Skip to main content

Advertisement

SpringerLink
Log in

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

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 70:181–193

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 31:607–611

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  21. National Cancer Institute (2009) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

  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–958s

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  28. Institute of Medicine (2011) Dietary reference intakes for calcium and vitamin D. National Academies Press, Washington, DC

    Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  30. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281. https://doi.org/10.1056/NEJMra070553

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 29:2707–2711

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  34. True LD (2008) Quality control in molecular immunohistochemistry. Histochem Cell Biol 130:473–480. https://doi.org/10.1007/s00418-008-0481-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ma Y, Trump DL, Johnson CS (2010) Vitamin D in combination cancer treatment. J Cancer 1:101–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Ottawa Hospital, Ottawa, Canada

    Angel Arnaout

  2. Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada

    Angel Arnaout, Ahwon Jeong, John Hilton & Mark Clemons

  3. Division of Anatomical Pathology, Ottawa Hospital, Ottawa, Canada

    Susan Robertson

  4. Department of Oncology, McMaster University, Hamilton, Canada

    Gregory R. Pond

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    Reinhold Vieth

  6. Division of Medical Oncology, Department of Medicine, University of Ottawa and Ottawa Hospital Cancer Center, Ottawa, ON, Canada

    John Hilton & Mark Clemons

  7. Center for Practice Changing Research, Ottawa Hospital Research Institute, Ottawa, Canada

    Timothy Ramsey

Authors
  1. Angel Arnaout
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gregory R. Pond
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reinhold Vieth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahwon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Hilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Timothy Ramsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark Clemons
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark Clemons.

Ethics declarations

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.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arnaout, A., Robertson, S., Pond, G.R. et al. Randomized window of opportunity trial evaluating high-dose vitamin D in breast cancer patients. Breast Cancer Res Treat 178, 347–356 (2019). https://doi.org/10.1007/s10549-019-05392-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-019-05392-9

Keywords

Search

Navigation