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Total, bioavailable and free 25-hydroxyvitamin D are associated with the prognosis of patients with non-small cell lung cancer

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Abstract

Purpose

To analyze the prognostic value of total, bioavailable and free 25-hydroxyvitamin D [25(OH)D] as well as vitamin D-binding protein (VDBP) in patients with non-small cell lung cancer (NSCLC).

Methods

We prospectively collected and analyzed data for 395 patients diagnosed with NSCLC between January 2016 and December 2018 in two university-affiliated hospitals. Total and free 25(OH)D and VDBP were measured directly, and bioavailable 25(OH)D was calculated using a validated formula. Their prognostic values were evaluated by Cox proportional hazards model, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.

Results

Patients with NSCLC had significantly lower levels of total, bioavailable, and free 25(OH)D and higher VDBP levels in comparison to healthy controls (all p < 0.001). In multivariate analyses, higher levels of total, bioavailable, and free 25(OH)D were independently associated better overall survival (OS) and progression-free survival (PFS). For OS, the adjusted HRs were 0.58 (95% CI, 0.40–0.87; p for trend = 0.008), 0.45 (95% CI, 0.30–0.67; p for trend < 0.001) and 0.49 (95% CI, 0.33–0.73; p for trend < 0.001) for the highest versus the lowest tertile of total, bioavailable and free 25(OH)D, respectively. The corresponding adjusted HRs for PFS were 0.61 (95% CI, 0.43–0.86; p for trend = 0.006), 0.56 (95% CI, 0.40–0.80; p for trend = 0.001) and 0.60 (95% CI, 0.42–0.85; p for trend = 0.004), respectively. However, VDBP was not associated with either OS or PFS.

Conclusion

The current study suggested that total, bioavailable and free 25(OH)D may be reliable prognosis indicators in NSCLC patients, though the optimal 25(OH)D form for NSCLC prognosis remains to be assessed in future studies.

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Data availability

All datasets generated for this manuscript can be obtained from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    PubMed  Google Scholar 

  2. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359:1367–1380

    Article  CAS  Google Scholar 

  3. Hirsch FR, Scagliotti GV, Mulshine JL et al (2017) Lung cancer: current therapies and new targeted treatments. Lancet 389:299–311

    Article  CAS  Google Scholar 

  4. Allemani C, Matsuda T, Di Carlo V et al (2018) Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 391:1023–1075

    Article  Google Scholar 

  5. Hossein-nezhad A, Holick MF (2013) Vitamin D for health: a global perspective. Mayo Clin Proc 88:720–755

    Article  CAS  Google Scholar 

  6. Jeon S-M, Shin E-A (2018) Exploring vitamin D metabolism and function in cancer. Exp Mol Med 50:1–14

    PubMed  Google Scholar 

  7. Amrein K, Scherkl M, Hoffmann M et al (2020) Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr 74:1498–1513

    Article  CAS  Google Scholar 

  8. Aguirre M, Manzano N, Salas Y, Angel M, Díaz-Couselo FA, Zylberman M (2016) Vitamin D deficiency in patients admitted to the general ward with breast, lung, and colorectal cancer in Buenos Aires, Argentina. Arch Osteoporosis 11:4

    Article  Google Scholar 

  9. Zhou W, Heist RS, Liu G et al (2007) Circulating 25-hydroxyvitamin D levels predict survival in early-stage non-small-cell lung cancer patients. J Clin Oncol 25:479–485

    Article  CAS  Google Scholar 

  10. Liu Y, Chen W, Hu Z-B et al (2011) Plasma vitamin D levels and vitamin D receptor polymorphisms are associated with survival of non-small cell lung cancer. Chin J Cancer Res 23:33–37

    Article  CAS  Google Scholar 

  11. Ma K, Xu W, Wang C, Li B, Su K, Li W (2017) Vitamin D deficiency is associated with a poor prognosis in advanced non-small cell lung cancer patients treated with platinum-based first-line chemotherapy. Cancer Biomark 18:297–303

    Article  CAS  Google Scholar 

  12. Heist RS, Zhou W, Wang Z et al (2008) Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non-small-cell lung cancer. J Clin Oncol 26:5596–5602

    Article  CAS  Google Scholar 

  13. Vashi PG, Edwin P, Popiel B, Gupta D (2015) The relationship between circulating 25-hydroxyvitamin D and survival in newly diagnosed advanced non-small-cell lung cancer. BMC Cancer 15:1012

    Article  Google Scholar 

  14. Holick MF (2017) The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 18:153–165

    Article  CAS  Google Scholar 

  15. Tsuprykov O, Chen X, Hocher C-F, Skoblo R, Lianghong Y, Hocher B (2018) Why should we measure free 25(OH) vitamin D? J Steroid Biochem Mol Biol 180:87–104

    Article  CAS  Google Scholar 

  16. Powe CE, Evans MK, Wenger J et al (2013) Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 369:1991–2000

    Article  CAS  Google Scholar 

  17. Yu C, Xue H, Wang L et al (2018) Serum bioavailable and free 25-hydroxyvitamin D levels, but not its total level, are associated with the risk of mortality in patients with coronary artery disease. Circul Res 123:996–1007

    Article  CAS  Google Scholar 

  18. Bouillon R, Schuit F, Antonio L, Rastinejad F (2019) Vitamin D binding protein: a historic overview. Front Endocrinol 10:910

    Article  Google Scholar 

  19. Yang J-R, Chen G-C, Xu J-Y et al (2019) Fasting blood glucose levels and prognosis in patients with non-small-cell lung cancer: a prospective cohort study in China. Onco Targets Ther 12:5947–5953

    Article  CAS  Google Scholar 

  20. Holick MF, Binkley NC, Bischoff-Ferrari HA et al (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930

    Article  CAS  Google Scholar 

  21. Li R, Wu J, Xiong L, Han B (2012) Lung cancer and benign lung diseases in patients with serious vitamin D deficiency in eastern China. Thoracic cancer 3:303–306

    Article  CAS  Google Scholar 

  22. Liu N, Li X, Fu Y et al (2021) Inhibition of lung cancer by vitamin D depends on downregulation of histidine-rich calcium-binding protein. J Adv Res 29:13–22

    Article  CAS  Google Scholar 

  23. Upadhyay SK, Verone A, Shoemaker S et al (2013) 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) signaling capacity and the epithelial-mesenchymal transition in non-small cell lung cancer (NSCLC): implications for use of 1,25(OH)2D3 in NSCLC treatment. Cancers 5:1504–1521

    Article  CAS  Google Scholar 

  24. Mazzilli SA, Hershberger PA, Reid ME et al (2015) Vitamin D repletion reduces the progression of premalignant squamous lesions in the NTCU lung squamous cell carcinoma mouse model. Cancer Prev Res (Phila) 8:895–904

    Article  CAS  Google Scholar 

  25. Verone-Boyle AR, Shoemaker S, Attwood K et al (2016) Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppresses EGFR mutant non-small cell lung cancer growth in vitro and in vivo. Oncotarget 7:995–1013

    Article  Google Scholar 

  26. Maj E, Filip-Psurska B, Milczarek M, Psurski M, Kutner A, Wietrzyk J (2018) Vitamin D derivatives potentiate the anticancer and anti-angiogenic activity of tyrosine kinase inhibitors in combination with cytostatic drugs in an A549 non-small cell lung cancer model. Int J Oncol 52:337–366

    CAS  PubMed  Google Scholar 

  27. Songyang Y, Song T, Shi Z, Li W, Yang S, Li D (2021) Effect of vitamin D on malignant behavior of non-small cell lung cancer cells. Gene 768:145309

    Article  CAS  Google Scholar 

  28. Anic GM, Weinstein SJ, Mondul AM, Männistö S, Albanes D (2014) Serum vitamin D, vitamin D binding protein, and lung cancer survival. Lung Cancer (Amsterdam, Netherlands) 86:297–303

    Article  Google Scholar 

  29. Chen P, Cao Y, Duan X, Li J, Zhao W, Wang H (2021) Bioavailable 25(OH)D level is associated with clinical outcomes of patients with diffuse large B-cell lymphoma: an exploratory study. Clin Nutr 40:157–165

    Article  CAS  Google Scholar 

  30. Yang L, Chen H, Zhao M, Peng P (2017) Prognostic value of circulating vitamin D binding protein, total, free and bioavailable 25-hydroxy vitamin D in patients with colorectal cancer. Oncotarget 8:40214–40221

    Article  Google Scholar 

  31. Fang A-P, Long J-A, Zhang Y-J et al (2020) Serum bioavailable, rather than total, 25-hydroxyvitamin D levels are associated with hepatocellular carcinoma survival. Hepatology 72:169–182

    Article  CAS  Google Scholar 

  32. Yuan C, Shui IM, Wilson KM, Stampfer MJ, Mucci LA, Giovannucci EL (2019) Circulating 25-hydroxyvitamin D, vitamin D binding protein and risk of advanced and lethal prostate cancer. Int J Cancer 144:2401–2407

    Article  CAS  Google Scholar 

  33. Yuan C, Song M, Zhang Y et al (2020) Prediagnostic circulating concentrations of vitamin D binding protein and survival among patients with colorectal cancer. Cancer Epidemiol Biomark Prev 29:2323–2331

    Article  CAS  Google Scholar 

  34. Gregory KJ, Zhao B, Bielenberg DR et al (2010) Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS ONE 5:e13428

    Article  Google Scholar 

  35. Thyer L, Ward E, Smith R et al (2013) A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages. Nutrients 5:2577–2589

    Article  CAS  Google Scholar 

  36. Turner AM, McGowan L, Millen A et al (2013) Circulating DBP level and prognosis in operated lung cancer: an exploration of pathophysiology. Eur Respir J 41:410–416

    Article  CAS  Google Scholar 

  37. Ko D-H, Jun S-H, Nam Y et al (2021) Multiplex LC-MS/MS for simultaneous determination of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, albumin, and vitamin D-binding protein with its isoforms: one-step estimation of bioavailable vitamin D and vitamin D metabolite ratio. J Steroid Biochem Mol Biol 206:105796

    Article  CAS  Google Scholar 

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Funding

This work was supported by the project of State key laboratory of radiation medicine and protection (GZK1202007); the second affiliate hospital of Soochow university science and technology innovation team project funding (XKTJ-TD202009); and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, 199 Renai Road, Suzhou, 215123, China

    Si-Min Peng, Guo-Chong Chen & Li-Qiang Qin

  2. Department of Oncology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China

    Na Yu & Yu-Song Zhang

  3. Department of Radiation Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, 214062, China

    Jun Che

  4. School of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China

    Jia-Ying Xu

  5. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Da-Peng Li

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  1. Si-Min Peng
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  3. Jun Che
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Correspondence to Yu-Song Zhang or Li-Qiang Qin.

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The authors declare no conflict of interest.

Ethical approval

This study was approved by the Research Ethics Committee of Soochow University (Approval No. ESCU-2015-0002). All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Written informed consent was obtained from all participants.

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Peng, SM., Yu, N., Che, J. et al. Total, bioavailable and free 25-hydroxyvitamin D are associated with the prognosis of patients with non-small cell lung cancer. Cancer Causes Control 33, 983–993 (2022). https://doi.org/10.1007/s10552-022-01579-6

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  • DOI: https://doi.org/10.1007/s10552-022-01579-6

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