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Randomized window of opportunity trial evaluating high-dose vitamin D in breast cancer patients

  • Angel Arnaout
  • Susan Robertson
  • Gregory R. Pond
  • Reinhold Vieth
  • Ahwon Jeong
  • John Hilton
  • Timothy Ramsey
  • Mark ClemonsEmail author
Clinical trial

Abstract

Purpose

Epidemiologic and preclinical data suggest a potential role for vitamin D in breast cancer treatment and prevention. However, results of prospective randomized trials are inconsistent. The objective of this study was to assess the effects of high-dose cholecalciferol (vitamin D3) on breast tumour proliferation and apoptosis.

Methods

We conducted a prospective, randomized, phase 2, double-blinded pre-surgical window of opportunity trial. Newly diagnosed breast cancer patients were randomized to receive 40,000 IU of vitamin D3 per day or placebo for 2 to 6 weeks prior to breast surgery. The primary outcome was the relative change in proliferation (Ki67) and apoptosis (cleaved caspase 3 apoptotic assay [CC3]) in primary breast cancer cells pre and post treatment.

Results

Of 83 patients randomized, 80 completed the study (43 (53.8%) vitamin D and 37 (46.3%) placebo). Mean duration of drug intake was 19 days (range 9–28 days). There were no significant differences between the control arm and the vitamin D arm in percent changes of either Ki67 index (1.6% vs. 16.7%, p = 0.25) or CC3 (− 55.9% vs. − 45.9%, p = 0.28). Serum 25-hydroxyvitamin D (25-OHD) levels were 3 times higher in the vitamin D arm (62 nmol/L vs. 246 nmol/L, p < 0.001). Adverse effects were minimal and all classified as grade 1.

Conclusions

Despite significantly higher levels of serum 25-OHD in the vitamin D-treated group, this was not associated with any significant effects on tumour proliferation or apoptosis. These findings are consistent with the lack of benefit observed in prospective prevention trials.

Trial registry

Trial registration clinicaltrials.gov NCT01948128.

Keywords

Vitamin D Window of opportunity Clinical trial Breast cancer 

Notes

Acknowledgements

The primary investigator developed the protocol during 14th Annual Joint ECCO-AACR-EORTC-ESMO Flims “Methods in Clinical Cancer Research” Workshop 2012. The authors are grateful to the research staff for their assistance in recruiting participants and for data collection.

Funding

This work was supported by the Canadian Breast Cancer Foundation and University of Ottawa Department of Surgery research grant.

Compliance with ethical standards

Conflict of interest

Dr Vieth is an unpaid advisor to the Vitamin D Society, and receives royalties from partial ownership and a patent pertaining to vitamin D supplementation.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ottawa Hospital Research Ethics Board) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Feldman D, Krishnan AV, Swami S et al (2014) The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 14:342–357.  https://doi.org/10.1038/nrc3691 CrossRefGoogle Scholar
  2. 2.
    Duffy MJ, Murray A, Synnott NC et al (2017) Vitamin D analogues: potential use in cancer treatment. Crit Rev Oncol Hematol 112:190–197.  https://doi.org/10.1016/j.critrevonc.2017.02.015 CrossRefGoogle Scholar
  3. 3.
    Jacobs ET, Kohler LN, Kunihiro AG, Jurutka PW (2016) Vitamin D and colorectal, breast, and prostate cancers: a review of the epidemiological evidence. J Cancer 7:232–240.  https://doi.org/10.7150/jca.13403 CrossRefGoogle Scholar
  4. 4.
    Albanes D (2015) Vitamin D and cancer: diversity, complexity, and still a ways to go. Cancer Prev Res (Phila) 8:657–661.  https://doi.org/10.1158/1940-6207.CAPR-15-0207 CrossRefGoogle Scholar
  5. 5.
    Zhang X, Harbeck N, Jeschke U, Doisneau-Sixou S (2017) Influence of vitamin D signaling on hormone receptor status and HER2 expression in breast cancer. J Cancer Res Clin Oncol 143:1107–1122.  https://doi.org/10.1007/s00432-016-2325-y CrossRefGoogle Scholar
  6. 6.
    Narvaez CJ, Matthews D, LaPorta E et al (2014) The impact of vitamin D in breast cancer: genomics, pathways, metabolism. Front Physiol 5:213.  https://doi.org/10.3389/fphys.2014.00213 CrossRefGoogle Scholar
  7. 7.
    Mehta RG, Peng X, Alimirah F et al (2013) Vitamin D and breast cancer: emerging concepts. Cancer Lett 334:95–100.  https://doi.org/10.1016/j.canlet.2012.10.034 CrossRefGoogle Scholar
  8. 8.
    Welsh J (2018) Vitamin D and breast cancer: past and present. J Steroid Biochem Mol Biol 177:15–20.  https://doi.org/10.1016/j.jsbmb.2017.07.025 CrossRefGoogle Scholar
  9. 9.
    Bandera Merchan B, Morcillo S, Martin-Nuñez G et al (2017) The role of vitamin D and VDR in carcinogenesis: through epidemiology and basic sciences. J Steroid Biochem Mol Biol 167:203–218.  https://doi.org/10.1016/j.jsbmb.2016.11.020 CrossRefGoogle Scholar
  10. 10.
    Shao T, Klein P, Grossbard ML (2012) Vitamin D and breast cancer. Oncologist 17:36–45.  https://doi.org/10.1634/theoncologist.2011-0278 CrossRefGoogle Scholar
  11. 11.
    Scragg R, Khaw K-T, Toop L et al (2018) Monthly high-dose vitamin D supplementation and cancer risk. JAMA Oncol 4:e182178.  https://doi.org/10.1001/jamaoncol.2018.2178 CrossRefGoogle Scholar
  12. 12.
    Manson JE, Cook NR, Lee I-M et al (2019) Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 380:33–44.  https://doi.org/10.1056/NEJMoa1809944 CrossRefGoogle Scholar
  13. 13.
    Zeichner SB, Koru-Sengul T, Shah N et al (2015) Improved clinical outcomes associated with vitamin D supplementation during adjuvant chemotherapy in patients with HER2+ nonmetastatic breast cancer. Clin Breast Cancer 15:e1–e11.  https://doi.org/10.1016/j.clbc.2014.08.001 CrossRefGoogle Scholar
  14. 14.
    Amir E, Simmons CE, Freedman OC et al (2010) A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D3 in breast cancer patients with bone metastases. Cancer 116:284–291.  https://doi.org/10.1002/cncr.24749 CrossRefGoogle Scholar
  15. 15.
    Levasseur N, Clemons M, Hilton J et al (2015) Neoadjuvant endocrine therapy and window of opportunity trials: new standards in the treatment of breast cancer? Minerva Chir 70:181–193Google Scholar
  16. 16.
    Arnaout A, Robertson S, Kuchuk I et al (2015) Evaluating the feasibility of performing window of opportunity trials in breast cancer. Int J Surg Oncol 2015:785793.  https://doi.org/10.1155/2015/785793 Google Scholar
  17. 17.
    Wagner D, Trudel D, Van der Kwast T et al (2013) Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and Ki67 labeling in prostate cancer patients. J Clin Endocrinol Metab 98:1498–1507.  https://doi.org/10.1210/jc.2012-4019 CrossRefGoogle Scholar
  18. 18.
    Garland CF, French CB, Baggerly LL, Heaney RP (2011) Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 31:607–611Google Scholar
  19. 19.
    Yerushalmi R, Woods R, Ravdin PM et al (2010) Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 11:174–183.  https://doi.org/10.1016/S1470-2045(09)70262-1 CrossRefGoogle Scholar
  20. 20.
    Pu X, Storr SJ, Zhang Y et al (2017) Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival. Apoptosis 22:357–368.  https://doi.org/10.1007/s10495-016-1323-5 CrossRefGoogle Scholar
  21. 21.
    National Cancer Institute (2009) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0Google Scholar
  22. 22.
    Dowsett M, Smith IE, Ebbs SR et al (2005) Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res 11:951s–958sGoogle Scholar
  23. 23.
    Vrieling A, Hein R, Abbas S et al (2011) Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study. Breast Cancer Res 13:R74.  https://doi.org/10.1186/bcr2920 CrossRefGoogle Scholar
  24. 24.
    Swami S, Krishnan AV, Wang JY et al (2012) Dietary vitamin D3 and 1,25-dihydroxyvitamin D3 (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinology 153:2576–2587.  https://doi.org/10.1210/en.2011-1600 CrossRefGoogle Scholar
  25. 25.
    Glimelius B, Lahn M (2011) Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol 22:1717–1725.  https://doi.org/10.1093/annonc/mdq622 CrossRefGoogle Scholar
  26. 26.
    Kalinsky K, Hershman DL (2012) Cracking open window of opportunity trials. J Clin Oncol 30:2573–2575.  https://doi.org/10.1200/JCO.2012.42.3293 CrossRefGoogle Scholar
  27. 27.
    Urata YN, de Lyra EC, Katayama MLH et al (2014) Calcitriol supplementation effects on Ki67 expression and transcriptional profile of breast cancer specimens from post-menopausal patients. Clin Nutr 33:136–142.  https://doi.org/10.1016/j.clnu.2013.04.001 CrossRefGoogle Scholar
  28. 28.
    Institute of Medicine (2011) Dietary reference intakes for calcium and vitamin D. National Academies Press, Washington, DCGoogle Scholar
  29. 29.
    Vieth R, Cole D, Hawker G et al (2001) Wintertime vitamin D insufficiency is common in young Canadian women and their vitamin D intake does not prevent it. Eur J Clin Nutr 55:1091–1097.  https://doi.org/10.1038/sj.ejcn.1601275 CrossRefGoogle Scholar
  30. 30.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281.  https://doi.org/10.1056/NEJMra070553 CrossRefGoogle Scholar
  31. 31.
    Hadji P, Coleman RE, Wilson C et al (2016) Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol 27:379–390.  https://doi.org/10.1093/annonc/mdv617 CrossRefGoogle Scholar
  32. 32.
    Simmons C, Amir E, Dranitsaris G et al (2009) Altered calcium metabolism in patients on long-term bisphosphonate therapy for metastatic breast cancer. Anticancer Res 29:2707–2711Google Scholar
  33. 33.
    Martínez-Alonso M, Dusso A, Ariza G, Nabal M (2016) Vitamin D deficiency and its association with fatigue and quality of life in advanced cancer patients under palliative care: a cross-sectional study. Palliat Med 30:89–96.  https://doi.org/10.1177/0269216315601954 CrossRefGoogle Scholar
  34. 34.
    True LD (2008) Quality control in molecular immunohistochemistry. Histochem Cell Biol 130:473–480.  https://doi.org/10.1007/s00418-008-0481-0 CrossRefGoogle Scholar
  35. 35.
    Polley M-YC, Leung SCY, McShane LM et al (2013) An International Ki67 Reproducibility study. JNCI J Natl Cancer Inst 105:1897–1906.  https://doi.org/10.1093/jnci/djt306 CrossRefGoogle Scholar
  36. 36.
    Schmitz S, Duhoux F, Machiels J-P (2016) Window of opportunity studies: do they fulfil our expectations? Cancer Treat Rev 43:50–57.  https://doi.org/10.1016/j.ctrv.2015.12.005 CrossRefGoogle Scholar
  37. 37.
    Sherman MH, Yu RT, Engle DD et al (2014) Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159:80–93.  https://doi.org/10.1016/j.cell.2014.08.007 CrossRefGoogle Scholar
  38. 38.
    Ma Y, Trump DL, Johnson CS (2010) Vitamin D in combination cancer treatment. J Cancer 1:101–107CrossRefGoogle Scholar
  39. 39.
    Beer TM, Lemmon D, Lowe BA, Henner WD (2003) High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer 97:1217–1224.  https://doi.org/10.1002/cncr.11179 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Surgical Oncology, Department of SurgeryOttawa HospitalOttawaCanada
  2. 2.Cancer Therapeutics ProgramOttawa Hospital Research InstituteOttawaCanada
  3. 3.Division of Anatomical PathologyOttawa HospitalOttawaCanada
  4. 4.Department of OncologyMcMaster UniversityHamiltonCanada
  5. 5.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  6. 6.Division of Medical Oncology, Department of MedicineUniversity of Ottawa and Ottawa Hospital Cancer CenterOttawaCanada
  7. 7.Center for Practice Changing Research, Ottawa Hospital Research InstituteOttawaCanada

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