This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dowsett, M. Articles by Smith, I. Search for Related Content PubMed PubMed Citation Articles by Dowsett, M. Articles by Smith, I.

HER-2 Amplification Impedes the Antiproliferative Effects of Hormone Therapy in Estrogen Receptor-positive Primary Breast Cancer

Breast Unit, Royal Marsden Hospital, London SW3 6JJ [M. D., C. H-W., I. B., J. S., M. H., G. G., N. S., I. S.]; Department of Surgery, Royal Infirmary, Edinburgh EH4 2XU [M. D.]; and Mayday University Hospital, Surrey CR7 7YE [S. E.], United Kingdom

In experimental models, human epidermal growth factor receptor-2 (HER-2) amplification leads to estrogen independence and tamoxifen resistance in estrogen receptor (ER)-positive human breast cancer cells. Some but not all reports suggest an association between HER-2 positivity and hormone independence in breast cancer patients. This study aimed to evaluate the antiproliferative effects of endocrine therapy in HER-2-positive/ER-positive primary human breast cancer.

The effect on proliferation (Ki67) of hormone therapy was assessed at 2 weeks and/or 12 weeks in biopsies from 115 primary breast cancers with ER-positive tumors. The patients took part in one of 3 neoadjuvant trials of hormonal therapy with a SERM (tamoxifen or idoxifene) or an aromatase inhibitor (anastrozole or vorozole). HER-2 status was assessed by immunocytochemistry and fluorescence in situ hybridization (FISH). Fifteen patients were defined as HER-2 positive by both immunohistochemistry and FISH, with the remaining 100 patients HER-2 negative. Geometric mean Ki67 levels were substantially higher in HER-2-positive than HER-2-negative tumors (27.7% versus 11.5%, respectively; P = 0.003). In HER-2-negative patients, Ki67 was reduced by 62 and 71% at 2 and 12 weeks, respectively (P < 0.0001 for both), but HER-2-positive patients showed no significant fall. The proportional change in Ki67 was significantly different between HER-2-positive and -negative patients (P = 0.014 at 2 weeks; P = 0.047 at 12 weeks). Mean ER levels were lower in the HER-2-positive patients (P = 0.06) but the change in Ki67 was impeded even in those with high ER. Apoptotic index was reduced by 30% at 2 weeks in the HER-2-negative group. However, there were no statistically significant differences in apoptotic index between the groups. It is concluded that ER-positive/HER-2-positive primary breast carcinomas show an impeded antiproliferative response to endocrine therapy that nonetheless may vary between individual treatments. This together with high baseline proliferation is likely to translate to poor clinical response.

This article has been cited by other articles:

				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. van Agthoven, A. M. Sieuwerts, M. E. Meijer-van Gelder, M. P. Look, M. Smid, J. Veldscholte, S. Sleijfer, J. A. Foekens, and L. C.J. Dorssers Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance J. Clin. Oncol., February 1, 2009; 27(4): 542 - 549. [Abstract] [Full Text] [PDF]

				S. Pancholi, A. E Lykkesfeldt, C. Hilmi, S. Banerjee, A. Leary, S. Drury, S. Johnston, M. Dowsett, and L.-A. Martin ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2 Endocr. Relat. Cancer, December 1, 2008; 15(4): 985 - 1002. [Abstract] [Full Text] [PDF]

				H. Yamashita, M. Nishio, T. Toyama, H. Sugiura, N. Kondo, S. Kobayashi, Y. Fujii, and H. Iwase Low phosphorylation of estrogen receptor {alpha} (ER{alpha}) serine 118 and high phosphorylation of ER{alpha} serine 167 improve survival in ER-positive breast cancer Endocr. Relat. Cancer, September 1, 2008; 15(3): 755 - 763. [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]

				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]

				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]

				E. A. Ariazi, R. J. Kraus, M. L. Farrell, V. C. Jordan, and J. E. Mertz Estrogen-Related Receptor {alpha}1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway Mol. Cancer Res., January 1, 2007; 5(1): 71 - 85. [Abstract] [Full Text] [PDF]

				G. E. Weitsman, L. Li, G. P. Skliris, J. R. Davie, K. Ung, Y. Niu, L. Curtis-Snell, L. Tomes, P. H. Watson, and L. C. Murphy Estrogen Receptor-{alpha} Phosphorylated at Ser118 Is Present at the Promoters of Estrogen-Regulated Genes and Is Not Altered Due to HER-2 Overexpression. Cancer Res., October 15, 2006; 66(20): 10162 - 10170. [Abstract] [Full Text] [PDF]

				X.-J. Ma, S. G. Hilsenbeck, W. Wang, L. Ding, D. C. Sgroi, R. A. Bender, C. K. Osborne, D. C. Allred, and M. G. Erlander The HOXB13:IL17BR Expression Index Is a Prognostic Factor in Early-Stage Breast Cancer J. Clin. Oncol., October 1, 2006; 24(28): 4611 - 4619. [Abstract] [Full Text] [PDF]

				X. Lin, Y. Yu, H. Zhao, Y. Zhang, J. Manela, and D. A. Tonetti Overexpression of PKC{alpha} is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model Carcinogenesis, August 1, 2006; 27(8): 1538 - 1546. [Abstract] [Full Text] [PDF]

				M. J. Ellis, Y. Tao, O. Young, S. White, A. D. Proia, J. Murray, L. Renshaw, D. Faratian, J. Thomas, M. Dowsett, et al. Estrogen-Independent Proliferation Is Present in Estrogen-Receptor HER2-Positive Primary Breast Cancer After Neoadjuvant Letrozole J. Clin. Oncol., July 1, 2006; 24(19): 3019 - 3025. [Abstract] [Full Text] [PDF]

				S. P. Linke, T. M. Bremer, C. D. Herold, G. Sauter, and C. Diamond A Multimarker Model to Predict Outcome in Tamoxifen-Treated Breast Cancer Patients Clin. Cancer Res., February 15, 2006; 12(4): 1175 - 1183. [Abstract] [Full Text] [PDF]

				H.-J. Kim, X. Cui, S. G. Hilsenbeck, and A. V. Lee Progesterone Receptor Loss Correlates with Human Epidermal Growth Factor Receptor 2 Overexpression in Estrogen Receptor-Positive Breast Cancer Clin. Cancer Res., February 1, 2006; 12(3): 1013s - 1018s. [Abstract] [Full Text] [PDF]

				N. Normanno, M. Di Maio, E. De Maio, A. De Luca, A. de Matteis, A. Giordano, F. Perrone, and on behalf of the NCI-Naples Breast Cancer Group Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 721 - 747. [Abstract] [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]

				A. Urruticoechea, I. E. Smith, and M. Dowsett Proliferation Marker Ki-67 in Early Breast Cancer J. Clin. Oncol., October 1, 2005; 23(28): 7212 - 7220. [Abstract] [Full Text] [PDF]

				G. Arpino, H. Weiss, A. V. Lee, R. Schiff, S. De Placido, C. K. Osborne, and R. M. Elledge Estrogen Receptor-Positive, Progesterone Receptor-Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance J Natl Cancer Inst, September 7, 2005; 97(17): 1254 - 1261. [Abstract] [Full Text] [PDF]

				N. C. Peterson, M. D. Servinsky, A. Christian, Z. Peng, W. Qiu, J. Mann, J. Dicello, and D. L. Huso Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model Carcinogenesis, September 1, 2005; 26(9): 1542 - 1552. [Abstract] [Full Text] [PDF]

				A. V. Bassarova, J. M. Nesland, T. Sedloev, W. Lilleby, S. L. Hristova, D. Y. Trifonov, and E. Torlakovic Simultaneous Bilateral Breast Carcinomas: A Category with Frequent Coexpression of HER-2 and ER-{alpha}, High Ki-67 and bcl-2, and Low p53 International Journal of Surgical Pathology, July 1, 2005; 13(3): 239 - 246. [Abstract] [PDF]

				A. J Butt, C. M McNeil, E. A Musgrove, and R. L Sutherland Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S47 - S59. [Abstract] [Full Text] [PDF]

				J M Gee, J F Robertson, E Gutteridge, I O Ellis, S E Pinder, M Rubini, and R I Nicholson Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S99 - S111. [Abstract] [Full Text] [PDF]

				M. Dowsett, S. R. Ebbs, J. M. Dixon, A. Skene, C. Griffith, I. Boeddinghaus, J. Salter, S. Detre, M. Hills, S. Ashley, et al. Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer--A Study from the IMPACT Trialists J. Clin. Oncol., April 10, 2005; 23(11): 2477 - 2492. [Abstract] [Full Text] [PDF]

				S. Dellapasqua, M. Colleoni, R. D. Gelber, and A. Goldhirsch Adjuvant Endocrine Therapy for Premenopausal Women With Early Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1736 - 1750. [Full Text] [PDF]

				C. K. Osborne, J. Shou, S. Massarweh, and R. Schiff Crosstalk between Estrogen Receptor and Growth Factor Receptor Pathways as a Cause for Endocrine Therapy Resistance in Breast Cancer Clin. Cancer Res., January 15, 2005; 11(2): 865s - 870s. [Abstract] [Full Text] [PDF]

				R I Nicholson, C Staka, F Boyns, I R Hutcheson, and J M W Gee Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy Endocr. Relat. Cancer, December 1, 2004; 11(4): 623 - 641. [Abstract] [Full Text] [PDF]

				A. Ring and M. Dowsett Mechanisms of tamoxifen resistance Endocr. Relat. Cancer, December 1, 2004; 11(4): 643 - 658. [Abstract] [Full Text] [PDF]

				J. S. Tobias Recent advances in endocrine therapy for postmenopausal women with early breast cancer: implications for treatment and prevention Ann. Onc., December 1, 2004; 15(12): 1738 - 1747. [Abstract] [Full Text] [PDF]

				G. Arpino, S. J. Green, D. C. Allred, D. Lew, S. Martino, C. K. Osborne, and R. M. Elledge HER-2 Amplification, HER-1 Expression, and Tamoxifen Response in Estrogen Receptor-Positive Metastatic Breast Cancer: A Southwest Oncology Group Study Clin. Cancer Res., September 1, 2004; 10(17): 5670 - 5676. [Abstract] [Full Text] [PDF]

				M. J. Ellis, A. Coop, B. Singh, Y. Tao, A. Llombart-Cussac, F. Janicke, L. Mauriac, E. Quebe-Fehling, H. A. Chaudri-Ross, D. B. Evans, et al. Letrozole Inhibits Tumor Proliferation More Effectively than Tamoxifen Independent of HER1/2 Expression Status Cancer Res., October 1, 2003; 63(19): 6523 - 6531. [Abstract] [Full Text] [PDF]

				X. Cui, P. Zhang, W. Deng, S. Oesterreich, Y. Lu, G. B. Mills, and A. V. Lee Insulin-Like Growth Factor-I Inhibits Progesterone Receptor Expression in Breast Cancer Cells via the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway: Progesterone Receptor as a Potential Indicator of Growth Factor Activity in Breast Cancer Mol. Endocrinol., April 1, 2003; 17(4): 575 - 588. [Abstract] [Full Text] [PDF]

				Y. Bai and V. Giguere Isoform-Selective Interactions between Estrogen Receptors and Steroid Receptor Coactivators Promoted by Estradiol and ErbB-2 Signaling in Living Cells Mol. Endocrinol., April 1, 2003; 17(4): 589 - 599. [Abstract] [Full Text] [PDF]

				M. Dowsett Preoperative Models to Evaluate Endocrine Strategies for Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 502s - 510s. [Abstract] [Full Text]

				E. A. Ariazi, G. M. Clark, and J. E. Mertz Estrogen-related Receptor {alpha} and Estrogen-related Receptor {gamma} Associate with Unfavorable and Favorable Biomarkers, Respectively, in Human Breast Cancer Cancer Res., November 15, 2002; 62(22): 6510 - 6518. [Abstract] [Full Text] [PDF]