© 2005 Oxford University Press
ARTICLE |
Estrogen Receptor–Positive, Progesterone Receptor–Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance
Affiliations of authors: Breast Center, Baylor College of Medicine and The Methodist Hospital, Houston, TX (GA, HW, AVL, RS, CKO, RME); Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita di Napoli Federico II, Naples, Italy (SDP)
Correspondence to: Richard M. Elledge, MD, Breast Care Center, 6550 Fannin St., Ste. 701, Houston, TX 77030 (e-mail: relledge{at}breastcenter.tmc.edu).
Background: Clinical data indicate that estrogen receptor–positive/progesterone receptor–negative (ER+/PR–) breast cancers are less sensitive to tamoxifen than are ER+/PR+ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER+/PR– breast tumors are more likely than ER+/PR+ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy. Methods: Clinical and biological features of 31 415 patients with ER+/PR+ tumors were compared with those of 13 404 patients with ER+/PR– tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11 399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan–Meier analyses, and all statistical tests were two-sided. Results: ER+/PR– tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER+/PR+ tumors. Furthermore, three times as many ER+/PR– tumors as ER+/PR+ tumors expressed HER-1 (25% versus 8%; P<.001) and 50% more overexpressed HER-2 (21% versus 14%; P<.001). Among all tamoxifen-treated women, recurrence was higher among women with HER-1–expressing tumors than with HER-1–negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER+/PR+ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER+/PR– tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence. Conclusions: ER+/PR– tumors express higher levels of HER-1 and HER-2 and display more aggressive features than ER+/PR+ tumors. As in laboratory models, lack of PR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.
CiteULike 
Connotea 
Del.icio.us What's this?
Editorial about this Article
- Evolving Understanding of Growth Regulation in Human Breast Cancer: Interactions of the Steroid and Peptide Growth Regulatory Pathways
- Cindy A. Wilson and Dennis J. Slamon
J Natl Cancer Inst 2005 97: 1238-1239.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
|
|
 |
|
  D. B. Hardy, B. A. Janowski, C.-C. Chen, and C. R. Mendelson Progesterone Receptor Inhibits Aromatase and Inflammatory Response Pathways in Breast Cancer Cells via Ligand-Dependent and Ligand-Independent Mechanisms Mol. Endocrinol., August 1, 2008; 22(8): 1812 - 1824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Masri, S. Phung, X. Wang, X. Wu, Y.-C. Yuan, L. Wagman, and S. Chen Genome-Wide Analysis of Aromatase Inhibitor-Resistant, Tamoxifen-Resistant, and Long-Term Estrogen-Deprived Cells Reveals a Role for Estrogen Receptor Cancer Res., June 15, 2008; 68(12): 4910 - 4918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Chen, O. Nalcioglu, and M. Y. Su MR imaging features of invasive breast cancer correlated with hormonal receptors: does progesterone receptor matter? Ann. Onc., May 1, 2008; 19(5): 1024 - 1026. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Arpino, L. Wiechmann, C. K. Osborne, and R. Schiff Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance Endocr. Rev., April 1, 2008; 29(2): 217 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Wu, M. J. Fackler, M. K. Halushka, D. W. Molavi, M. E. Taylor, W. W. Teo, C. Griffin, J. Fetting, N. E. Davidson, A. M. De Marzo, et al. Heterogeneity of Breast Cancer Metastases: Comparison of Therapeutic Target Expression and Promoter Methylation Between Primary Tumors and Their Multifocal Metastases Clin. Cancer Res., April 1, 2008; 14(7): 1938 - 1946. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dowsett, C. Allred, J. Knox, E. Quinn, J. Salter, C. Wale, J. Cuzick, J. Houghton, N. Williams, E. Mallon, et al. 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., March 1, 2008; 26(7): 1059 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Colleoni, G. Viale, D. Zahrieh, L. Bottiglieri, R. D. Gelber, P. Veronesi, A. Balduzzi, R. Torrisi, A. Luini, M. Intra, et al. Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy Ann. Onc., March 1, 2008; 19(3): 465 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Parton and I. E. Smith Controversies in the Management of Patients With Breast Cancer: Adjuvant Endocrine Therapy in Premenopausal Women J. Clin. Oncol., February 10, 2008; 26(5): 745 - 752. [Full Text] [PDF]
|
|
|
|
|
|
A. C. Wolff, D. Berry, L. A. Carey, M. Colleoni, M. Dowsett, M. Ellis, J. E. Garber, D. Mankoff, S. Paik, L. Pusztai, et al. Research Issues Affecting Preoperative Systemic Therapy for Operable Breast Cancer J. Clin. Oncol., February 10, 2008; 26(5): 806 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Jordan and B. W. O'Malley Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer J. Clin. Oncol., December 20, 2007; 25(36): 5815 - 5824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Harrell, W. W. Dye, D. M.E. Harvell, M. Pinto, P. Jedlicka, C. A. Sartorius, and K. B. Horwitz Estrogen Insensitivity in a Model of Estrogen Receptor Positive Breast Cancer Lymph Node Metastasis Cancer Res., November 1, 2007; 67(21): 10582 - 10591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D Francis, M. Dimech, L. Giles, and A. Hopkins Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program J. Clin. Pathol., November 1, 2007; 60(11): 1277 - 1283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Rakha, M. E. El-Sayed, A. R. Green, E. C. Paish, D. G. Powe, J. Gee, R. I. Nicholson, A. H.S. Lee, J. F.R. Robertson, and I. O. Ellis Biologic and Clinical Characteristics of Breast Cancer With Single Hormone Receptor Positive Phenotype J. Clin. Oncol., October 20, 2007; 25(30): 4772 - 4778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. E. Smith, G. Walsh, A. Skene, A. Llombart, J. I. Mayordomo, S. Detre, J. Salter, E. Clark, P. Magill, and M. Dowsett A Phase II Placebo-Controlled Trial of Neoadjuvant Anastrozole Alone or With Gefitinib in Early Breast Cancer J. Clin. Oncol., September 1, 2007; 25(25): 3816 - 3822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bartsch, C. Wenzel, G. Altorjai, U. Pluschnig, R. M. Mader, M. Gnant, R. Jakesz, M. Rudas, C. C. Zielinski, and G. G. Steger Her2 and Progesterone Receptor Status Are Not Predictive of Response to Fulvestrant Treatment Clin. Cancer Res., August 1, 2007; 13(15): 4435 - 4439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Giltnane, L. Ryden, M. Cregger, P.-O. Bendahl, K. Jirstrom, and D. L. Rimm Quantitative Measurement of Epidermal Growth Factor Receptor Is a Negative Predictive Factor for Tamoxifen Response in Hormone Receptor Positive Premenopausal Breast Cancer J. Clin. Oncol., July 20, 2007; 25(21): 3007 - 3014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Naderi, A. E. Teschendorff, J. Beigel, M. Cariati, I. O. Ellis, J. D. Brenton, and C. Caldas BEX2 Is Overexpressed in a Subset of Primary Breast Cancers and Mediates Nerve Growth Factor/Nuclear Factor-{kappa}B Inhibition of Apoptosis in Breast Cancer Cell Lines Cancer Res., July 15, 2007; 67(14): 6725 - 6736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Silva and M. A. Shupnik Integration of Steroid and Growth Factor Pathways in Breast Cancer: Focus on Signal Transducers and Activators of Transcription and Their Potential Role in Resistance Mol. Endocrinol., July 1, 2007; 21(7): 1499 - 1512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. V. Dimitrov, P. Colucci, and S. Nagpal Some Aspects of the Endocrine Profile and Management of Hormone-Dependent Male Breast Cancer Oncologist, July 1, 2007; 12(7): 798 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L Mauriac, A Keshaviah, M Debled, H Mouridsen, J. Forbes, B Thurlimann, R Paridaens, A Monnier, I Lang, A Wardley, et al. Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial Ann. Onc., May 1, 2007; 18(5): 859 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Massarweh and R. Schiff Unraveling the Mechanisms of Endocrine Resistance in Breast Cancer: New Therapeutic Opportunities Clin. Cancer Res., April 1, 2007; 13(7): 1950 - 1954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kennecke, I. Olivotto, C Speers, B Norris, S. Chia, C Bryce, and K. Gelmon Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen Ann. Onc., January 1, 2007; 18(1): 45 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bardia, L. C. Hartmann, C. M. Vachon, R. A. Vierkant, A. H. Wang, J. E. Olson, T. A. Sellers, and J. R. Cerhan Recreational Physical Activity and Risk of Postmenopausal Breast Cancer Based on Hormone Receptor Status Arch Intern Med, December 11, 2006; 166(22): 2478 - 2483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Massarweh and R. Schiff Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S15 - S24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Hicks, B. J. Yoder, S. Short, S. Tarr, N. Prescott, J. P. Crowe, A. E. Dawson, G. T. Budd, S. Sizemore, M. Cicek, et al. Loss of Breast Cancer Metastasis Suppressor 1 Protein Expression Predicts Reduced Disease-Free Survival in Subsets of Breast Cancer Patients. Clin. Cancer Res., November 15, 2006; 12(22): 6702 - 6708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Ponzone, F Montemurro, F Maggiorotto, C Robba, D Gregori, M. Jacomuzzi, F Kubatzki, D Marenco, A Dominguez, N Biglia, et al. Clinical outcome of adjuvant endocrine treatment according to PR and HER-2 status in early breast cancer Ann. Onc., November 1, 2006; 17(11): 1631 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Filardo, C. T. Graeber, J. A. Quinn, M. B. Resnick, D. Giri, R. A. DeLellis, M. M. Steinhoff, and E. Sabo Distribution of GPR30, a Seven Membrane-Spanning Estrogen Receptor, in Primary Breast Cancer and its Association with Clinicopathologic Determinants of Tumor Progression. Clin. Cancer Res., November 1, 2006; 12(21): 6359 - 6366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Moy and P. E. Goss Lapatinib: Current Status and Future Directions in Breast Cancer Oncologist, November 1, 2006; 11(10): 1047 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kim, M. Kaneko, K. Arihiro, M. Emi, K. Tanabe, S. Murakami, A. Osaki, and K. Inai Extranuclear expression of hormone receptors in primary breast cancer Ann. Onc., August 1, 2006; 17(8): 1213 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stendahl, L. Ryden, B. Nordenskjold, P. E. Jonsson, G. Landberg, and K. Jirstrom High Progesterone Receptor Expression Correlates to the Effect of Adjuvant Tamoxifen in Premenopausal Breast Cancer Patients Clin. Cancer Res., August 1, 2006; 12(15): 4614 - 4618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. Ryan and P. E. Goss Adjuvant Hormonal Therapy in Peri- and Postmenopausal Breast Cancer Oncologist, July 1, 2006; 11(7): 718 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Neven, N. Pochet, M. Drijkoningen, F. Amant, F. De Smet, R. Paridaens, M.-R. Christiaens, and I. Vergote Progesterone Receptor in Estrogen Receptor-Positive Breast Cancer: The Association Between HER-2 and Lymph Node Involvement Is Age Related J. Clin. Oncol., June 1, 2006; 24(16): 2595 - 2595. [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan Pak up your breast tumor--and grow! J Natl Cancer Inst, May 17, 2006; 98(10): 657 - 659. [Full Text] [PDF]
|
|
|
|
|
|
R. Ponzone, F. Maggiorotto, C. Robba, L. Fuso, and P. Sismondi Progesterone Receptor and Human Epidermal Growth Factor Receptor 2 Status: An Independent Influence on the Efficacy of Endocrine Therapy in Breast Cancer? J. Clin. Oncol., March 20, 2006; 24(9): 1481 - 1482. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Swain Aromatase Inhibitors -- A Triumph of Translational Oncology N. Engl. J. Med., December 29, 2005; 353(26): 2807 - 2809. [Full Text] [PDF]
|
|
|
|
|
|
X. Cui, R. Schiff, G. Arpino, C. K. Osborne, and A. V. Lee Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy J. Clin. Oncol., October 20, 2005; 23(30): 7721 - 7735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Wilson and D. J. Slamon Evolving Understanding of Growth Regulation in Human Breast Cancer: Interactions of the Steroid and Peptide Growth Regulatory Pathways J Natl Cancer Inst, September 7, 2005; 97(17): 1238 - 1239. [Full Text] [PDF]
|
|