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British Journal of Cancer (1999) 79, 1220–1226. doi:10.1038/sj.bjc.6690196 www.bjcancer.com
Published online 12 February 1999

Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer

S J Houston1,*, T A Plunkett1,*, D M Barnes1, P Smith1, R D Rubens1 and D W Miles1

1ICRF Clinical Oncology Unit, Guy’s Hospital, London SE1 9RT, UK

*Joint first authors

Received 21 April 1998; Accepted 3 August 1998

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Abstract

The present study investigated the interaction between c-erbB2 overexpression and the response to first-line endocrine therapy in patients with advanced breast cancer. The primary tumours of 241 patients who were treated at first relapse with endocrine therapy were assessed for overexpression of c-erbB2 by immunohistochemistry. c-erbB2 was overexpressed in 76 (32%) of primary breast cancers and did not correlate with any other prognostic factor. The overall response to treatment and time to progression were significantly lower in patients with c-erbB2-positive tumours compared to those that were c-erbB2-negative (38% vs 56%, P = 0.02; and 4.1 months vs 8.7 months, P < 0.001, respectively). In multivariate analysis, c-erbB2 status was the most significant predictive factor for a short time to progression (P = 0.0009). In patients with ER-positive primary tumours treated at relapse with tamoxifen (n = 170), overexpression of c-erbB2 was associated with a significantly shorter time to progression (5.5 months vs 11.2 months, P < 0.001). In conclusion, overexpression of c-erbB2 in the primary tumour is an independent marker of relative resistance to first-line endocrine therapy in patients with advanced breast cancer. In patients with ER-positive primary tumours, the overexpression of c-erbB2 defines a subgroup less likely to respond to endocrine therapy.

Keywords:

c-erbB2; breast cancer; endocrine therapy; tamoxifen

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References

  1. Allred, D. C., Clark, G., Tandon, A., Schnitt, S. J., Gilchrist, K. W., Osborne, C. K., Tormey, D. C. & McGuire, W. L. (1992). HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. J Clin Oncol 10: 599–605. | PubMed | ISI | CAS |
  2. Andrulis, I. L., Bull, S. B., Blackstein, M. E., Sutherland, D., Mak, C., Sidlofsky, S., Pritzker, K. P., Hartwick, R. W., Hinna, W., Lickley, L., Wilkinson, R., Qizlbash, A., Ambus, U., Lipa, M., Weizel, H., Katz, A., Baida, M., Mariz, S., Stoik, G., Dacamara, P., Strongitharm, D., Geddie, W. & McCready, D. (1998). neu/erbB2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. J Clin Oncol 16: 1340–1349. | PubMed | ISI | CAS |
  3. Archer, S. G., Eliopoulos, A., Spandidos, D., Barnes, D., Ellis, I. O., Blamey, R. W., Nicholson, R. I. & Robertson, J. F. (1995). Expression of ras p21, p53 and c-erbB2 in advanced breast cancer and response to first line hormonal therapy. Br J Cancer 72: 1259–1266. | Article | PubMed | ISI | CAS |
  4. Barnes, D. M., Lammie, G. A., Millis, R. R., Gullick, W. J., Allen, D. S. & Altman, D. G. (1988). An immunohistochemical evaluation of c-erbB2 expression in human breast carcinoma. Br J Cancer 58: 448–452. | Article | PubMed | ISI | CAS |
  5. Barnes, D. M., Millis, R. R., Beex, LVAM, Thorpe, S. M. & Leake, R. E. (1998). Increased use of immunohistochemistry for oestrogen receptor measurement in mammary carcinoma: the need for quality assurance. Eur J Cancer 34: 1677–1682. | Article | PubMed | CAS |
  6. Baselga, J., Tripathy, D., Mendelsohn, J., Baugham, S., Benz, C. C., Dantis, L., Sklarin, N. J., Seidman, A. D., Hndis, C. A., Moore, J., Rosen, P. P., Twaddell, T., Henderson, I. C. & Norton, L. (1996). Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14: 737–744. | PubMed | ISI | CAS |
  7. Benz, C. C., Scott, G. K. & Sarup, J. C. (1992). Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24: 85–95. | Article | PubMed | ISI | CAS |
  8. Berns, EMJJ, Foekens, J. A., van Staveren, I. L., van Putten, W. L. J., de Koning, HYWCM, Portengen, H. & Klijn, J. G. M. (1995). Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159: 11–18. | Article | PubMed | ISI | CAS |
  9. Borg, A., Baldetorp, B., Ferno, M., Killander, D., Olsson, H., Ryden, S. & Sigurdsson, H. (1994). ERBB2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer Lett 81: 137–144. | Article | PubMed | ISI | CAS |
  10. Carlomagno, C., Perrone, F., Gallo, C., De Laurentis, M. D., Lauria, R., Morabito, A., Pettinato, G., Panico L D’Antonio, A., Bianco, R. & De Placido, S. (1996). c-erbB2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol 14: 2702–2708. | PubMed | ISI | CAS |
  11. Charpin, C., Garcia, S., Bouvier, C., Martini, F., Lavaut, M-N, Allasia, C., Bonnier, P. & Andrac, L. (1997). c-erbB2 oncoprotein detected by automated quantitative immunocytochemistry in breast carcinomas correlates with patients’ overall and disease-free survival. Br J Cancer 75: 1667–1673. | Article | PubMed | ISI | CAS |
  12. Ciocca, D. R., Fujimura, F. K., Tandon, A. K., Clark, G. M., Mark, C., Lee-Chen, G. J., Pounds, G. W., Vendely, P., Owens, M. A., Pandian, M. R. & McGuire, W. L. (1992). Correlation of HER-2/neu amplification with expression and with other prognostic factors in 1103 breast cancers. J Natl Cancer Inst 84: 1279–1282. | Article | PubMed | CAS |
  13. Clinical Practice Guidelines for the Use of Tumor Markers in Breast and Colorectal Cancer. (1996). J Clin Oncol 14: 2843–2877. | PubMed | ISI |
  14. Coussens, L., Yang-Feng, T. L., Liao, T. L., Chen, E., Gray, A., McGrath, J., Seeburg, P. H., Libermann, T. A., Schlessinger, J., Francke, U., Levinson, A. & Ullrich, A. (1985). Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132–1139. | Article | PubMed | ISI | CAS |
  15. Elledge, R. M., Green, S., Ciocca, D., Pugh, R., Allred, C. A., Clark, G. M., Hill, J., Ravdin, P., O’Sullivan, J., Martino, S. & Osborne, C. K. (1998). HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group study. Clin Cancer Res 4: 7–12. | PubMed | ISI | CAS |
  16. Elston, C. W. (1984). The assessment of histological differentiation in breast cancer. Aust NZ J Surg 54: 11–15. | Article | CAS |
  17. Gullick, W. J., Love, S. B., Wright, C., Barnes, D. M., Gusterson, B., Harris, A. L. & Altman, D. G. (1991). c-erbB2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63: 434–438. | Article | PubMed | ISI | CAS |
  18. Gusterson, B. A., Gelber, R. D., Goldhirsch, A., Price, K. N., Save-Soderborgh, J., Anbazhagan, R., Styles, J., Rudenstam, C-M, Goloum, R., Reed, R., Martinez-Tello, F., Tiltman, A., Torhorst, J., Grigolato, P., Bettelheim, R., Neville, A. M., Burki, K., Castiglione, M., Collins, J., Lintner, J. & Senn, H-J (1992). Prognostic importance of c-erbB2 expression in breast cancer. J Clin Oncol 10: 1049–1056. | PubMed | ISI | CAS |
  19. Hayward, J. L., Carbone, P. P., Heuson, J. C., Kumaoka, S., Segaloff, A. & Rubens, R. D. (1977). Assessment of response to therapy in advanced breast cancer. Cancer 39: 1289–1294. | Article | PubMed | ISI | CAS |
  20. Karunagaran, D., Tzahar, E., Beerli, R. R., Chen, X., Graus-Porta, D., Ratzkin, B. J., Seger, R., Hynes, N. E. & Yarden, Y. (1996). ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15: 254–264. | PubMed | ISI | CAS |
  21. Kath, R., Hoffken, K. & Otte, C. (1993). The neu oncogene product in serum and tissue of patients with breast carcinoma. Ann Oncol 4: 585–590. | PubMed |
  22. Kern, F. G., Cheville, A. L. & Liu, Y. (1990). Growth factor receptors and the progression of breast cancer. Semin Cancer Biol 1: 317–328. | PubMed |
  23. King, R. J. B., Redgraves, J. & Hayward, J. L. (1979). The measurement of receptors for oestradiol and proesterone in human breast tumours. In Steroid Receptor Assays in Breast Tumours: Methodological and Clinical Aspects, King RJB (ed), pp. 55–73, Alpha-Omega: Cardiff
  24. Klijn, J. G. M., Berns, EMJJ, Bontebal, M. & Foekens, J. (1993). Cell biological factors associated with the response of breast cancer to systemic treatment. Cancer Treat Rev 19SB: 45–63.
  25. Kuukasjarvi, T., Kononen, J., Helin, H., Holli, K. & Isola, J. (1996). Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14: 2584–2589. | PubMed | ISI | CAS |
  26. Leitzel, K., Teramoto, Y., Sampson, E., Mauceri, J., Langton, B. C., Demers, L., Podczaski, E., Harvey, H., Shambaugh, S., Volas, G., Weaver, S. & Lipton, A. (1992). Elevated soluble c-erbB2 antigen levels in the serum and effusions of a proportion of breast cancer patients. J Clin Oncol 10: 1436–1443. | PubMed | ISI | CAS |
  27. Leitzel, K., Teramoto, Y., Konrad, K., Chinchilli, V. M., Volas, G., Grossberg, H., Harvey, H., Demers, L. & Lipton, A. (1995). Elevated serum c-erbB2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13: 1129–1135. | PubMed | ISI | CAS |
  28. Manni, T. & Trujillo, J. E. Marshall (1989). Anti-hormone treatment of stage IV breast cancer. Cancer 43: 444–450. | Article |
  29. Newby, J. C., Johnston, S. R. D., Smith, I. E. & Dowsett, M. (1997). Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res 3: 1643–1651. | PubMed | ISI | CAS |
  30. Niehans, G. A., Singleton, T. P. & Dykoski, D. (1993). Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst 5: 1230–1235. | Article |
  31. O’Malley, F. P., Saad, Z., Kerkvliet, N., Doig, G., Stitt, L., Ainsworth, P., Hundal, H., Chambers, A. F., Turnbull, D. I. & Bramwell, V. (1996). The predictive power of semiquantitative immunohistochemical assessment of p53 and c-erbB2 in lymph node negative breast cancer. Hum Pathol 27: 955–963. | Article | PubMed |
  32. Pietras, R. J., Arboleda, J. & Reese, D. M. (1995). HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10: 2435–2446. | PubMed | ISI | CAS |
  33. Press, M. F., Pike, M. C., Chazin, V. R., Hung, G., Udove, J. A., Markowicz, M., Danyluk, J., Godolphin, W., Sliwkowski, M., Akita, R., Brandeis, J., Paterson, M. C. & Slamon, D. J. (1993). Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res 53: 4960–4970. | PubMed | ISI | CAS |
  34. Press, M. F., Bernstein, L., Thomas, P. A., Meisner, L. F., Zhou, J-Y, Ma, Y., Hung, G., Robinson, R. A., Harris, C., El-Naggar, A., Slamon, D. J., Philips, R. N., Ross, J. S., Wolman, S. R. & Flom, K. J. (1997). HER-2/neu gene amplification characterised by fluoresence in situ hybridisation: poor prognosis in node-negative breast carcinomas. J Clin Oncol 15: 2894–2904. | PubMed | ISI | CAS |
  35. Ravdin, P. M., Green, S., Door, T. M., McGuire, W. L., Fabian, C., Pugh, R. P., Carter, R. D., Rivkin, S. E., Borst, J. R., Belt, R. J., Metch, B. & Osborne, C. K. (1992). Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective SWOG study. J Clin Oncol 10: 1284–1291. | PubMed | ISI | CAS |
  36. Rubens, R. D. & Hayward, J. L. (1980). Estrogen receptors and response to endocrine therapy and cytotoxic chemotherapy in advanced breast cancer. Cancer 46: 2922–2924. | Article | PubMed |
  37. Saceda, M., Grunt, T. W., Colomer, R., Lippman, M. E., Lupu, R. & Martin, M. B. (1996). Regulation of estrogen receptor concentration and activity by an erbB/HER ligand in breast carcinoma cell lines. Endocrinology 137: 4322–4330. | Article | PubMed |
  38. Sjogren, S., Inganas, M., Lindgren, A., Holmberg, L. & Bergh, J. (1998). Prognostic and predictive value of c-erbB2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 16: 462–469. | PubMed | ISI | CAS |
  39. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A. & McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182. | Article | PubMed | ISI | CAS |
  40. Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J. A., Wong, S. G., Keith, D. E., Levin, W. J., Stuart, S. G., Udove, J., Ullrich, A. & Press, M. F. (1989). Studies of the HER-2/neu proto-oncogene in human breast cancer and ovarian cancer. Science 244: 707–712. | Article | PubMed | ISI | CAS |
  41. Stal, O., Ferno, M., Borg, A. & Nordenskjold, B. (1997). ERBB2 expression and benefit from 5 versus 2 years of adjuvant tamoxifen for postmenopausal stage II breast cancer patients. Breast Cancer Res Treat 46: 32 (abstr)
  42. Tetu, B. & Brisson, J. (1994). Prognostic significance of the pattern of immunostaining and adjuvant therapy. Cancer 73: 2358–2365. | Article |
  43. Witters, L. M., Kumar, R., Chinchilli, V. M. & Lipton, A. (1997). Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 42: 1–5. | Article | PubMed | ISI | CAS |
  44. Wright, C., Nicholson, S., Angus, B., Sainsbury, J. R. C., Farndon, J., Cairns, J., Harris, A. L. & Horne, C. (1992). Relationship between c-erbB2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer 65: 118–121. | Article | PubMed | ISI | CAS |
  45. Yamauchi, H., O’Neill, A., Gelman, R., Carney, W., Tenney, D. Y., Hosch, S. & Hayes, D. F. (1997). Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein. J Clin Oncol 15: 2518–2525. | PubMed | ISI | CAS |
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