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Targeted Oncology

, Volume 13, Issue 6, pp 795–800 | Cite as

Low Baseline Serum Sodium Concentration Is Associated with Poor Clinical Outcomes in Metastatic Non-Small Cell Lung Cancer Patients Treated with Immunotherapy

  • Giovanni FucàEmail author
  • Giulia Galli
  • Marta Poggi
  • Giuseppe Lo Russo
  • Claudia Proto
  • Martina Imbimbo
  • Milena Vitali
  • Monica Ganzinelli
  • Claudia Lanti
  • Giuliano Molino
  • Fabiano Stangoni
  • Nicoletta Zilembo
  • Filippo de Braud
  • Marina Chiara Garassino
  • Diego Signorelli
Short Communication

Abstract

Background

A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO).

Objective

Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (≤ 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO.

Patients and Methods

We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model.

Results

Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15–0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80–4.80; P < .001) and progression-free survival (PFS) (1.8 vs. 3.3 months; HR 2.60; 95% CI, 1.70–3.90; P < .001) compared to patients in the control cohort. At multivariate analyses, low baseline serum sodium concentration was independently associated with disease control and OS, but not with PFS.

Conclusions

Our study showed for the first time that low baseline serum sodium concentration is associated with impaired clinical outcomes in patients with metastatic NSCLC treated with IO. The role of serum sodium concentration in this setting warrants further pre-clinical and clinical investigation.

Notes

Compliance with Ethical Standards

Funding

No external funding was used in the preparation of this manuscript.

Conflict of Interest

Giovanni Fucà, Giulia Galli, Marta Poggi, Giuseppe Lo Russo, Claudia Proto, Martina Imbimbo, Milena Vitali, Monica Ganzinelli, Claudia Lanti, Giuliano Molino, Fabiano Stangoni, Nicoletta Zilembo, Filippo de Braud, Marina Chiara Garassino, and Diego Signorelli declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Supplementary material

11523_2018_599_MOESM1_ESM.pdf (574 kb)
ESM 1 (PDF 574 kb)

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2018;68:7–30.CrossRefGoogle Scholar
  2. 2.
    Yi J, Wei X, Li X, et al. A genome-wide comprehensive analysis of alterations in driver genes in non-small-cell lung cancer. Anti-Cancer Drugs. 2018;29:10–8.CrossRefGoogle Scholar
  3. 3.
    Mayekar MK, Bivona TG. Current landscape of targeted therapy in lung cancer. Clin Pharmacol Ther. 2017;102:757–64.CrossRefGoogle Scholar
  4. 4.
    Fucà G, de Braud F, Di Nicola M. Immunotherapy-based combinations: an update. Curr Opin Oncol. 2018;30:345–51.PubMedGoogle Scholar
  5. 5.
    Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med. 2015;373:123–35.CrossRefGoogle Scholar
  6. 6.
    Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373:1627–39.CrossRefGoogle Scholar
  7. 7.
    Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.CrossRefGoogle Scholar
  8. 8.
    Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375:1823–33.CrossRefGoogle Scholar
  9. 9.
    Aguiar PN Jr, De Mello RA, Hall P, et al. PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data. Immunotherapy. 2017;9:499–506.CrossRefGoogle Scholar
  10. 10.
    Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;48:124–8.CrossRefGoogle Scholar
  11. 11.
    Shi T, Ma Y, Yu L, et al. Cancer immunotherapy: a focus on the regulation of immune checkpoints. Int J Mol Sci. 2018;19:E1389.CrossRefGoogle Scholar
  12. 12.
    Castillo JJ, Glezerman IG, Boklage SH, et al. The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients. BMC Cancer. 2016;16:564.CrossRefGoogle Scholar
  13. 13.
    Berardi R, Santoni M, Newsom-Davis T, et al. Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy. Oncotarget. 2017;8:23871–9.CrossRefGoogle Scholar
  14. 14.
    Svaton M, Fiala O, Pesek M, et al. Predictive and prognostic significance of sodium levels in patients with NSCLC treated by erlotinib. Anticancer Res. 2014;34:7461–5.PubMedGoogle Scholar
  15. 15.
    Ramirez GA, Coletto LA, Sciorati C, et al. Ion channels and transporters in inflammation: special focus on TRP channels and TRPC6. Cell. 2018;7:E70.CrossRefGoogle Scholar
  16. 16.
    Levy GB. Determination of sodium with ion-selective electrodes. Clin Chem. 1981;27:1435–8.PubMedGoogle Scholar
  17. 17.
    Dacic S. Time is up for PD-L1 testing standardization in lung cancer. Ann Oncol. 2018;29:791–2.CrossRefGoogle Scholar
  18. 18.
    Platania M, Verzoni E, Vitali M. Hyponatremia in cancer patients. Tumori. 2015;101:246–8.CrossRefGoogle Scholar
  19. 19.
    Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist. 2012;17:756–65.CrossRefGoogle Scholar
  20. 20.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefGoogle Scholar
  21. 21.
    Gyawali B, Hey SP, Kesselheim AS. A comparison of response patterns for progression-free survival and overall survival following treatment for Cancer with PD-1 inhibitors: a meta-analysis of correlation and differences in effect sizes. JAMA Network Open. 2018;1:e180416.CrossRefGoogle Scholar
  22. 22.
    Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20.CrossRefGoogle Scholar
  23. 23.
    Jeppesen AN, Jensen HK, Donskov F, et al. Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma. Br J Cancer. 2010;102:867–72.CrossRefGoogle Scholar
  24. 24.
    Berardi R, Caramanti M, Fiordoliva I, et al. Hyponatraemia is a predictor of clinical outcome for malignant pleural mesothelioma. Support Care Cancer. 2015;23:621–6.CrossRefGoogle Scholar
  25. 25.
    Litan A, Langhans SA. Cancer as a channelopathy: ion channels and pumps in tumor development and progression. Front Cell Neurosci. 2015;9:86.CrossRefGoogle Scholar
  26. 26.
    Brackenbury WJ. Voltage-gated sodium channels and metastatic disease. Channels. 2012;6:352–61.CrossRefGoogle Scholar
  27. 27.
    House CD, Vaske CJ, Schwartz AM, et al. Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. Cancer Res. 2010;70:6957–67.CrossRefGoogle Scholar
  28. 28.
    Liu C, Zhu LL, Xu SG, et al. ENaC/DEG in tumor development and progression. J Cancer. 2016;7:1888–91.CrossRefGoogle Scholar
  29. 29.
    Chifflet S, Hernandez JA. The epithelial Sodium Channel and the processes of wound healing. Biomed Res Int. 2016;2016:5675047.CrossRefGoogle Scholar
  30. 30.
    Bruhn MA, Pearson RB, Hannan RD, et al. Second AKT: the rise of SGK in cancer signalling. Growth Factors. 2010;28:394–408.CrossRefGoogle Scholar
  31. 31.
    Zhou R, Snyder PM. Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem. 2005;280:4518–23.CrossRefGoogle Scholar
  32. 32.
    Compan V, Baroja-Mazo A, López-Castejón G, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012;37:487–500.CrossRefGoogle Scholar
  33. 33.
    Kim JH, Park JH, Eisenhut M, et al. Inflammasome activation by cell volume regulation and inflammation-associated hyponatremia: a vicious cycle. Med Hypotheses. 2016;93:117–21.CrossRefGoogle Scholar
  34. 34.
    Binger KJ, Linker RA, Muller DN, et al. Sodium chloride, SGK1, and Th17 activation. Pflugers Arch. 2015;467:543–50.CrossRefGoogle Scholar
  35. 35.
    Toussirot E, Béreau M, Vauchy C, et al. Could sodium chloride be an environmental trigger for immune-mediated diseases? An overview of the experimental and clinical evidence. Front Physiol. 2018;9:440.CrossRefGoogle Scholar
  36. 36.
    Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol. 2015;33:291–353.CrossRefGoogle Scholar
  37. 37.
    Hucke S, Eschborn M, Liebmann M, et al. Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity. J Autoimmun. 2016;67:90–101.CrossRefGoogle Scholar
  38. 38.
    Binger KJ, Gebhardt M, Heinig M, et al. High salt reduces the activation of IL-4- and IL-13-stimulated macrophages. J Clin Invest. 2015;125:4223–38.CrossRefGoogle Scholar
  39. 39.
    Zhang WC, Zheng XJ, Du LJ, et al. High salt primes a specific activation state of macrophages, M(Na). Cell Res. 2015;25:893–910.CrossRefGoogle Scholar
  40. 40.
    Cassetta L, Kitamura T. Macrophage targeting: opening new possibilities for cancer immunotherapy. Immunology. 2018.  https://doi.org/10.1111/imm.12976.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Giovanni Fucà
    • 1
    Email author
  • Giulia Galli
    • 1
  • Marta Poggi
    • 1
  • Giuseppe Lo Russo
    • 1
  • Claudia Proto
    • 1
  • Martina Imbimbo
    • 1
  • Milena Vitali
    • 1
  • Monica Ganzinelli
    • 1
  • Claudia Lanti
    • 1
  • Giuliano Molino
    • 1
  • Fabiano Stangoni
    • 1
  • Nicoletta Zilembo
    • 1
  • Filippo de Braud
    • 1
    • 2
  • Marina Chiara Garassino
    • 1
  • Diego Signorelli
    • 1
  1. 1.Medical Oncology DepartmentFondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
  2. 2.Department of Oncology and Hemato-OncologyUniversity of MilanMilanItaly

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