Breast Cancer Research and Treatment

, Volume 143, Issue 1, pp 159–169 | Cite as

Symptoms of endocrine treatment and outcome in the BIG 1-98 study

  • J. HuoberEmail author
  • B. F. Cole
  • M. Rabaglio
  • A. Giobbie-Hurder
  • J. Wu
  • B. Ejlertsen
  • H. Bonnefoi
  • J. F. Forbes
  • P. Neven
  • I. Láng
  • I. Smith
  • A. Wardley
  • K. N. Price
  • A. Goldhirsch
  • A. S. Coates
  • M. Colleoni
  • R. D. Gelber
  • B. Thürlimann
  • for the BIG 1-98 Collaborative and International Breast Cancer Study Groups
Clinical trial


There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen. Data on patients randomized into the monotherapy arms of the BIG 1-98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n = 4,798) and at the 12-month landmark (n = 4,682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed for disease-free survival (DFS) and for breast cancer free interval (BCFI), using regression analysis to estimate hazard ratios (HR) and 95 % confidence intervals (CI). Median follow-up was 7.0 years. Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses [e.g., 12-month landmark, HR (95 % CI) for DFS = 0.65 (0.49–0.87), and for BCFI = 0.70 (0.49–0.99)]. By contrast, reporting of vasomotor symptoms was less clearly associated with DFS [12-month DFS HR (95 % CI) = 0.82 (0.70–0.96)] and BCFI (12-month DFS HR (95 % CI) = 0.97 (0.80–1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes. While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.


Aromatase inhibitor Side effects Breast cancer Endocrine therapy 



The BIG 1-98 trial was sponsored 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), the National Cancer Institute Grant CA-75362, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK).

Conflicts of interest

None: Jens Huober, Bernard F. Cole, Manuela Rabaglio, Anita Giobbie-Hurder, Jimin Wu, Karen N. Price, Alan S. Coates, Richard D. Gelber, Hervé Bonnefoi, István Láng, Ian Smith, Marco Colleoni, Aron Goldhirsch, Patrick Neven Novartis advisory board, Novartis research support: Bent Ejlertsen Novartis honoraria: Andrew Wardley, John F. Forbes Astra Zeneca honoraria, Genomic Health Consultancy/Advisory: John F. Forbes Novartis stock: Beat Thürlimann


  1. 1.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378:771–784PubMedCrossRefGoogle Scholar
  2. 2.
    Regan MM, Neven P, Giobbie-Hurder A et al (2011) Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol 12:1101–1108PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Cuzick J, Sestak I, Baum M et al (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer. 10-year analysis of the ATAC trial. Lancet Oncol 11:1135–1141PubMedCrossRefGoogle Scholar
  4. 4.
    Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092PubMedCrossRefGoogle Scholar
  5. 5.
    Simpson ER, Davis SR (2001) Minireview: aromatase and the regulation of estrogen biosynthesis-some new perspectives. Endocrinology 142:4589–4594PubMedCrossRefGoogle Scholar
  6. 6.
    Gaillard S, Stearns V (2011) Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management. Breast Cancer Res 13:205PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Stearns V, Johnson MD, Rae JM et al (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764PubMedCrossRefGoogle Scholar
  8. 8.
    Jin Y, Desta Z, Stearns V et al (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39PubMedCrossRefGoogle Scholar
  9. 9.
    Borges S, Desta Z, Li L et al (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61–74PubMedCrossRefGoogle Scholar
  10. 10.
    Amir E, Seruga B, Niraula S et al (2011) Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 103:1299–1309PubMedCrossRefGoogle Scholar
  11. 11.
    Henry NL, Azzouz F, Desta Z et al (2012) Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol 30:936–942PubMedCrossRefGoogle Scholar
  12. 12.
    Peréz-Soler R, Saltz L (2005) Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 23:5235–5246PubMedCrossRefGoogle Scholar
  13. 13.
    Jubb AM, Harris AL (2010) Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 11:1172–1183PubMedCrossRefGoogle Scholar
  14. 14.
    Anderson JR, Cain KC, Gelber RD (1983) Analysis of survival by tumor response. J Clin Oncol 11:710–719Google Scholar
  15. 15.
    Agresti A (2001) Exact inference for categorical data: recent advances and continuing controversies. Stat Med 20:2709–2722PubMedCrossRefGoogle Scholar
  16. 16.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  17. 17.
    Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemotherapy Reports 50:163–170Google Scholar
  18. 18.
    Gray RJ (1988) A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154CrossRefGoogle Scholar
  19. 19.
    Cox DR (1972) Regression models and life tables. J R Stat Soc B 34:187–220Google Scholar
  20. 20.
    Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509CrossRefGoogle Scholar
  21. 21.
    Fleming TR, Harrington DP (1991) Counting processes and survival analysis. Wiley, New York, pp 147–148Google Scholar
  22. 22.
    Cuzick J, Sestak I, Cella D et al (2008) Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol 9:1143–1148PubMedCrossRefGoogle Scholar
  23. 23.
    van de Velde CJ, Rea D, Seynaeve C et al (2011) Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377:321–331PubMedCrossRefGoogle Scholar
  24. 24.
    Hadji P, Kieback DG, Tams J et al (2012) Correlation of treatment-emergent adverse events and clinical response to endocrine therapy in early breast cancer: a retrospective analysis of the German cohort of TEAM. Ann Oncol 23:2566–2572PubMedCrossRefGoogle Scholar
  25. 25.
    Fontein DB, Seynaeve C, Hadji P et al (2013) Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol 31:2257–2264PubMedCrossRefGoogle Scholar
  26. 26.
    Stearns V, Chapman JW, Ma CX et al (2011) Relationship of treatment-emergent symptoms and recurrence-free survival in the NCIC CTG MA.27 adjuvant aromatase inhibitor trial. J Clin Oncol 29(31):4189–4198CrossRefGoogle Scholar
  27. 27.
    Stearns V, Chapman JA, Ma C et al (2009) Treatment emergent symptoms and the risk of breast cancer recurrence in the NCIC CTG MA 27. Adjuvant aromatase inhibitor trial. Cancer Res 69(20):1489–1498Google Scholar
  28. 28.
    Mieog JSD, Morden JP, Bliss JM et al (2012) Carpal tunnel symptoms and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2–3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study. Lancet Oncol 13:420–432PubMedCrossRefGoogle Scholar
  29. 29.
    Park IH, Lee YS, Lee KS et al (2011) Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer. Cancer Chemother Pharmacol 68:1263–1271PubMedCrossRefGoogle Scholar
  30. 30.
    Mao JJ, Su HI, Feng R et al (2011) Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors. Breast Cancer Res 13:R8PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Ingle JN, Schaid DJ, Goss PE (2010) Genome-wide association and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. J Clin Oncol 28:4674–4682PubMedCrossRefGoogle Scholar
  32. 32.
    Mortimer JE, Flatt SW, Parker BA et al (2008) Tamoxifen, hot flashes and breast cancer recurrence. Breast Cancer Res and Treat 108:421–426CrossRefGoogle Scholar
  33. 33.
    Regan MM, Leyland-Jones B, Bouzyk M et al (2012) CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst 104:441–451PubMedCrossRefGoogle Scholar
  34. 34.
    Rae JM, Drury S, Hayes DF et al (2012) CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst 104:452–460PubMedCrossRefGoogle Scholar
  35. 35.
    Basch E, Jia X, Heller G et al (2009) Adverse symptom event reporting by patients versus clinicians: relationships with clinical outcomes. J Natl Cancer Inst 101:1624–1632PubMedCrossRefGoogle Scholar
  36. 36.
    Basch E, Iasonos A, McDonough T et al (2006) Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol 7:903–909PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • J. Huober
    • 1
    • 2
    • 19
    Email author
  • B. F. Cole
    • 3
    • 4
  • M. Rabaglio
    • 5
    • 6
  • A. Giobbie-Hurder
    • 4
  • J. Wu
    • 3
  • B. Ejlertsen
    • 7
  • H. Bonnefoi
    • 8
  • J. F. Forbes
    • 9
  • P. Neven
    • 10
  • I. Láng
    • 11
  • I. Smith
    • 12
  • A. Wardley
    • 13
  • K. N. Price
    • 4
    • 14
  • A. Goldhirsch
    • 15
  • A. S. Coates
    • 5
    • 16
  • M. Colleoni
    • 17
  • R. D. Gelber
    • 4
    • 14
    • 18
  • B. Thürlimann
    • 1
    • 2
  • for the BIG 1-98 Collaborative and International Breast Cancer Study Groups
  1. 1.Breast CenterKantonsspital St. GallenSt. GallenSwitzerland
  2. 2.Swiss Group for Clinical Cancer Research (SAKK)BernSwitzerland
  3. 3.Department of Mathematics and Statistics, College of Engineering and Mathematical SciencesUniversity of VermontBurlingtonUSA
  4. 4.IBCSG Statistical Center, Department of Biostatistics and Computational BiologyDana-Farber Cancer InstituteBostonUSA
  5. 5.International Breast Cancer Study GroupBernSwitzerland
  6. 6.Department of Medical OncologyInselspitalBernSwitzerland
  7. 7.Danish Breast Cancer Cooperative Group (DBCG) Statistical Center and Department of Oncology, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  8. 8.Department of Medical Oncology, Institut BergoniéUniversité de Bordeaux, INSERM U916, FNCLCC (Unicancer)BordeauxFrance
  9. 9.Australia and New Zealand Breast Cancer Trials GroupUniversity of Newcastle, Calvary Mater NewcastleNewcastleAustralia
  10. 10.Department of Medical OncologyUniversity Hospital Gasthuisberg, Catholic University of LeuvenLeuvenBelgium
  11. 11.National Institute of OncologyBudapestHungary
  12. 12.The Royal Marsden HospitalLondonUK
  13. 13.Christie Hospital NHS TrustSouth Manchester University Hospital TrustManchesterUK
  14. 14.Frontier Science and Technology Research FoundationBostonUSA
  15. 15.Department of MedicineEuropean Institute of OncologyMilanItaly
  16. 16.University of SydneySydneyAustralia
  17. 17.Research Unit in Medical Senology, Department of MedicineEuropean Institute of OncologyMilanItaly
  18. 18.Harvard School of Public Health and Harvard Medical SchoolBostonUSA
  19. 19.Department of GynecologyUniversity of UlmUlmGermany

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