© 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:
|
|
 |
|
  S. Johnston, J. Pippen Jr, X. Pivot, M. Lichinitser, S. Sadeghi, V. Dieras, H. L. Gomez, G. Romieu, A. Manikhas, M. J. Kennedy, et al. Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer J. Clin. Oncol., November 20, 2009; 27(33): 5538 - 5546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vivacqua, R. Lappano, P. De Marco, D. Sisci, S. Aquila, F. De Amicis, S. A. W. Fuqua, S. Ando, and M. Maggiolini G Protein-Coupled Receptor 30 Expression Is Up-Regulated by EGF and TGF{alpha} in Estrogen Receptor {alpha}-Positive Cancer Cells Mol. Endocrinol., November 1, 2009; 23(11): 1815 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, J. Greger, H. Shi, Y. Liu, J. Greshock, R. Annan, W. Halsey, G. M. Sathe, A.-M. Martin, and T. M. Gilmer Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL Cancer Res., September 1, 2009; 69(17): 6871 - 6878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Daniel and C. A. Lange Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells PNAS, August 25, 2009; 106(34): 14287 - 14292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Finn, M. F. Press, J. Dering, M. Arbushites, M. Koehler, C. Oliva, L. S. Williams, and A. Di Leo Estrogen Receptor, Progesterone Receptor, Human Epidermal Growth Factor Receptor 2 (HER2), and Epidermal Growth Factor Receptor Expression and Benefit From Lapatinib in a Randomized Trial of Paclitaxel With Lapatinib or Placebo As First-Line Treatment in HER2-Negative or Unknown Metastatic Breast Cancer J. Clin. Oncol., August 20, 2009; 27(24): 3908 - 3915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Shi, B. Dong, Z. Li, Y. Lu, T. Ouyang, J. Li, T. Wang, Z. Fan, T. Fan, B. Lin, et al. Expression of ER-{alpha}36, a Novel Variant of Estrogen Receptor {alpha}, and Resistance to Tamoxifen Treatment in Breast Cancer J. Clin. Oncol., July 20, 2009; 27(21): 3423 - 3429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Radaelli, A. Arnold, A. Papanikolaou, R. A. Garcia-Fernandez, S. Mattiello, E. Scanziani, and R. D. Cardiff Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas Vet. Pathol., July 1, 2009; 46(4): 736 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Merglen, H. M. Verkooijen, G. Fioretta, I. Neyroud-Caspar, V. Vinh-Hung, G. Vlastos, P. O. Chappuis, M. Castiglione, E. Rapiti, and C. Bouchardy Hormonal therapy for oestrogen receptor-negative breast cancer is associated with higher disease-specific mortality Ann. Onc., May 1, 2009; 20(5): 857 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. BROOM, P. A. TANG, C. SIMMONS, L. BORDELEAU, A. M. MULLIGAN, F. P. O'MALLEY, N. MILLER, I. L. ANDRULIS, D. M. BRENNER, and M. J. CLEMONS Changes in Estrogen Receptor, Progesterone Receptor and Her-2/neu Status with Time: Discordance Rates Between Primary and Metastatic Breast Cancer Anticancer Res, May 1, 2009; 29(5): 1557 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Rose-Hellekant, A. J. Skildum, O. Zhdankin, A. L. Greene, R. R. Regal, K. D. Kundel, and D. W. Kundel Short-term Prophylactic Tamoxifen Reduces the Incidence of Antiestrogen-Resistant/Estrogen Receptor-Positive/Progesterone Receptor-Negative Mammary Tumors Cancer Prevention Research, May 1, 2009; 2(5): 496 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Iverson, C. Gillett, P. Cane, C. D. Santini, T. M. Vess, L. Kam-Morgan, A. Wang, M. Eisenberg, C. M. Rowland, J. J. Hessling, et al. A Single-Tube Quantitative Assay for mRNA Levels of Hormonal and Growth Factor Receptors in Breast Cancer Specimens J. Mol. Diagn., March 1, 2009; 11(2): 117 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Arendt, T. L. Grafwallner-Huseth, and L. A. Schuler Prolactin-Growth Factor Crosstalk Reduces Mammary Estrogen Responsiveness Despite Elevated ER{alpha} Expression Am. J. Pathol., March 1, 2009; 174(3): 1065 - 1074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Di Leo and E. Moretti Anthracyclines: The First Generation of Cytotoxic Targeted Agents? A Possible Dream J. Clin. Oncol., November 1, 2008; 26(31): 5011 - 5013. [Full Text] [PDF]
|
|
|
|
|
|
S. D. Conzen Minireview: Nuclear Receptors and Breast Cancer Mol. Endocrinol., October 1, 2008; 22(10): 2215 - 2228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|