Breast Cancer Research and Treatment

, Volume 116, Issue 3, pp 595–602

Hazard of recurrence and adjuvant treatment effects over time in lymph node-negative breast cancer

  • James J. Dignam
  • Vanja Dukic
  • Stewart J. Anderson
  • Eleftherios P. Mamounas
  • D. Lawrence Wickerham
  • Norman Wolmark


Background For patients with axillary lymph node-negative breast cancer, benefits from adjuvant therapy are smaller than in node-positive disease and thus more selective use is warranted, prompting development of risk profiling to identify those most likely to benefit. Examination of the magnitude and changes in the hazard of failure over time in node-negative breast cancer may also be informative in this regard. Methods Among 9,444 participants from five randomized trials (accrual 1982–1998) investigating chemotherapy and tamoxifen for node-negative breast cancer, we estimated recurrence hazards over time by tumor estrogen receptor (ER) status and adjuvant treatment. Results In patients treated by surgery only, we observed the previously noted larger hazard peak followed by a rapid decrease in ER-negative patients and smaller but more persistent hazard in ER-positive patients. After approximately 48 months, the ER-positive hazard is greater. For adjuvant treatment, while tamoxifen decreases the early hazard in ER-positive patients to that of the chemotherapy-treated ER-negative group, in later follow-up (beyond 5 years) the hazard for ER-positive patients again exceeds that of ER-negative patients. Adding chemotherapy to tamoxifen in ER-positive patients results in large early hazard reduction, but in later follow-up the hazard converges with those of patients treated by surgery only or tamoxifen. Conclusions Recurrence hazards over time reveal changes in risk that may have biologic and therapeutic strategy relevance. In ER-negative tumors, a large early chemotherapy benefit is followed by a consistently low recurrence hazard over time. In ER-positive patients, the chemotherapy benefit appears concentrated mostly in earlier follow-up, and a greater recurrence risk remains.


Lymph node-negative Estrogen receptor Systemic adjuvant therapy Hazard Prognosis 


  1. 1.
    National Institutes of Health Consensus Development Panel (2001) National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst Monogr 30:5–15Google Scholar
  2. 2.
    Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival. Lancet 365:1687–1717CrossRefGoogle Scholar
  3. 3.
    Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826PubMedCrossRefGoogle Scholar
  4. 4.
    Paik S, Tang G, Shak S et al (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734PubMedCrossRefGoogle Scholar
  5. 5.
    Robbins GF, Berg J (1977) Curability of patients with invasive breast carcinoma based on a 30-year study. World J Surg 1:284–286PubMedCrossRefGoogle Scholar
  6. 6.
    Karrison T, Ferguson D, Meier P (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91:80–85PubMedCrossRefGoogle Scholar
  7. 7.
    Saphner T, Tormey D, Gray R (1996) Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738–2746PubMedGoogle Scholar
  8. 8.
    Hilsenbeck SG, Ravdin PM, de Moor CA et al (1998) Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 52:227–237PubMedCrossRefGoogle Scholar
  9. 9.
    Hess K, Pusztai L, Buzdar A et al (2003) Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat 78:105–118PubMedCrossRefGoogle Scholar
  10. 10.
    Anderson WF, Chen RE, Jatoi I et al (2006) Effect of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer. Breast Cancer Res Treat 100:121–126PubMedCrossRefGoogle Scholar
  11. 11.
    Fisher B, Jeong J-H, Anderson S et al (2004) Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96:1823–1831PubMedGoogle Scholar
  12. 12.
    Fisher B, Jeong J-H, Bryant J et al (2004) Treatment of lymph node-negative, estrogen receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. Lancet 364:858–868PubMedCrossRefGoogle Scholar
  13. 13.
    Fisher B, Redmond C, Dimitrov NV et al (1989) A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 320:473–478PubMedGoogle Scholar
  14. 14.
    Fisher B, Dignam J, Mamounas EP et al (1996) Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 14:1982–1992PubMedGoogle Scholar
  15. 15.
    Fisher B, Anderson S, Tan-Chiu E et al (2001) Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19:931–942PubMedGoogle Scholar
  16. 16.
    Fisher B, Costantino J, Redmond C et al (1989) A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med 320:479–484PubMedGoogle Scholar
  17. 17.
    Fisher B, Dignam J, Bryant J et al (1996) Five versus more than five years of tamoxifen for lymph node-negative breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 88:1529–1542PubMedCrossRefGoogle Scholar
  18. 18.
    Fisher B, Dignam JJ, Wolmark N et al (1997) Tamoxifen and chemotherapy for lymph node-negative, estrogen-receptor positive breast cancer. J Natl Cancer Inst 89:1673–1682PubMedCrossRefGoogle Scholar
  19. 19.
    Cox DR (1972) Regression models and life tables. J R Stat Soc B 34:187–220Google Scholar
  20. 20.
    Prentice RL, Kalbfleisch JD, Peterson AV et al (1978) The analysis of failure times in the presence of competing risks. Biometrics 34:541–554PubMedCrossRefGoogle Scholar
  21. 21.
    Kalbfleisch J, Prentice R (1980) The statistical analysis of failure time data. Wiley, New YorkGoogle Scholar
  22. 22.
    Sargent D (1997) A flexible approach to time-varying coefficients in the Cox regression setting. Lifetime Data Anal 3:13–25PubMedCrossRefGoogle Scholar
  23. 23.
    Gray RJ (1992) Flexible methods for analyzing survival data using splines, with applications to breast cancer prognosis. J Am Stat Assoc 87:942–951CrossRefGoogle Scholar
  24. 24.
    Hess KR (1994) Assessing time-by-covariate interactions in proportional hazards regression models using cubic spline functions. Stat Med 13:1045–1062PubMedCrossRefGoogle Scholar
  25. 25.
    Grambsch PM, Therneau TM, Fleming TR (1995) Diagnostic plots to reveal functional form for covariates in multiplicative intensity models. Biometrics 51:1469–1482PubMedCrossRefGoogle Scholar
  26. 26.
    Müller HG, Wang JL (1994) Hazard rates estimation under random censoring with varying kernels and bandwidths. Biometrics 50:61–76PubMedCrossRefGoogle Scholar
  27. 27.
    Hess KR, Serachitopol DM, Brown BW (1999) Hazard function estimators: a simulation study. Stat Med 18:3075–3088PubMedCrossRefGoogle Scholar
  28. 28.
    Berry DA, Cirrincione C, Henderson IC et al (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658–1667PubMedCrossRefGoogle Scholar
  29. 29.
    Cardoso F, Van’t Veer L, Rutgers E et al (2008) Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 26:729–735PubMedCrossRefGoogle Scholar
  30. 30.
    Bryant J, Fisher B, Gündüz N et al (1998) S-phase fraction combined with other patient and tumor characteristics for the prognosis of node-negative, estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 51:239–253PubMedCrossRefGoogle Scholar
  31. 31.
    Goss PE, Ingle JN, Martino S et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA. 17. J Natl Cancer Inst 97:1262–1271PubMedCrossRefGoogle Scholar
  32. 32.
    Goss PE, Ingle JN, Pater JL et al (2008) Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol 26:1948–1955PubMedCrossRefGoogle Scholar
  33. 33.
    Mamounas EP, Jeong JH, Wickerham DL et al (2008) Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol 26:1965–1971PubMedCrossRefGoogle Scholar
  34. 34.
    Lin NU, Winer EP (2008) Advances in adjuvant endocrine therapy for postmenopausal women. J Clin Oncol 26:798–805PubMedCrossRefGoogle Scholar
  35. 35.
    Aalen O, Gjessing H (2001) Understanding the shape of the hazard rate: a process point of view. Stat Sci 16:1–22Google Scholar
  36. 36.
    Singpurwulla N (2006) The hazard potential: introduction and overview. J Am Stat Assoc 101:1705–1717CrossRefGoogle Scholar
  37. 37.
    Lawless J (1982) Statistical models and methods for lifetime data. Wiley, New YorkGoogle Scholar
  38. 38.
    Berry D (2005) Breast cancer heterogeneity may explain peaks in recurrence. Int J Surg 3:287PubMedCrossRefGoogle Scholar
  39. 39.
    Dignam JJ, Dukic V (2008) Comment on: Yin W Di G, Zhou L et al. Time-varying patterns of recurrence risk for Chinese breast cancer patients. Breast Cancer Res Treat Jun 21 (Epub ahead of print)Google Scholar
  40. 40.
    Demicheli R, Abbattista A, Miceli R et al (1996) Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res Treat 41:177–185PubMedCrossRefGoogle Scholar
  41. 41.
    Demicheli R, Valagussa P, Bonadonna G (2001) Does surgery modify growth kinetics of breast cancer micrometastases? Br J Cancer 85:490–492PubMedCrossRefGoogle Scholar
  42. 42.
    Baum M, Cuzick J, Howell A et al (2005) An exploration of relapse data by hazard rate as a means of developing biological insights into the natural history and treatment of breast cancer. J Clin Oncol. 2005 ASCO annual meeting proceedings, vol 23, No. 16S (June 1 Supplement), p 612Google Scholar
  43. 43.
    Rastogi P, Anderson SJ, Bear HD et al (2008) Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26:778–785PubMedCrossRefGoogle Scholar
  44. 44.
    Jeong JH, Jung SH, Wieand S (2003) A parametric model for long-term follow-up data from phase III breast cancer clinical trials. Stat Med 22:339–352PubMedCrossRefGoogle Scholar
  45. 45.
    Dukic V, Dignam J (2007) Bayesian hierarchical multiresolution model for the study of time-dependent patterns of failure in early stage breast cancer. Bayesian Anal 2:591–610CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • James J. Dignam
    • 1
    • 2
  • Vanja Dukic
    • 1
  • Stewart J. Anderson
    • 2
    • 3
  • Eleftherios P. Mamounas
    • 4
    • 5
  • D. Lawrence Wickerham
    • 4
    • 6
  • Norman Wolmark
    • 4
    • 6
  1. 1.Department of Health StudiesThe University of ChicagoChicagoUSA
  2. 2.National Surgical Adjuvant Breast and Bowel Project (NSABP) Biostatistical CenterPittsburghUSA
  3. 3.Department of BiostatisticsUniversity of PittsburghPittsburghUSA
  4. 4.NSABP Operation CenterPittsburghUSA
  5. 5.Altman Cancer CenterCantonUSA
  6. 6.Allegheny General HospitalPittsburghUSA

Personalised recommendations