Breast Cancer Research and Treatment

, Volume 144, Issue 2, pp 321–329 | Cite as

Bone mineral density and circulating biomarkers in the BIG 1-98 trial comparing adjuvant letrozole, tamoxifen and their sequences

  • Andrea DeCensi
  • Zhuoxin Sun
  • Aliana Guerrieri-Gonzaga
  • Beat Thürlimann
  • Christina McIntosh
  • Carlo Tondini
  • Alain Monnier
  • Mario Campone
  • Marc Debled
  • Astrid Schönenberger
  • Khalil Zaman
  • Harriet Johansson
  • Karen N. Price
  • Richard D. Gelber
  • Aron Goldhirsch
  • Alan S. Coates
  • Stefan Aebi
Clinical trial


The purpose of the study is to determine the effects of the BIG 1-98 treatments on bone mineral density. BIG 1-98 compared 5-year adjuvant hormone therapy in postmenopausal women allocated to four groups: tamoxifen (T); letrozole (L); 2-years T, 3-years L (TL); and 2-years L, 3-years T (LT). Bone mineral density T-score was measured prospectively annually by dual energy X-ray absorption in 424 patients enrolled in a sub-study after 3 (n = 150), 4 (n = 200), and 5 years (n = 74) from randomization, and 1 year after treatment cessation. Prevalence of osteoporosis and the association of C-telopeptide, osteocalcin, and bone alkaline phosphatase with T-scores were assessed. At 3 years, T had the highest and TL the lowest T-score. All arms except for LT showed a decline up to 5 years, with TL exhibiting the greatest. At 5 years, there were significant differences on lumbar T-score only between T and TL, whereas for femur T-score, differences were significant for T versus L or TL, and L versus LT. The 5-year prevalence of spine and femur osteoporosis was the highest on TL (14.5 %, 7.1 %) then L (4.3 %, 5.1 %), LT (4.2 %, 1.4 %) and T (4 %, 0). C-telopeptide and osteocalcin were significantly associated with T-scores. While adjuvant L increases bone mineral density loss compared with T, the sequence LT has an acceptable bone safety profile. C-telopeptide and osteocalcin are useful markers of bone density that may be used to monitor bone health during treatment. The sequence LT may be a valid treatment option in patients with low and intermediate risk of recurrence.


Breast cancer Adjuvant drug therapy Aromatase inhibitor Bone density Bone turnover 



This work was supported by Novartis and coordinated by IBCSG. Support for the IBCSG: Swedish Cancer Society; the Cancer Council Australia; Australia and New Zealand Breast Cancer Trials Group; Frontier Science and Technology Research Foundation; Swiss Group for Clinical Cancer Research (SAKK); National Institutes of Health [grant number CA-75362] to [RDG], Cancer Research Switzerland/Oncosuisse; and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK). We thank the patients, physicians, investigators, nurses, and data managers who participated in the BIG 1-98 Bone Sub-study

Conflict of interest

M. Campone: Honorarium and consultant from Novartis; B. Thürlimann stock ownership Novartis; M Debled: consultant from Novartis; A Monnier consultant from Novartis; all remaining authors have declared no conflicts of interest.

Supplementary material

10549_2014_2849_MOESM1_ESM.pdf (23 kb)
Supplementary material 1 (PDF 23 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Andrea DeCensi
    • 1
    • 3
  • Zhuoxin Sun
    • 2
  • Aliana Guerrieri-Gonzaga
    • 3
  • Beat Thürlimann
    • 4
  • Christina McIntosh
    • 5
  • Carlo Tondini
    • 6
  • Alain Monnier
    • 7
  • Mario Campone
    • 8
  • Marc Debled
    • 9
  • Astrid Schönenberger
    • 10
  • Khalil Zaman
    • 11
  • Harriet Johansson
    • 3
  • Karen N. Price
    • 12
  • Richard D. Gelber
    • 13
  • Aron Goldhirsch
    • 14
  • Alan S. Coates
    • 15
    • 16
  • Stefan Aebi
    • 17
  1. 1.Division of Medical OncologyE.O. Ospedali GallieraGenoaItaly
  2. 2.International Breast Cancer Study Group (IBCSG) Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer InstituteHarvard School of Public healthBostonUSA
  3. 3.Division of Cancer Prevention and GeneticsEuropean Institute of OncologyMilanItaly
  4. 4.Breast CenterKantonsspital, St. Gallen and Swiss Group for Clinical Cancer Research (SAKK)BernSwitzerland
  5. 5.Department of BiostatisticsHarvard School of Public HealthBostonUSA
  6. 6.Oncologia MedicaOspedale Papa Giovanni XXIIIBergamoItaly
  7. 7.University of Franche Comté, IRMA Team-UMR 6249 CNRSMontbèliardFrance
  8. 8.Department of Medical OncologyInstitut de Cancérologie de l’OUESTNantesFrance
  9. 9.Department of MedicineInstitut BergoniéBordeauxFrance
  10. 10.Spital Langenthal SRO AGLangenthalSwitzerland
  11. 11.Breast CenterUniversity Hospital CHUV, Lausanne, Switzerland and Swiss Group for Clinical Cancer Research (SAKK)BernSwitzerland
  12. 12.International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer InstituteFrontier Science and Technology Research FoundationBostonUSA
  13. 13.International Breast Cancer Study Group (IBCSG) Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public HealthHarvard Medical SchoolBostonUSA
  14. 14.Division of Medical OncologyEuropean Institute of OncologyMilanItaly
  15. 15.International Breast Cancer Study GroupBernSwitzerland
  16. 16.University of SydneyDarlingtonAustralia
  17. 17.Luzerner Kantonsspital, LucerneUniversity of Bern, and Swiss Group for Clinical Cancer Research (SAKK)BernSwitzerland

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