Skip to main content

Advertisement

SpringerLink
Log in

A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women

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

Abstract

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

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

Similar content being viewed by others

References

  1. Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O et al (1999) Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Postmenopausal estrogen/progestin interventions (PEPI) investigators. Ann Intern Med 130(4 Pt 1):262–269

    PubMed  CAS  Google Scholar 

  2. Knight JA, Martin LJ, Greenberg CV, Lockwood GA, Byng JW, Yaffe MJ et al (1999) Macronutrient intake and change in mammographic density at menopause: results from a randomized trial. Cancer Epidemiol Biomarkers Prev 8(2):123–128

    PubMed  CAS  Google Scholar 

  3. Boyd NF, Byng JW, Jong RA, Fishell EK, Little LE, Miller AB et al (1995) Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87(9):670–675

    Article  PubMed  CAS  Google Scholar 

  4. Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E et al (2007) Mammographic density and the risk and detection of breast cancer. N Engl J Med 356(3):227–236

    Article  PubMed  CAS  Google Scholar 

  5. Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ et al (2005) Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 6(10):798–808

    Article  PubMed  Google Scholar 

  6. Byrne C, Schairer C, Brinton LA, Wolfe J, Parekh N, Salane M et al (2001) Effects of mammographic density and benign breast disease on breast cancer risk (United States). Cancer Causes Control 12(2):103–110

    Article  PubMed  CAS  Google Scholar 

  7. Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA et al (1995) Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87(21):1622–1629

    Article  PubMed  CAS  Google Scholar 

  8. Harvey JA, Bovbjerg VE (2004) Quantitative assessment of mammographic breast density: relationship with breast cancer risk. Radiology 230(1):29–41

    Article  PubMed  Google Scholar 

  9. McCormack VA, dos Santos Silva I (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15(6):1159–1169

    Article  PubMed  Google Scholar 

  10. Ursin G, Ma H, Wu AH, Bernstein L, Salane M, Parisky YR et al (2003) Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomarkers Prev 12(4):332–338

    PubMed  Google Scholar 

  11. Wolfe JN, Saftlas AF, Salane M (1987) Mammographic parenchymal patterns and quantitative evaluation of mammographic densities: a case–control study. AJR Am J Roentgenol 148(6):1087–1092

    PubMed  CAS  Google Scholar 

  12. Biong M, Gram IT, Brill I, Johansen F, Solvang HK, Alnaes GI et al (2010) Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density. BMC Med Genomics 3:9

    Article  PubMed  CAS  Google Scholar 

  13. Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M et al (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87(8):876–882

    Article  PubMed  CAS  Google Scholar 

  14. Diorio C, Brisson J, Berube S, Pollak M (2008) Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels. Cancer Epidemiol Biomarkers Prev 17(4):880–888

    Article  PubMed  CAS  Google Scholar 

  15. Taverne CW, Verheus M, McKay JD, Kaaks R, Canzian F, Grobbee DE et al (2010) Common genetic variation of insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, and acid labile subunit in relation to serum IGF-I levels and mammographic density. Breast Cancer Res Treat 123(3):843–855

    Article  PubMed  CAS  Google Scholar 

  16. Warren R, Skinner J, Sala E, Denton E, Dowsett M, Folkerd E et al (2006) Associations among mammographic density, circulating sex hormones, and polymorphisms in sex hormone metabolism genes in postmenopausal women. Cancer Epidemiol Biomarkers Prev 15(8):1502–1508

    Article  PubMed  CAS  Google Scholar 

  17. Cyrlak D, Wong CH (1993) Mammographic changes in postmenopausal women undergoing hormonal replacement therapy. AJR Am J Roentgenol 161(6):1177–1183

    PubMed  CAS  Google Scholar 

  18. Rutter CM, Mandelson MT, Laya MB, Seger DJ, Taplin S (2001) Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. JAMA 285(2):171–176

    Article  PubMed  CAS  Google Scholar 

  19. Stomper PC, Van Voorhis BJ, Ravnikar VA, Meyer JE (1990) Mammographic changes associated with postmenopausal hormone replacement therapy: a longitudinal study. Radiology 174(2):487–490

    PubMed  CAS  Google Scholar 

  20. Atkinson C, Warren R, Bingham SA, Day NE (1999) Mammographic patterns as a predictive biomarker of breast cancer risk: effect of tamoxifen. Cancer Epidemiol Biomarkers Prev 8(10):863–866

    PubMed  CAS  Google Scholar 

  21. Brisson J, Brisson B, Cote G, Maunsell E, Berube S, Robert J (2000) Tamoxifen and mammographic breast densities. Cancer Epidemiol Biomarkers Prev 9(9):911–915

    PubMed  CAS  Google Scholar 

  22. Chow CK, Venzon D, Jones EC, Premkumar A, O’Shaughnessy J, Zujewski J (2000) Effect of tamoxifen on mammographic density. Cancer Epidemiol Biomarkers Prev 9(9):917–921

    PubMed  CAS  Google Scholar 

  23. Cuzick J, Warwick J, Pinney E, Warren RM, Duffy SW (2004) Tamoxifen and breast density in women at increased risk of breast cancer. J Natl Cancer Inst 96(8):621–628

    Article  PubMed  CAS  Google Scholar 

  24. Konez O, Goyal M, Reaven RE (2001) Can tamoxifen cause a significant mammographic density change in breast parenchyma? Clin Imaging 25(5):303–308

    Article  PubMed  CAS  Google Scholar 

  25. Son HJ, Oh KK (1999) Significance of follow-up mammography in estimating the effect of tamoxifen in breast cancer patients who have undergone surgery. AJR Am J Roentgenol 173(4):905–909

    PubMed  CAS  Google Scholar 

  26. Ursin G, Pike MC, Spicer DV, Porrath SA, Reitherman RW (1996) Can mammographic densities predict effects of tamoxifen on the breast? J Natl Cancer Inst 88(2):128–129

    PubMed  CAS  Google Scholar 

  27. Cuzick J, Warwick J, Pinney L et al (2008) Change in breast density as a biomarker of breast cancer risk reduction; results from IBIS-1. In: Abstract #61. Presented at the 2008 annual San Antonio breast cancer symposium, 2008

  28. Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE (1995) In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1(12):1511–1515

    PubMed  CAS  Google Scholar 

  29. Geisler J (2003) Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol 86(3–5):245–253

    Article  PubMed  CAS  Google Scholar 

  30. Miller WR, Dixon JM (2001) Local endocrine effects of aromatase inhibitors within the breast. J Steroid Biochem Mol Biol 79(1–5):93–102

    Article  PubMed  CAS  Google Scholar 

  31. Cigler T, Tu D, Yaffe MJ, Findlay B, Verma S, Johnston D et al (2010) A randomized, placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women. Breast Cancer Res Treat 120(2):427–435

    Article  PubMed  CAS  Google Scholar 

  32. Vachon CM, Ingle JN, Suman VJ, Scott CG, Gottardt H, Olson JE et al (2007) Pilot study of the impact of letrozole vs. placebo on breast density in women completing 5 years of tamoxifen. Breast 16(2):204–210

    Article  PubMed  CAS  Google Scholar 

  33. Jong R, Fishell E, Little L, Lockwood G, Boyd NF (1996) Mammographic signs of potential relevance to breast cancer risk: the agreement of radiologists’ classification. Eur J Cancer Prev 5(4):281–286

    Article  PubMed  CAS  Google Scholar 

  34. Byng JW, Boyd NF, Fishell E, Jong RA, Yaffe MJ (1994) The quantitative analysis of mammographic densities. Phys Med Biol 39(10):1629–1638

    Article  PubMed  CAS  Google Scholar 

  35. Fabian CJ, Kimler BF, Zalles CM, Khan QJ, Mayo MS, Phillips TA et al (2007) Reduction in proliferation with six months of letrozole in women on hormone replacement therapy. Breast Cancer Res Treat 106(1):75–84

    Article  PubMed  CAS  Google Scholar 

  36. Becker S, Kaaks R (2009) Exogenous and endogenous hormones, mammographic density and breast cancer risk: can mammographic density be considered an intermediate marker of risk? Recent Results Cancer Res 181:135–157

    Article  PubMed  CAS  Google Scholar 

  37. Martin LJ, Minkin S, Boyd NF (2009) Hormone therapy, mammographic density, and breast cancer risk. Maturitas 64(1):20–26

    Article  PubMed  CAS  Google Scholar 

  38. Barni S, Lissoni P, Meregalli S, Ardizzoia A, Mengo S, Musco F et al (1998) Clinical efficacy of the aromatase inhibitor anastrozole in relation to prolactin secretion in heavily pretreated metastatic breast cancer. Tumori 84(1):45–47

    PubMed  CAS  Google Scholar 

  39. Harper-Wynne C, Ross G, Sacks N, Salter J, Nasiri N, Iqbal J et al (2002) Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention. Cancer Epidemiol Biomarkers Prev 11(7):614–621

    PubMed  CAS  Google Scholar 

  40. Lonning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI et al (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23(22):5126–5137

    Article  PubMed  CAS  Google Scholar 

  41. Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP et al (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 24(22):3629–3635

    Article  PubMed  CAS  Google Scholar 

  42. Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S et al (2005) The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 16(5):707–715

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Paul Goss is supported in part by The Avon Foundation, New York. This project was supported by Pfizer Inc and the Canadian Cancer Society. We are also indebted to the hardworking investigators and staff at the participating MAP.2 centres and to all the women who generously agreed to participate in this trial.

Author information

Authors and Affiliations

  1. Weill Cornell Medical College, New York, NY, USA

    T. Cigler

  2. NCIC Clinical Trials Group, Kingston, ON, Canada

    H. Richardson, D. Johnston, J. L. Pater & D. Tu

  3. Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    M. J. Yaffe

  4. Kansas University Medical Center, Kansas City, KS, USA

    C. J. Fabian

  5. Mayo Clinic, Rochester, MN, USA

    J. N. Ingle

  6. Notre Dame Hospital, Montreal, QC, Canada

    E. Nassif

  7. University of Nevada School of Medicine, Reno, NV, USA

    R. L. Brunner

  8. Fletcher Allen Health Care, Burlington, VT, USA

    M. E. Wood

  9. Harvard Medical School, Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Lawrence House, LRH-302, Boston, Massachusetts, 02114, USA

    H. Hu, S. Qi & P. E. Goss

Authors
  1. T. Cigler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. J. Yaffe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. J. Fabian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. N. Ingle
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Nassif
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. L. Brunner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. E. Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. L. Pater
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H. Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S. Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D. Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P. E. Goss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. E. Goss.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cigler, T., Richardson, H., Yaffe, M.J. et al. A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women. Breast Cancer Res Treat 126, 453–461 (2011). https://doi.org/10.1007/s10549-010-1322-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-1322-0

Keywords

Search

Navigation