Skip to main content

Advertisement

SpringerLink
Log in

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

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

Abstract

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000–1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35–80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.

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. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  2. Sledge GW Jr, Miller KD (2003) Exploiting the hallmarks of cancer: the future conquest of breast cancer. Eur J Cancer 39(12):1668–1675

    Article  PubMed  Google Scholar 

  3. Steeg PS, Bevilacqua G, Pozzatti R, Liotta LA, Sobel ME (1988) Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 Ela inhibition of experimental metastasis. Cancer Res 48(22):6550–6554

    PubMed  CAS  Google Scholar 

  4. Ouatas T, Halverson D, Steeg P (2003) Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor expression in metastatic human breast carcinoma cells: New uses for old compounds. Clin Cancer Res 9:3763–3772

    PubMed  CAS  Google Scholar 

  5. Yoshida B, Sokoloff M, Welch D, Rinker-Schaeffer C (2000) Metastasis-suppressor genes: a review and perspective on an emerging field. J Natl Cancer Inst 92:1717–1730

    Article  PubMed  CAS  Google Scholar 

  6. Leone A, Flatow U, King C, Sandeen M, Margulies I, Liotta L, Steeg P (1991) Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65:25–35

    Article  PubMed  CAS  Google Scholar 

  7. Leone A, Flatow U, VanHoutte K, Steeg P (1993) Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization, and enzymatic activity. Oncogene 8:2325–2333

    PubMed  CAS  Google Scholar 

  8. Cropp C, Lidereau R, Leone A, Liscia D, Cappa A, Campbell G, Barker E, Doussal V, Steeg P, Callahan R et al (1994) NME1 protein expression and loss of heterozygosity mutations in primary human breast tumors. J Natl Cancer Inst 86:1167–1169

    Article  PubMed  CAS  Google Scholar 

  9. Ouatas T, Clare S, Hartsough M, DeLaRosa A, Steeg P (2002) MMTV-associated transcription factor binding sites increase nm23-H1 metastasis suppressor gene expression in human breast carcinoma cell lines. Clin Exp Metast 19:35–42

    Article  CAS  Google Scholar 

  10. Palmieri D, Halverson D, Ouatas T, Salerno M, Johnson J, Figg W, Hollingshead M, Hursting S, Berigan D, Steinberg S et al (2005) Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor—negative breast cancer. J Natl Cancer Inst 97:632–642

    Article  PubMed  CAS  Google Scholar 

  11. Van Veelen H, Willemse P, Tjabbes T et al (1986) Oral high-dose medroxyprogesterone acetate versus tamoxifen. Cancer 58:7–13

    Article  PubMed  Google Scholar 

  12. Nishimura R, Nagao K, Matsuda M, Baba K, Matsuoka Y, Yamashita H, Fukuda M, Higuchi A, Ikeda K (1997) Predictive value of serum medroxyprogesterone acetate concentration for response or recurrent breast cancer. Eur J Cancer 33(9):1407–1412

    Article  PubMed  CAS  Google Scholar 

  13. Tashiro H, Nomura Y (1995) Mitomycin C, methotrexate, and vincristine with medroxyprogesterone acetate or prednisolone for doxorubicin resistant advanced breast cancer–a randomized control study. Anticancer Res 15(5B):2229–2237

    PubMed  CAS  Google Scholar 

  14. Koyama H, Tominaga T, Asaishi K, Abe R, Iino Y, Enomoto K, Miura S, Nomura Y, Nakazato H, Abe O (1999) A randomized controlled comparative study of oral medroxyprogesterone acetate 1,200 and 600 mg in patients with advanced or recurrent breast cancer. Oncology 56(4):283–290

    Article  PubMed  CAS  Google Scholar 

  15. Byrne MJ, Gebski V, Forbes J, Tattersall MH, Simes RJ, Coates AS, Dewar J, Lunn M, Flower C, Gill PG et al (1997) Medroxyprogesterone acetate addition or substitution for tamoxifen in advanced tamoxifen-resistant breast cancer: a phase III randomized trial. Australian-New Zealand Breast Cancer Trials Group. J Clin Oncol 15(9):3141–3148

    PubMed  CAS  Google Scholar 

  16. Hortobagyi GN, Buzdar AU, Frye D, Yap HY, Hug V, Pinnamaneni K, Fraschini G, Halvorson HC, Blumenschein GR (1985) Oral medroxyprogesterone acetate in the treatment of metastatic breast cancer. Breast Cancer Res Treat 5(3):321–326

    Article  PubMed  CAS  Google Scholar 

  17. Gallagher CJ, Cairnduff F, Smith IE (1987) High dose versus low dose medroxyprogesterone acetate: a randomized trial in advanced breast cancer. Eur J Cancer Clin Oncol 23(12):1895–1900

    Article  PubMed  CAS  Google Scholar 

  18. Davila E, Vogel CL, East D, Cairns V, Hilsenbeck S (1988) Clinical trial of high-dose oral medroxyprogesterone acetate in the treatment of metastatic breast cancer and review of the literature. Cancer 61(11):2161–2167

    Article  PubMed  CAS  Google Scholar 

  19. Pannuti F, Camaggi CM, Strocchi E, Martoni A (1986) MPA at high doses in advanced breast cancer: a statistical evaluation. Chemioterapia 5(3):159–163

    PubMed  CAS  Google Scholar 

  20. Zhou L, Isenberg J, Cao Z, Roberts D (2006) Type I collagen is a molecular target for inhibition of angiogenesis by endogenous thrombospondin-1. Oncogene 25:536–545

    Article  PubMed  CAS  Google Scholar 

  21. Isenberg J, Calzada M, Zhou L, Guo N, Lawler J, Wang XQ, Frazier W, Roberts D (2005) Endogenous thrombospondin-1 is not necessary for proliferation but is permissive for vascular smooth muscle cell responses to platelet-derived growth factor. Matrix Biol 24:110–123

    Article  PubMed  CAS  Google Scholar 

  22. Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 100(22):12917–12922

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  PubMed  CAS  Google Scholar 

  24. Nishimura R, Nagao K, Matsuda M, Baba K, Matsuoka Y, Yamashita H, Fukuda M, Higuchi A, Ikeda K (1997) Predictive value of serum medroxyprogesterone acetate concentration for response in advanced or recurrent breast cancer. Eur J Cancer 33(9):1407–1412

    Article  PubMed  CAS  Google Scholar 

  25. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri S et al (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13(1):73–80

    Article  PubMed  CAS  Google Scholar 

  26. Adams J, Carder PJ, Downey S, Forbes MA, MacLennan K, Allgar V, Kaufman S, Hallam S, Bicknell R, Walker JJ et al (2000) Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 60(11):2898–2905

    PubMed  CAS  Google Scholar 

  27. Verheul HM, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, Pinedo HM (1997) Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3(12 Pt 1):2187–2190

    PubMed  CAS  Google Scholar 

  28. Wynendaele W, Derua R, Hoylaerts MF, Pawinski A, Waelkens E, de Bruijn EA, Paridaens R, Merlevede W, van Oosterom AT (1999) Vascular endothelial growth factor measured in platelet poor plasma allows optimal separation between cancer patients and volunteers: a key to study an angiogenic marker in vivo? Ann Oncol 10(8):965–971

    Article  PubMed  CAS  Google Scholar 

  29. Perou CM, Jeffrey SS, van de Rijn M, Rees CA, Eisen MB, Ross DT, Pergamenschikov A, Williams CF, Zhu SX, Lee JC et al (1999) Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A 96(16):9212–9217

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Perou C, Sorlie T, Eisen M et al (2000) Molecular portraits of human breast tumours. Nature 406:747

    Article  PubMed  CAS  Google Scholar 

  32. Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD (2001) Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem 276(20):16649–16654

    Article  PubMed  CAS  Google Scholar 

  33. Pan D, Kocherginsky M, Conzen SD (2011) Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res 71(20):6360–6370

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Steeg PS, Zollo M, Wieland T (2011) A critical evaluation of biochemical activities reported for the nucleoside diphosphate kinase/Nm23/Awd family proteins: opportunities and missteps in understanding their biological functions. Naunyn-Schmiedeberg’s Arch Pharmacol 384(4–5):331–339

    Article  CAS  Google Scholar 

  35. Chang CL, Zhu XX, Thoraval DH, Ungar D, Rawwas J, Hora N, Strahler JR, Hanash SM, Radany E (1994) Nm23-H1 mutation in neuroblastoma. Nature 370(6488):335–336

    Article  PubMed  CAS  Google Scholar 

  36. Leone A, Seeger RC, Hong CM, Hu YY, Arboleda MJ, Brodeur GM, Stram D, Slamon DJ, Steeg PS (1993) Evidence for nm23 RNA overexpression, DNA amplification and mutation in aggressive childhood neuroblastomas. Oncogene 8(4):855–865

    PubMed  CAS  Google Scholar 

  37. Leone A, Flatow U, VanHoutte K, Steeg PS (1993) Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene 8(9):2325–2333

    PubMed  CAS  Google Scholar 

  38. Steeg PS (2012) Perspective: the right trials. Nature 485(7400):S58–59

    Article  PubMed  CAS  Google Scholar 

  39. Brabletz T, Lyden D, Steeg PS, Werb Z (2013) Roadblocks to translational advances on metastasis research. Nat Med 19(9):1104–1109

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

Supported by NIH/NCI P30 CA082709-AV-133 (Avon Partners for Progress Supplement) and the Breast Cancer Research Foundation (KDM). In addition, we are grateful for the funding support to the Translational Breast Cancer Research Consortium (TBCRC) from The AVON Foundation, The Breast Cancer Research Foundation, and Susan G. Komen for the Cure.

Conflict of Interest

None of the authors have any conflicts to disclose

Author information

Authors and Affiliations

  1. Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN, 46202, USA

    Kathy D. Miller, Sandra K. Althouse & David R. Jones

  2. University of Alabama Birmingham, Birmingham, USA

    Lisle Nabell

  3. University of California San Francisco, San Francisco, USA

    Hope Rugo

  4. University of North Carolina, Chapel Hill, USA

    Lisa Carey

  5. Duke University Medical Center, Durham, USA

    Gretchen Kimmick

  6. Laboratory of Pathology, National Cancer Institute, Bethesda, USA

    Maria J. Merino

  7. Women’s Malignancies Branch, National Cancer Institute, Bethesda, USA

    Patricia S. Steeg

Authors
  1. Kathy D. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra K. Althouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisle Nabell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hope Rugo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lisa Carey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gretchen Kimmick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David R. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maria J. Merino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patricia S. Steeg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathy D. Miller.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miller, K.D., Althouse, S.K., Nabell, L. et al. A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007. Breast Cancer Res Treat 148, 99–106 (2014). https://doi.org/10.1007/s10549-014-3131-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-3131-3

Keywords

Search

Navigation