagliamento, A. Alama & S. Coco

  6. Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy

    G. Rossi

  7. Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy

    F. Biello

  8. Cardiovascular Diseases Unit, IRCCS Ospedale Policlinico San Martino-Italian Cardiovascular Network, Genoa, Italy

    P. Spallarossa

  9. First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, viale Benedetto XV 6, 16132, Genoa, Italy

    F. Montecucco

Authors
  1. A. Bonaventura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Grossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Vecchié
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Minetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Bardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Elia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. M. Ansaldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D. Ferrara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E. Rijavec
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. G. Dal Bello
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G. Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. F. Biello
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M. Tagliamento
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. A. Alama
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S. Coco
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. P. Spallarossa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. F. Dallegri
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. C. Genova
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. F. Montecucco
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CG, MGDB, ER, GR, FB, MT, and FG recruited patients and collected clinical data. AA and SC stored samples and provided aliquots for measurement of resistin. AB, FC, AV, SM, NC, EE, AMA, and DF analyzed samples by ELISA. AB performed statistical analysis and wrote the manuscript draft. FD, FG, PS, and FM read critically the manuscript and gave suggestions to improve it. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to A. Bonaventura.

Ethics declarations

Conflict of interests

Francesco Grossi has consulting/advisory relationship with and received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre, and has consulting/advisory relationship with AstraZeneca and Roche. Carlo Genova received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Merck Sharp & Dohme, and Roche. Erika Rijavec received honoraria from Bristol-Myers Squibb. Paolo Spallarossa has consulting/advisory relationship with Incyte, Teva, and Bristol-Myers Squibb, and received honoraria from Incyte, Teva, and Servier. The other authors indicated no financial relationship.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 46 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bonaventura, A., Grossi, F., Carbone, F. et al. Resistin is associated with overall survival in non-small cell lung cancer patients during nivolumab treatment. Clin Transl Oncol 22, 1603–1610 (2020). https://doi.org/10.1007/s12094-020-02305-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-020-02305-x

Keywords

Search

Navigation