Abstract
One of the most controversial questions in early breast cancer treatment is the need of chemotherapy in patients with estrogen receptor positive disease. Therefore, we analyzed a group of patients with high estrogen receptor (ER) expression to scrutinize the role of chemotherapy in this situation. To gauge the effect of chemotherapy on recurrence free survival (RFS) three treatment modalities were compared: endocrine treatment only, chemoendocrine treatment, and chemotherapy. 3,971 breast cancer patients whose treatment modalities as well as ER level were known, were included in this retrospective analysis. Their level of ER expression was documented as immunoreactive score (IRS). A high ER group was defined as ER IRS ≥9; primary endpoint was RFS. RFS was associated with ER, with the best outcome for strong and the worst result for negative expression. Adjusted to Nottingham prognostic index (NPI), RFS did not differ between the treatment cohorts of endocrine treatment and chemoendocrine treatment (P = 0.828) in the high ER group. Patients with chemotherapy alone fared significantly worse (P = 0.003). Even in high risk patients (according to NPI) the chemoendocrine and the endocrine treatment only groups did not differ significantly (HR = 1.15; 95% CI (0.56–2.34), P = 0.709). Omission of endocrine treatment led to significantly worse outcome (P = 0.013). In conclusion, RFS was significantly longer in patients with high ER expression than with weak or no ER expression. In the high expression group, there was no significant difference in RFS between endocrine treatment only and chemoendocrine therapy—even in high risk patients, for whom chemoendocrine treatment is routinely indicated. It seems insufficient for high ER patients to only consider tumor size, nodal status, and grading in order to decide which patient will benefit from adding chemotherapy to endocrine treatment.
Similar content being viewed by others
References
Goldhirsch A, Ingle JN, Gelber RD et al (2009) Thresholds for therapies: highlights of the St. Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20(8):1319–1329
Montemurro F, Aglietta M (2009) Hormone receptor-positive early breast cancer: controversies in the use of adjuvant chemotherapy. Endocr Relat Cancer 16(4):1091–1102
Hassett MJ, Hughes ME, Niland JC et al (2008) Chemotherapy use for hormone receptor-positive, lymph node-negative breast cancer. J Clin Oncol 26(34):5553–5560
Thürlimann B, Price K, Gelber RD et al (2009) Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11–93. Breast Cancer Res Treat 113(1):137–144
Pagani O, Gelber S, Simoncini E et al; International Breast Cancer Study Group (2009) Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12–93. Breast Cancer Res Treat 116(3):491–500
Viale G, Regan MM, Maiorano E et al (2008) Chemoendocrine compared with endocrine adjuvant therapies for node-negative breast cancer: predictive value of centrally reviewed expression of estrogen and progesterone receptors—International Breast Cancer Study Group. J Clin Oncol 26(9):1404–1410
Colleoni M, Bagnardi V, Rotmensz N et al (2008) Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy. Breast Cancer Res Treat 116(2):359–369
Grimes DA, Schulz KF (2002) Bias and causal associations in observational research. Lancet 359:248–252
Booth CM, Tannock IF (2008) Reflections on medical oncology. Twenty-five years of clinical trials in oncology: where have we come and where are we going? J Clin Oncol 26:6–8
Haynes B (1999) Can it work? Does it work? Is it worth it? The testing of healthcare interventions is evolving. Br Med J 7211:652–653
Goldhirsch A, Wood WC, Gelber RD et al (2007) 10th St. Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18(7):1133–1144
International Breast Cancer Study Group (IBCSG) (2002) Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 94(14):1054–1065
International Breast Cancer Study Group, Colleoni M, Gelber S et al (2006) Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13–93. J Clin Oncol 24(9):1332–1341
Hutchins LF, Green SJ, Ravdin PM et al (2005) Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23(33):8313–8321
Chia S, Gradishar W (2008) Fulvestrant: expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer. Breast 17(Suppl 3):16–21
Harvey JM, Clark GM, Osborne CK et al (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481
Elledge RM, Green S, Pugh R et al (2000) Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer 89(2):111–117
Andre F, Broglio K, Roche H et al (2008) Estrogen receptor expression and efficacy of docetaxel-containing adjuvant chemotherapy in patients with node-positive breast cancer: results from a pooled analysis. J Clin Oncol 26(16):2636–2643
Reiner A, Spona J, Reiner G et al (1986) Estrogen receptor analysis on biopsies and fine-needle aspirates from human breast carcinoma. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Am J Pathol 125:443–449
Hammond M, Hayes D, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795
Allred DC, Harvey JM, Berardo M et al (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168
Remmele W, Stegner HE (1987) Vorschlag zur einheitlichen Definierung eines immunreaktiven Scores (IRS) für den immunhistochemischen Östrogenrezeptornachweis (ER-ICA) im Mammakarzinomgewebe. Pathologe 8:138–140
Remmele W (1997) Pathologie Bd 4. Weibliches Genitale; Mamma; Pathologie der Schwangerschaft, der Plazenta und des Neugeborenen; Infektionskrankheiten des Fetus und des Neugeborenen (ed 2). Springer Verlag, Berlin, Heidelberg, New York
Viale G, Regan MM, Maiorano E et al (2007) Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1–98. J Clin Oncol 25(25):3846–3852
Dowsett M, Allred C, Knox J et al (2008) Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 26(7):1059–1065
Paik S, Shak S, Tang G, et al (2005) Expression of the 21 genes in the Recurrence Score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen receptor positive breast cancer. 2005 ASCO Annual Meeting Proceedings. J Clin Oncol 23(16S); (Suppl, Abstr 510)
Fisher B, Jeong JH, Bryant J et al; National Surgical Adjuvant Breast and Bowel Project Randomised Clinical Trials (2004) Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364(9437):858–868
Mazouni C, Bonnier P, Goubar A et al (2010) Is quantitative oestrogen receptor expression useful in the evaluation of the clinical prognosis? Analysis of a homogeneous series of 797 patients with prospective determination of the ER status using simultaneous EIA and IHC. Eur J Cancer 46:2715–2716
Henriksen KL, Rasmussen BB, Lykkesfeldt AE et al (2009) An ER activity profile including ER, PR, Bcl-2 and IGF-IR may have potential as selection criterion for letrozole or tamoxifen treatment of patients with advanced breast cancer. Acta Oncol 48(4):522–531
De Laurentiis M, Cancello G, D’Agostino D et al (2008) Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26(1):44–53
Bedard PL, Di Leo A, Piccart-Gebhart MJ (2010) Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer. Nat Rev Clin Oncol 7:22–36
Berry DA, Cirrincione C, Henderson IC, Citron ML et al (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. J Am Med Assoc 295(14):1658–1667
Green MC, Buzdar AU, Smith T et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983–5992
Mazouni C, Kau SW, Frye D et al (2007) Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers. Ann Oncol 18:874–880
von Minckwitz G, Blohmer JU, Raab G et al; German Breast Group (2005) In vivo chemosensitivity adapted preoperative chemotherapy in patients with early-stage breast cancer—the GEPARTRIO pilot study. Ann Oncol 16:56–63
Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800
Pusztai L (2006) Chips to bedside: incorporation of microarray data into clinical practice. Clin Cancer Res 12(24):7209–7214
Mook S, Schmidt MK, Viale G et al (2009) The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat 116(2):295–302
Bueno-de-Mesquita JM, Linn SC, Keijzer R et al (2009) Validation of 70-gene prognosis signature in node-negative breast cancer. Breast Cancer Res Treat 117(3):483–495
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(27):2817–2826
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(23):3726–3734
Albain KS, Barlow WE, Shak S et al; Breast Cancer Intergroup of North America (2010) Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 11(1):55–65
Goldstein LJ, Gray R, Badve S et al (2008) Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol 26(25):4063–4071
Knauer M, Mook S, Rutgers EJ et al (2010) The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 120(3):655–661
Tang G, Cuzick J, Wale C, et al (2010) Recurrence risk of node-negative and ER-positive early-stage breast cancer patients by combining recurrence score, pathologic, and clinical information: a meta-analysis approach. J Clin Oncol 28:15s; (suppl, abstr 509)
Hauck W, Anderson S, Marcus S (1998) Should we adjust for covariates in nonlinear regression analyses of randomized trials? Control Clin Trials 19(3):249–256
Berger ML, Mamdani M, Atkins D et al (2009) Good research practices for comparative effectiveness research: defining, reporting and interpreting non-randomized studies of treatment effects using secondary data sources: the ISPOR good research practices for retrospective database analysis task force report—Part I. Value Health 12(8):1044–1052
Cox E, Martin BC, Van Staa T et al (2009) Good research practices for comparative effectiveness research: approaches to mitigate bias and confounding in the design of non-randomized studies of treatment effects using secondary data sources: the ISPOR good research practices for retrospective database analysis task force—Part II. Value Health 12(8):1053–1061
Acknowledgments
This study has been supported by the German Federal Ministry of Education and Research (BMBF) (grant number: 01ZP0505).
Author information
Authors and Affiliations
Corresponding author
Additional information
A. C. Regierer and R. Wolters have contributed equally to this manuscript.
Rights and permissions
About this article
Cite this article
Regierer, A.C., Wolters, R., Kurzeder, C. et al. High estrogen receptor expression in early breast cancer: chemotherapy needed to improve RFS?. Breast Cancer Res Treat 128, 273–281 (2011). https://doi.org/10.1007/s10549-010-1334-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-010-1334-9