Breast Cancer Research and Treatment

, Volume 78, Issue 1, pp 105–118 | Cite as

Estrogen Receptors and Distinct Patterns of Breast Cancer Relapse

  • Kenneth R. Hess
  • Lajos Pusztai
  • Aman U. Buzdar
  • Gabriel N. Hortobagyi


Background. We conducted an analysis of prospectively collected data to compare the clinical behavior of ER-negative versus ER-positive tumors with respect to rates and sites of recurrence.

Methods. A total of 647 patients with operable stage II or III breast cancer were enrolled in two consecutive adjuvant therapy protocols conducted between 1980 and 1986. The correlations between ER status and time to first recurrence, site of first recurrence, and time to breast cancer death were assessed on 558 (86%) patients with available ER status data using hazard function and hazard ratio function analysis.

Results. The rates of recurrence were significantly higher in patients with ER-negative status for the first two years of follow-up, but not thereafter. Similar results were observed for breast cancer death, and these results held up after adjustment for differences in treatment, age, menopausal status, and tumor burden. When the site of first recurrence was studied, ER-negative status was associated with a significantly higher rate of tumor recurrence in the viscera and soft tissues, while ER-positive status was associated with significantly higher rates of tumor recurrence involving bone.

Conclusions. The clinical behavior of ER-positive tumors is different from ER-negative cancer. ER status had a pronounced effect on the rates and sites of recurrence. Furthermore, this apparent association diminished over the follow-up period. Recurrence rates were significantly higher in patients with ER-negative status for the first two years of follow-up, but not thereafter.

breast cancer estrogen receptors recurrence rates recurrence sites relapse patterns 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tumor Marker Expert Panel of the American Society of Clinical Oncology: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. J Clin Oncol 14: 2843-2877, 1996Google Scholar
  2. 2.
    Scholl S, Lippman ME: Methods and clinical use of receptor assay. In: Bonadonna G (ed) Breast Cancer: Diagnosis and Management. John Wiley &; Sons, London, 1984, pp 75-108Google Scholar
  3. 3.
    Wang W, Smith R, Burghardt R, Safe SH: 17beta estradiolmediated growth inhibition of MDA-MB-468 cells stably Estrogen receptors and relapse patterns 117 transfected with the estrogen receptor: cell cycle effects. Mol Cell Endocrinol 133: 49-62, 1997Google Scholar
  4. 4.
    Sheikh MA, Garcia M, Pujol P, Fontana JA, Rochefort H:Why are estrogen-receptor-negative breast cancers more aggressive than the estrogen-receptor-positive breast cancers? Invas Metast 14: 329-336, 1995Google Scholar
  5. 5.
    Martin KJ, Kritzman BM, Price LM, Koh B, Kwan C-P, Zhang X, Mackay A, O'Hare MJ, Kaelin CM, Mutter GL, Pardee AB, Sager R: Linking gene expression patterns to therapeutic groups in breast cancer. Cancer Res 60: 2232-2238, 2000Google Scholar
  6. 6.
    Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer S: Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res 61: 5979-5984, 2001Google Scholar
  7. 7.
    Raemaekers JM, Beex LV, Koenders AJ, Pieters GF, Smals AG, Benraad TJ, Kloppenborg PW: Disease-free interval and estrogen receptor activity in tumor tissue of patients with primary breast cancer: analysis after long-term follow-up. Breast Cancer Res Treat 6(2): 123-130, 1985Google Scholar
  8. 8.
    Andry G, Suciu S, Pratola D, Sylvester R, Leclercq G, da Costa PM, Legros N, Andry-t'Hooft M, Verhest A, Mattheiem W: Relation between estrogen receptor concentration and clinical and histological factors: their relative prognostic importance after radical mastectomy for primary breast cancer. Eur J Cancer Clin Oncol 25(2): 319-329, 1989Google Scholar
  9. 9.
    Shek LL, Godolphin W: Survival with breast cancer: the importance of estrogen receptor quantity. Eur J Cancer Clin Oncol 25(2): 243-250, 1989Google Scholar
  10. 10.
    Crowe Jr JP, Gordon NH, Hubay CA, Shenk RR, Zollinger RM, Brumberg DJ, McGuire WL, Shuck JM: Estrogen receptor determination and long term survival of patients with carcinoma of the breast. Surg Gynecol Obstet 173(4): 273-278, 1991Google Scholar
  11. 11.
    Buzdar AU, Hortobagyi GN, Kau S-W, Holmes FA, Fraschini G, Theriault RL, McNeese M, Ross M, Singletary E: Breast cancer adjuvant therapy at the M.D. Anderson Cancer Center-results of four prospective studies. In: Salmon SE (ed) Adjuvant Therapy of Cancer VII: Proceedings of the Seventh International Conference on the Adjuvant Therapy of Cancer, Tuscon, AZ. J.B. Lippincott Co., Philadephia, PA, 1993, pp 220-225Google Scholar
  12. 12.
    Samaan NA, Buzdar AU, Aldinger KA, Schultz PN, Yang KP, Romsdahl MM, Martin R: Estrogen receptor: a prognostic factor in breast cancer. Cancer 47(3): 554-560, 1981Google Scholar
  13. 13.
    Holmes FA, Fritsche HA, Loewy JW: Measurement of estrogen and progesterone receptors in human breast tumors: enzyme immunoassay versus binding assay. J Clin Oncol 8: 1025-1035, 1990Google Scholar
  14. 14.
    Grambsch PM, Therneau TM: Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81: 515-526, 1994Google Scholar
  15. 15.
    Hess KR: Graphical methods for assessing violations of the proportional hazards assumption in Cox regression. Stat Med 14: 1707-1723, 1995Google Scholar
  16. 16.
    Hess KR, Serachitopol DM, Brown BW: Hazard function estimators: a simulation study. Stat Med 18(22): 3075-3088, 1999Google Scholar
  17. 17.
    Mueller HG, Wang JL: Hazard rate estimation under random censoring with varying kernels and bandwidth. Biometrics 50: 61-76, 1994Google Scholar
  18. 18.
    Therneau T, Grambsch P, Fleming T: Martingale based residuals for survival models. Biometrika 77: 147-160, 1990Google Scholar
  19. 19.
    Breiman L, Friedman JH, Olshen RA, Stone CJ: Classification and Regression Trees. Chapman and Hall, New York, NY, 1984Google Scholar
  20. 20.
    Hähnel R, Woodings T, Vivian AB: Prognostic value of estrogen receptors in primary breast cancer. Cancer 44(2): 671-675, 1979Google Scholar
  21. 21.
    Aamdal S, Børmer O, Jørgensen O: Estrogen receptors and long-term prognosis in breast cancer. Cancer 53: 2525-2529, 1984Google Scholar
  22. 22.
    Klintenberg C, Stål O, Nordenskjöld B, Wallgren A, Arvidsson S, Skoog L: Proliferative index, cytosol estrogen receptor and axillary node status as prognostic predictors in human mammary carcinoma. Breast Cancer Res Treat 7(Suppl): S99-S106, 1986Google Scholar
  23. 23.
    Winstanley J, Cooke T, Murray GD, Platt-Higgins A, George WD, Holt S, Myskov M, Spedding A, Barraclough BR, Rudland PS: The long term prognostic significance of oestrogen receptor analysis in early carcinoma of the breast. B J Cancer 64(1): 99-101, 1991Google Scholar
  24. 24.
    Howell A, Barnes DM, Harland RN, Reford J, Bramwell VH, Wilkinson MJ, Swindell R, Crowther D, Sellwood RA: Steroid-hormone receptors and survival after first relapse in breast cancer. Lancet 1(8377): 588-591, 1984Google Scholar
  25. 25.
    Blamey RW, Bishop HM, Blake JR, Doyle PJ, Elston CW, Haybittle JL, Nicholson RI, Griffiths K: Relationship between primary breast tumor receptor status and patient survival. Cancer 46(12 Suppl): 2765-2769, 1980Google Scholar
  26. 26.
    Saez S, Cheix F, Asselain B: Prognostic value of estrogen and progesterone receptors in primary breast cancer. Breast Cancer Res Treat 3: 345-354, 1983Google Scholar
  27. 27.
    Von Maillot K, Horke W, Prestele H: Prognostic significance of the steroid receptor content in primary breast cancer. Arch Gynecol Obstet 231: 185-190, 1982Google Scholar
  28. 28.
    Andersen J, Thorpe SM, Rose C, Christensen I, Rasmussen BB, Poulsen HS: Estrogen receptor in primary breast cancer estimated in paraffin-embedded tissue. A study of its usefulness compared to dextran-coated charcoal assay. Acta Oncol 30(6): 685-690, 1991Google Scholar
  29. 29.
    Cowen PN, Teasdale J, Jackson P, Reid BJ: Oestrogen receptor in breast cancer: prognostic studies using a new immunohistochemical assay. Histopathology 17(4): 319-325, 1990Google Scholar
  30. 30.
    Ciatto S, Palli D, Iossa A, Pacini P, Cataliotti L, Distante V, Teglia C, Caridi G, Messeri G: Prognostic significance of estrogen receptor determination in primary breast cancer. Radiother Oncol 12(3): 187-192, 1988Google Scholar
  31. 31.
    Clark GM, Wenger CR, Beardslee S, Owens MA, Pounds G, Oldaker T, Vendely P, Pandian MR, Harrington D, McGuire WL: How to integrate steroid hormone receptor, flow cytometric, and other prognostic information in regard to primary breast cancer. Cancer 71(6 Suppl): 2157-2162, 1993Google Scholar
  32. 32.
    Hawkins RA, White G, Bundred NJ, Dixon JM, Miller WR, Stewart HJ, Forrest AP: Prognostic significance of oestrogen and progestogen receptor activities in breast cancer. Br J Surg 74(11): 1009-1013, 1987Google Scholar
  33. 33.
    Butler JA, Bretsky S, Menendez-Botet C, Kinne DW: Estrogen receptor protein of breast cancer as a predictor of recurrence. Cancer 55(6): 1178-1181, 1985Google Scholar
  34. 34.
    Parl FF, Schmidt BP, Dupont WD, Wagner RK: Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading. Cancer 54(10): 2237-2242, 1984Google Scholar
  35. 35.
    Clark GM, Sledge GWJr, Osborne CK, McGuire WL: Survival from first recurrence: relative importance of prognostic factors in 1015 breast cancer patients. J Clin Oncol 5(1): 55-61, 1987Google Scholar
  36. 36.
    Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14(10): 2738-2746, 1996Google Scholar
  37. 37.
    Alanko A, Heinonen E, Scheinin T, Tolppanen EM, Vihko R: Significance of estrogen and progesterone receptors, diseasefree interval, and site of first metastasis on survival of breast cancer patients. Cancer 56(7): 1696-1700, 1985Google Scholar
  38. 38.
    Goldhirsch A, Gelber RD, Castiglione M: Relapse of breast cancer after adjuvant treatment in premenopausal and perimenopausal women: patterns and prognoses. J Clin Oncol 6: 89-97, 1988Google Scholar
  39. 39.
    Stewart JF, King RJ, Sexton SA, Millis RR, Rubens RD, Hayward JL: Oestrogen receptors, sites of metastatic disease and survival in recurrent breast cancer. Eur J Cancer 17(4): 449-453, 1981Google Scholar
  40. 40.
    Campbell FC, Blamey RW, Elston CW, Nicholson RJ, Griffiths K, Haybittle JL: Oestrogen-receptor status and sites of metastasis in breast cancer. Br J Cancer 44(3): 456-459, 1981Google Scholar
  41. 41.
    Lee Y-TN: Correlation of estrogen receptor with site of recurrence or metastasis and breast cancer prognosis. Breast 10: 27-31, 1984Google Scholar
  42. 42.
    Walt AJ, Singhakowinta A, Brooks SC, Cortez A: The surgical implications of estrophile protein estimations in carcinoma of the breast. Surgery 80(4): 506-512, 1976Google Scholar
  43. 43.
    Singhakowinta A, Potter HG, Buroker TR, Samal B, Brooks SC, Vaitkevicius VK: Estrogen receptor and natural course of breast cancer. Ann Surg 183(1): 84-88, 1976Google Scholar
  44. 44.
    Qazi R, Chuang J-LC, Drobyski W: Estrogen receptors and the pattern of relapse in breast cancer. Arch Intern Med 144: 2365-2367, 1984Google Scholar
  45. 45.
    Solomayer E-F, Diel IJ, Meyberg GC, Gollan Ch, Bastert G: Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59: 271-278, 2000Google Scholar
  46. 46.
    Goldhirsch A, Gelber RD, Price KN, Castiglione M, Coates AS, Rudenstam CM, Collins J, Lindtner J, Hacking A, Marini G: Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet 343(8894): 377-381, 1994Google Scholar
  47. 47.
    Balslev I, Christensen IJ, Rasmussen BB, Larsen JK, Lykkesfeldt AE, Thorpe SM, Rose C, Briand P, Mouridsen HT: Flow cytometric DNA ploidy defines patients with poor prognosis in node-negative breast cancer. Int J Cancer 56(1): 16-25, 1994Google Scholar
  48. 48.
    Yoshimoto M, Sakamoto G, Ohashi Y: Time dependence of the influence of prognostic factors on relapse in breast cancer. Cancer 72: 2993-3001, 1993Google Scholar
  49. 49.
    Gilchrist KW, Gray R, Fowble B, Tormev DC, Taylor 4th SG: Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node positive breast cancer: 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients. J Clin Oncol 11(10): 1929-1935, 1993Google Scholar
  50. 50.
    Gore SM, Pocock SJ, Kerr GR: Regression models and nonproportional hazards in the analysis of breast cancer survival. Appl Statist 33: 176-195, 1984Google Scholar
  51. 51.
    Gray RJ: Flexible methods for analyzing survival data using splines, with application to breast cancer prognosis. J Am Stat Assoc 87: 942-951, 1992Google Scholar
  52. 52.
    Hilsenbeck SG, Ravdin PM, de Moor CA, Chamness GC, Osborne CK, Clark GM: Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 52(1-3): 227-237, 1998Google Scholar
  53. 53.
    Schmitt M, Thomssen C, Ulm K, Seiderer A, Harbeck N, Hofler H, Janicke F, Graeff H: Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer. Br J cancer 76(3): 306-311, 1997Google Scholar
  54. 54.
    Collett K, Skjaerven R, Maehle BO: The prognostic contribution of estrogen and progesterone receptor status to a modified version of the Nottingham prognostic index. Breast Cancer Res Treat 48: 1-9, 1998Google Scholar
  55. 55.
    Coradini D, Daidone MG, Boracchi P, Biganzoli E, Oriana S, Bresciani G, Pellizzaro C, Tomasci G, Di Fronzo G, Marubini E: Time-dependent relevance of steroid receptors in breast cancer. J Clin Oncol 18: 2702-2709, 2000Google Scholar
  56. 56.
    Prentice RL, Kalbfleisch JD, Peterson Jr AV, Flournoy N, Farewell VI, Breslow NE: The analysis of failure times in the presence of competing risks. Biometrics 34(4): 541-554, 1978Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Kenneth R. Hess
    • 1
  • Lajos Pusztai
    • 2
  • Aman U. Buzdar
    • 2
  • Gabriel N. Hortobagyi
    • 2
  1. 1.Department of BiostatisticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Breast Medical OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations