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Her-2/neu as a Predictive Marker of Response to Breast Cancer Therapy

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Abstract

Amplification of the HER-2/neu (c-erbB-2) gene resulting in overexpression of the p185HER-2 growth factor receptor occurs in ~25% of early stage breast cancers. HER- 2/neu has been established as an important independent prognostic factor in early stage breast cancer in large cohorts of patients and in cohorts with very long (30 year) follow-up duration. New data are emerging to suggest that HER-2/neu may be useful not only as a prognostic factor but also as a predictive marker for projecting response to chemotherapeutics, antiestrogens, and therapeutic anti-HER- 2/neu monoclonal antibodies. In this review we highlight recent data on HER-2/neu as a predictive marker of response to breast cancer therapy and discuss the clinical implications of this information. The difficulty in comparing results from different data sets due to the wide variety of reagents and technologies used to detect HER-2/neu amplification/overexpression in clinical specimens is also discussed. Finally, we report results from experimental models of HER-2/neu overexpression which have been used in an effort to understand the relationship between HER- 2/neu and response to chemotherapeutics and antiestrogens in breast cancer.

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References

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987

    Google Scholar 

  2. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press M: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989

    Google Scholar 

  3. Clark GM, McGuire WL: Follow-up study of HER-2/neu amplification in primary breast cancer. Cancer Res 51:944-948, 1991

    Google Scholar 

  4. Lovekin C, Ellis IO, Locker A, Robertson JF, Bell J, Nicholson R, Gullick WJ, Elston CW, Blamey RW: c-erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer 63:439-443, 1991

    Google Scholar 

  5. Berns PMJJ, Klijn JGM, van Staveren IL, Portengen H, Foekens JA: Prevalence of amplification of the oncogenes c-myc, HER-2/neu and int-2 in one thousand human breast tumors: correlation with steroid receptors. Eur J Cancer 28:697-700, 1992

    Google Scholar 

  6. Seshadri R, Firgaira FA, Horsfall DJ, McCaul K, Setlur V, Kitchen P: Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. J Clin Oncol 11:1936-1942, 1993

    Google Scholar 

  7. Toikkanen S, Helin H, Isola J, Joensuu H: Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up. J Clin Oncol 10:1044-1048, 1992

    Google Scholar 

  8. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME, King CR: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 8:103-112, 1990

    Google Scholar 

  9. Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S, Pritzker KP, Hartwick RW, Hanna W, Lickley L, Wilkinson R, Qizilbash A, Ambus U, Lipa M, Weizel H, Katz A, Baida M, Mariz S, Stoik G, Dacamara P, Strongitharm D, Geddie W, McCready D, for the Toronto Breast Cancer Study Group: neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. J Clin Oncol 16:1340-1349, 1998

    Google Scholar 

  10. Allred DC, Clark GM, Tandon AK, Molina R, Tormey DC, Osborne CK, Gilchrist KW, Mansour EG, Abeloff M, Eudey L, McGuire W: 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, 1992

    Google Scholar 

  11. Gusterson BA, Gelber RD, Goldhirsch A, Price KN, Save-Soderborgh J, Anbazhagan R, Styles J, Rudenstam CM, Golouh R, Reed R, Martinez-Tello F, Tiltman A, Torhorst J, Grigolato P, Bettelheim R, Neville A, Burki K, Castiglione M, Collins J, Lindtner J, Senn H-J, for the International (Ludwig) Breast Cancer Study Group: Prognostic importance of c-erbB-2 expression in breast cancer. J Clin Oncol 10:1049-1056, 1992

    Google Scholar 

  12. Levine MN, Andrulis I: The HER-2/neu oncogene in breast cancer: so what is new? [editorial; comment]. J Clin Oncol 10:1034-1036, 1992

    Google Scholar 

  13. Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, Morabito A, Pettinato G, Panico L, D'Antonio A, Bianco AR, De Placido S: c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol 14:2702-2708, 1996

    Google Scholar 

  14. Tetu B, Brisson J: Prognostic significance of HER-2/neu oncoprotein expression in node-positive breast cancer. The influence of the pattern of immuno-staining and adjuvant therapy. Cancer 73:2359-2365, 1994

    Google Scholar 

  15. Berns EM, Foekens JA, van Staveren IL, van Putten WL, de Koning HY, Portengen H, Klijn JG: Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159:11-18, 1995

    Google Scholar 

  16. Wright C, Cairns J, Cantwell BJ, Cattan AR, Hall AG, Harris AL, Horne CH: Response to mitoxantrone in advanced breast cancer: correlation with expression of c-erbB-2 protein and glutathione S-transferases. Br J Cancer 65:271-274, 1992

    Google Scholar 

  17. Stender MJ, Neuberg D, Wood W, Sledge G: Correlation of circulating c-erbB-2 extracellular domain (Her-2) with clinical outcome in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 16:154a, 1997

    Google Scholar 

  18. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson C: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Medicine 330:1260-1266, 1994

    Google Scholar 

  19. Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537-547, 1997

    Google Scholar 

  20. Stein D, Wu J, Fuqua SA, Roonprapunt C, Yajnik V, D'Eustachio P, Moskow JJ, Buchberg AM, Osborne CK, Margolis B: The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. EMBO J 13:1331-1340, 1994

    Google Scholar 

  21. Smith K, Houlbrook S, Greenall M, Carmichael J, Harris AL: Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity. Oncogene 8:933-938, 1993

    Google Scholar 

  22. Nicholson S, Wright C, Sainsbury JR, Halcrow P, Kelly P, Angus B, Farndon JR, Harris AL: Epidermal growth factor receptor (EGFr) as a marker for poor prognosis in node-negative breast cancer patients: neu and tamoxifen failure. J Steroid Biochem Molec Biol 37:811-814, 1990

    Google Scholar 

  23. Wright C, Nicholson S, Angus B, Sainsbury JR, Farndon J, Cairns J, Harris AL, Horne CH: Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer 65:118-121, 1992

    Google Scholar 

  24. Borg A, Baldetorp B, Ferno M, Killander D, Olsson H, Ryden S, Sigurdsson H: ERBB2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer Lett 81:137-144, 1994

    Google Scholar 

  25. Bianco AR, De Laurentiis M, Carlomagno C, Lauria R, Petrella G, Panico L, Pettinato G, Perrone F, Gallo C, Marinelli A, De Placido S: 20 year update of the Naples GUN trial of adjuvant breast cancer therapy: Evidence of interaction between c-erbB-2 expression and tamoxifen efficacy. Proc Am Soc Clin Oncol 17:373, 1998

    Google Scholar 

  26. Sjogren S, Inganas M, Lindgren A, Holmberg L, Bergh J: Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 16:462-469, 1998

    Google Scholar 

  27. Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Parker MG, Sliwkowski MX, Slamon DJ: HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10:2435-2446, 1995

    Google Scholar 

  28. Yamauchi H, O'Neill A, Gelman R, Carney W, Tenney DY, Hosch S, Hayes DF: 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, 1997

    Google Scholar 

  29. Leitzel K, Teramoto Y, Konrad K, Chinchilli VM, Volas G, Grossberg H, Harvey H, Demers L, Lipton A: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13:1129-1135, 1995

    Google Scholar 

  30. Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ: Phase II study of receptor enhanced chemosensitivity using recombinant humanized anti-p185HER-2/neu monoclonal antibody (rhuMAb HER2) plus cisplatin in patients with HER-2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol, 1998 (in press)

  31. Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM, Osborne CK: Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24:85-95, 1993

    Google Scholar 

  32. Lewis GD, Figari I, Fendly B, Wong WL, Carter P, Gorman C, Shepard HM: Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37:255-263, 1993

    Google Scholar 

  33. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen P, Twaddell T, Henderson I, Norton L: 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, 1996

    Google Scholar 

  34. Slamon D, Leyland-Jones B, Shak S, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Baselga J, Norton L: Addition of Herceptin (humanized anti-HER-2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer markedly increases anticancer activity: A randomized, multinational controlled Phase III trial. Proc Am Soc Clin Oncol 17:377, 1998

    Google Scholar 

  35. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Paton V, Shak S, Lieberman G, Slamon D: Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 17:376, 1998

    Google Scholar 

  36. Pauletti G, Godolphin W, Press MF, Slamon DJ: Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 13:63-72, 1996

    Google Scholar 

  37. Graber JH, O'Donnell MJ, Smith CL, Cantor CR: Advances in DNA diagnostics. Curr Opin Biotech 9:14-18, 1998

    Google Scholar 

  38. Neubauer A, Neubauer B, He M, Effert P, Iglehart D, Frye R, Liu E: Analysis of gene amplification in archival tissue by differential polymerase chain reaction. Oncogene 7:1019-1025, 1992

    Google Scholar 

  39. Press MF, Hung G, Godolphin W, Slamon DJ: Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54:2771-2777, 1994

    Google Scholar 

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Authors
  1. Mark D. Pegram
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  2. Giovanni Pauletti
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  3. Dennis J. Slamon
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Pegram, M.D., Pauletti, G. & Slamon, D.J. Her-2/neu as a Predictive Marker of Response to Breast Cancer Therapy. Breast Cancer Res Treat 52, 65–77 (1998). https://doi.org/10.1023/A:1006111117877

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