Skip to main content
SpringerLink
Log in

HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

HER2 or ErbB2 is a member of the epidermal growth factor family and is overexpressed in subsets of breast, ovarian, gastric, colorectal, pancreatic, and endometrial cancers. HER2 regulates signaling through several pathways (Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin pathways) associated with cell survival and proliferation. HER2-overexpressed and/or gene-amplified tumors are generally regarded as biologically aggressive neoplasms. In breast, cervical, endometrial, and ovarian cancer, there have been several studies linking the amplification of the c-erbB2 gene with chemoresistance and overall poor survival. Tyrosine kinase inhibitors and immunotherapy with monoclonal antibodies targeting HER2 hold promise for patients harboring these aggressive neoplasms. Trastuzumab combined with cytotoxic chemotherapy agents or conjugated with radioactive isotopes is currently being investigated in clinical trials of several tumor types.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Slichenmyer WJ, Fry DW. Anticancer therapy targeting the erbB family of receptor tyrosine kinases. Semin Oncol. 2001;28(5 Suppl 16):67–79. Epub 2001 Nov 14.

    Article  PubMed  CAS  Google Scholar 

  2. Schmidt M, Lewark B, Kohlschmidt N, Glawatz C, Steiner E, Tanner B, et al. Long-term prognostic significance of HER-2/neu in untreated node-negative breast cancer depends on the method of testing. Breast Cancer Res. 2005;7(2):R256–66. Epub 2005 Mar 4.

    Article  PubMed  CAS  Google Scholar 

  3. Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist. 1998;3(4):237–52. Epub 1999 Jul 1.

    PubMed  Google Scholar 

  4. Ladjemi MZ, Jacot W, Chardes T, Pelegrin A, Navarro-Teulon I. Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother. 2010;59(9):1295–312. Epub 2010 Jun 10.

    Article  PubMed  CAS  Google Scholar 

  5. Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochimi Biophys Acta. 1994;1198(2–3):165–84. Epub 1994 Dec 30.

    PubMed  Google Scholar 

  6. Ravdin PM, Chamness GC. The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers—a review. Gene. 1995;159(1):19–27. Epub 1995 Jun 14.

    Article  PubMed  CAS  Google Scholar 

  7. Casalini P, Iorio MV, Galmozzi E, Menard S. Role of HER receptors family in development and differentiation. J Cell Physiol. 2004;200(3):343–50. Epub 2004 Jul 16.

    Article  PubMed  CAS  Google Scholar 

  8. Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, et al. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J. 1996;15(2):254–64. Epub 1996 Jan 15.

    PubMed  CAS  Google Scholar 

  9. Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16(7):1647–55. Epub 1997 Apr 1.

    Article  PubMed  CAS  Google Scholar 

  10. Busse D, Doughty RS, Arteaga CL. HER-2/neu (erbB-2) and the cell cycle. Semin Oncol. 2000;27(6 Suppl 11):3–8; discussion 92–100. Epub 2001 Mar 10.

    PubMed  CAS  Google Scholar 

  11. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12. Epub 1989 May 12.

    Article  PubMed  CAS  Google Scholar 

  12. Okines A, Cunningham D, Chau I. Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol. 2011;8(8):492–503. Epub 2011 Apr 7.

    Article  PubMed  CAS  Google Scholar 

  13. Serrano-Olvera A, Duenas-Gonzalez A, Gallardo-Rincon D, Candelaria M, De la Garza-Salazar J. Prognostic, predictive and therapeutic implications of HER2 in invasive epithelial ovarian cancer. Cancer Treat Rev. 2006;32(3):180–90. Epub 2006 Feb 18.

    Article  PubMed  CAS  Google Scholar 

  14. Penault-Llorca F, Bilous M, Dowsett M, Hanna W, Osamura RY, Ruschoff J, et al. Emerging technologies for assessing HER2 amplification. Am J Clin Pathol. 2009;132(4):539–48. Epub 2009 Sep 19.

    Article  PubMed  CAS  Google Scholar 

  15. Papouchado BG, Myles J, Lloyd RV, Stoler M, Oliveira AM, Downs-Kelly E, et al. Silver in situ hybridization (SISH) for determination of HER2 gene status in breast carcinoma: comparison with FISH and assessment of interobserver reproducibility. Am J Surg Pathol. 2010;34(6):767–76. Epub 2010 Apr 28.

    Article  PubMed  Google Scholar 

  16. Dietel M, Ellis IO, Hofler H, Kreipe H, Moch H, Dankof A, et al. Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists. Virchows Arch Int J Pathol. 2007;451(1):19–25. Epub 2007 Jun 15.

    Article  CAS  Google Scholar 

  17. Kakar S, Puangsuvan N, Stevens JM, Serenas R, Mangan G, Sahai S, et al. HER-2/neu assessment in breast cancer by immunohistochemistry and fluorescence in situ hybridization: comparison of results and correlation with survival. Mol Diagn. 2000;5(3):199–207. Epub 2000 Nov 9.

    Article  PubMed  CAS  Google Scholar 

  18. Tian Q, Stepaniants SB, Mao M, Weng L, Feetham MC, Doyle MJ, et al. Integrated genomic and proteomic analyses of gene expression in mammalian cells. Mol Cell Proteomics. 2004;3(10):960–9. Epub 2004 Jul 9.

    Article  PubMed  CAS  Google Scholar 

  19. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131(1):18–43. Epub 2007 Jan 1.

    PubMed  CAS  Google Scholar 

  20. Ioannides CG, Ioannides MG, O’Brian CA. T-cell recognition of oncogene products: a new strategy for immunotherapy. Mol Carcinog. 1992;6(2):77–82. Epub 1992 Jan 1.

    Article  PubMed  CAS  Google Scholar 

  21. Tal M, Wetzler M, Josefberg Z, Deutch A, Gutman M, Assaf D, et al. Sporadic amplification of the HER2/neu protooncogene in adenocarcinomas of various tissues. Cancer Res. 1988;48(6):1517–20. Epub 1988 Mar 15.

    PubMed  CAS  Google Scholar 

  22. 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. 1987;235(4785):177–82. Epub 1987 Jan 9.

    Article  PubMed  CAS  Google Scholar 

  23. Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, et al. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res. 1990;50(13):4087–91. Epub 1990 Jul 1.

    PubMed  CAS  Google Scholar 

  24. Kihana T, Tsuda H, Teshima S, Nomoto K, Tsugane S, Sonoda T, et al. Prognostic significance of the overexpression of c-erbB-2 protein in adenocarcinoma of the uterine cervix. Cancer. 1994;73(1):148–53. Epub 1994 Jan 1.

    Article  PubMed  CAS  Google Scholar 

  25. Arapantoni-Dadioti P, Valavanis C, Gavressea T, Tzaida O, Trihia H, Lekka I. Discordant expression of hormone receptors and HER2 in breast cancer. A retrospective comparison of primary tumors with paired metachronous recurrences or metastases. J BUON. 2012;17(2):277–83. Epub 2012 Jun 29.

    PubMed  CAS  Google Scholar 

  26. Bozzetti C, Negri FV, Lagrasta CA, Crafa P, Bassano C, Tamagnini I, et al. Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma. Br J Cancer. 2011;104(9):1372–6. Epub 2011 Apr 14.

    Article  PubMed  CAS  Google Scholar 

  27. Tewari KS, Kyshtoobayeva AS, Mehta RS, Yu IR, Burger RA, DiSaia PJ, et al. Biomarker conservation in primary and metastatic epithelial ovarian cancer. Gynecol Oncol. 2000;78(2):130–6. Epub 2000 Aug 6.

    Article  PubMed  CAS  Google Scholar 

  28. Gilks CB. Subclassification of ovarian surface epithelial tumors based on correlation of histologic and molecular pathologic data. Int J Gynecol Pathol. 2004;23(3):200–5. Epub 2004 Jun 24.

    Article  PubMed  Google Scholar 

  29. Nofech-Mozes S, Khalifa MA, Ismiil N, Saad RS, Hanna WM, Covens A, et al. Immunophenotyping of serous carcinoma of the female genital tract. Mod Pathol. 2008;21(9):1147–55. Epub 2008 Jun 24.

    Article  PubMed  CAS  Google Scholar 

  30. Sueblinvong T, Manchana T, Khemapech N, Triratanachat S, Termrungruanglert W, Tresukosol D. Lack of prognostic significance of HER-2/neu in early epithelial ovarian cancer. Asian Pac J Cancer Prev. 2007;8(4):502–6. Epub 2008 Feb 12.

    PubMed  Google Scholar 

  31. Oberaigner W, Minicozzi P, Bielska-Lasota M, Allemani C, De Angelis R, Mangone L, et al. Survival for ovarian cancer in Europe: the across-country variation did not shrink in the past decade. Acta Oncol. 2012;51(4):441–53. Epub 2012 Feb 9.

    Article  PubMed  Google Scholar 

  32. Wang DP, Konishi I, Koshiyama M, Nanbu Y, Iwai T, Nonogaki H, et al. Immunohistochemical localization of c-erbB-2 protein and epidermal growth factor receptor in normal surface epithelium, surface inclusion cysts, and common epithelial tumours of the ovary. Virchows Arch A Pathol Anat Histopathol. 1992;421(5):393–400. Epub 1992 Jan 1.

    Article  PubMed  CAS  Google Scholar 

  33. Marinas MC, Mogos G, Ciurea R, Mogos DG. EGFR, HER2/neu and Ki67 immunoexpression in serous ovarian tumors. Rom J Morphol Embryol. 2012;53(3):563–7. Epub 2012 Sep 20.

    PubMed  CAS  Google Scholar 

  34. Raspollini MR, Amunni G, Villanucci A, Castiglione F, Rossi Degl’Innocenti D, Baroni G, et al. HER-2/neu and bcl-2 in ovarian carcinoma: clinicopathologic, immunohistochemical, and molecular study in patients with shorter and longer survival. Appl Immunohistochem Mol Morphol. 2006;14(2):181–6. Epub 2006 Jun 21.

    Article  PubMed  Google Scholar 

  35. Lassus H, Leminen A, Vayrynen A, Cheng G, Gustafsson JA, Isola J, et al. ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma. Gynecol Oncol. 2004;92(1):31–9. Epub 2004 Jan 31.

    Article  PubMed  CAS  Google Scholar 

  36. Wu Y, Soslow RA, Marshall DS, Leitao M, Chen B. Her-2/neu expression and amplification in early stage ovarian surface epithelial neoplasms. Gynecol Oncol. 2004;95(3):570–5. Epub 2004 Dec 8.

    Article  PubMed  CAS  Google Scholar 

  37. Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2003;21(2):283–90. Epub 2003 Jan 15.

    Article  PubMed  CAS  Google Scholar 

  38. Camilleri-Broet S, Hardy-Bessard AC, Le Tourneau A, Paraiso D, Levrel O, Leduc B, et al. HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol. 2004;15(1):104–12. Epub 2003 Dec 18.

    Article  PubMed  CAS  Google Scholar 

  39. Lee CH, Huntsman DG, Cheang MC, Parker RL, Brown L, Hoskins P, et al. Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma. Int J Gynecol Pathol. 2005;24(2):147–52. Epub 2005 Mar 23.

    Article  PubMed  Google Scholar 

  40. McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Kobel M, et al. HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer. 2009;9:433. Epub 2009 Dec 17.

    Article  PubMed  CAS  Google Scholar 

  41. Anglesio M, Kommoss S, Tolcher M, Clarke B, Galletta L, Porter H, et al. Molecular characterization of mucinous ovarian tumors supports a stratified treatment approach with HER2 targeting in 18% of carcinomas. J Pathol. 2012;229:111–20. Epub 2012 Aug 18.

    Article  CAS  Google Scholar 

  42. Yan B, Choo SN, Mulyadi P, Srivastava S, Ong CW, Yong KJ, et al. Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours. J Clin Pathol. 2011;64(12):1097–101. Epub 2011 Sep 8.

    Article  PubMed  Google Scholar 

  43. McCaughan H, Um I, Langdon SP, Harrison DJ, Faratian D. HER2 expression in ovarian carcinoma: caution and complexity in biomarker analysis. J Clin Pathol. 2012;65(7):670–1; author reply 671–2. Epub 2012 Mar 14.

    Article  PubMed  Google Scholar 

  44. Tuefferd M, Couturier J, Penault-Llorca F, Vincent-Salomon A, Broet P, Guastalla JP, et al. HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients. PloS One. 2007;2(11):e1138. Epub 2007 Nov 8.

    Article  PubMed  CAS  Google Scholar 

  45. Faratian D, Christiansen J, Gustavson M, Jones C, Scott C, Um I, et al. Heterogeneity mapping of protein expression in tumors using quantitative immunofluorescence. J Vis Exp. 2011;56:e3334. Epub 2011 Nov 9.

    PubMed  Google Scholar 

  46. Tan DS, Iravani M, McCluggage WG, Lambros MB, Milanezi F, Mackay A, et al. Genomic analysis reveals the molecular heterogeneity of ovarian clear cell carcinomas. Clin Cancer Res. 2011;17(6):1521–34. Epub 2011 Mar 18.

    Article  PubMed  CAS  Google Scholar 

  47. Fujimura M, Katsumata N, Tsuda H, Uchi N, Miyazaki S, Hidaka T, et al. HER2 is frequently over-expressed in ovarian clear cell adenocarcinoma: possible novel treatment modality using recombinant monoclonal antibody against HER2, trastuzumab. Jpn J Cancer Res. 2002;93(11):1250–7. Epub 2002 Dec 4.

    Article  PubMed  CAS  Google Scholar 

  48. Uzan C, Darai E, Valent A, Graesslin O, Cortez A, Rouzier R, et al. Status of HER1 and HER2 in peritoneal, ovarian and colorectal endometriosis and ovarian endometrioid adenocarcinoma. Virchows Arch Int J Pathol. 2009;454(5):525–9. Epub 2009 Mar 19.

    Article  CAS  Google Scholar 

  49. Felip E, Del Campo JM, Rubio D, Vidal MT, Colomer R, Bermejo B. Overexpression of c-erbB-2 in epithelial ovarian cancer. Prognostic value and relationship with response to chemotherapy. Cancer. 1995;75(8):2147–52. Epub 1995 Apr 15.

    Article  PubMed  CAS  Google Scholar 

  50. Peiro G, Mayr D, Hillemanns P, Lohrs U, Diebold J. Analysis of HER-2/neu amplification in endometrial carcinoma by chromogenic in situ hybridization. Correlation with fluorescence in situ hybridization, HER-2/neu, p53 and Ki-67 protein expression, and outcome. Modern Pathol. 2004;17(3):227–87. Epub 2004 Jan 31.

    Article  CAS  Google Scholar 

  51. Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, et al. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol. 2006;24(15):2376–85. Epub 2006 May 20.

    Article  PubMed  CAS  Google Scholar 

  52. Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(1):15–20. Epub 2009 Oct 21.

    Article  PubMed  CAS  Google Scholar 

  53. Nicklin JL, Copeland LJ. Endometrial papillary serous carcinoma: patterns of spread and treatment. Clin Obstet Gynecol. 1996;39(3):686–95. Epub 1996 Sep 1.

    Article  PubMed  CAS  Google Scholar 

  54. Goff BA, Kato D, Schmidt RA, Ek M, Ferry JA, Muntz HG, et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol. 1994;54(3):264–8. Epub 1994 Sep 1.

    Article  PubMed  CAS  Google Scholar 

  55. Slomovitz BM, Burke TW, Eifel PJ, Ramondetta LM, Silva EG, Jhingran A, et al. Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases. Gynecol Oncol. 2003;91(3):463–9. Epub 2003 Dec 17.

    Article  PubMed  Google Scholar 

  56. Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol. 1982;6(2):93–108. Epub 1982 Mar 1.

    Article  PubMed  CAS  Google Scholar 

  57. Santin AD, Zhan F, Bellone S, Palmieri M, Cane S, Gokden M, et al. Discrimination between uterine serous papillary carcinomas and ovarian serous papillary tumours by gene expression profiling. Br J Cancer. 2004;90(9):1814–24. Epub 2004 Jun 23.

    Article  PubMed  CAS  Google Scholar 

  58. Santin AD, Bellone S, Gokden M, Palmieri M, Dunn D, Agha J, et al. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin Cancer Res. 2002;8(5):1271–9. Epub 2002 May 15.

    PubMed  CAS  Google Scholar 

  59. Rolitsky CD, Theil KS, McGaughy VR, Copeland LJ, Niemann TH. HER-2/neu amplification and overexpression in endometrial carcinoma. Int J Gynecol Pathol. 1999;18(2):138–43. Epub 1999 Apr 15.

    Article  PubMed  CAS  Google Scholar 

  60. Slomovitz BM, Broaddus RR, Burke TW, Sneige N, Soliman PT, Wu W, et al. Her-2/neu overexpression and amplification in uterine papillary serous carcinoma. J Clin Oncol. 2004;22(15):3126–32. Epub 2004 Jul 31.

    Article  PubMed  CAS  Google Scholar 

  61. Santin AD, Bellone S, Siegel ER, Palmieri M, Thomas M, Cannon MJ, et al. Racial differences in the overexpression of epidermal growth factor type II receptor (HER2/neu): a major prognostic indicator in uterine serous papillary cancer. Am J Obstet Gynecol. 2005;192(3):813–8. Epub 2005 Mar 5.

    Article  PubMed  CAS  Google Scholar 

  62. McCluggage WG. Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas? J Clin Pathol. 2002;55(5):321–5. Epub 2002 May 3.

    Article  PubMed  CAS  Google Scholar 

  63. Wada H, Enomoto T, Fujita M, Yoshino K, Nakashima R, Kurachi H, et al. Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Res. 1997;57(23):5379–85. Epub 1997 Dec 11.

    PubMed  CAS  Google Scholar 

  64. Jonson AL, Bliss RL, Truskinovsky A, Judson P, Argenta P, Carson L, et al. Clinical features and outcomes of uterine and ovarian carcinosarcoma. Gynecol Oncol. 2006;100(3):561–4. Epub 2005 Nov 8.

    Article  PubMed  Google Scholar 

  65. Livasy CA, Reading FC, Moore DT, Boggess JF, Lininger RA. EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma. Gynecol Oncol. 2006;100(1):101–6. Epub 2005 Sep 15.

    Article  PubMed  CAS  Google Scholar 

  66. Sawada M, Tsuda H, Kimura M, Okamoto S, Kita T, Kasamatsu T, et al. Different expression patterns of KIT, EGFR, and HER-2 (c-erbB-2) oncoproteins between epithelial and mesenchymal components in uterine carcinosarcoma. Cancer Sci. 2003;94(11):986–91. Epub 2003 Nov 13.

    Article  PubMed  CAS  Google Scholar 

  67. Guzzo F, Bellone S, Buza N, Hui P, Carrara L, Varughese J, et al. HER2/neu as a potential target for immunotherapy in gynecologic carcinosarcomas. Int J Gynecol Pathol. 2012;31(3):211–21. Epub 2012 Apr 14.

    Article  PubMed  CAS  Google Scholar 

  68. Hale RJ, Buckley CH, Fox H, Williams J. Prognostic value of c-erbB-2 expression in uterine cervical carcinoma. J Clin Pathol. 1992;45(7):594–6. Epub 1992 Jul 1.

    Article  PubMed  CAS  Google Scholar 

  69. Bellone S, Palmieri M, Gokden M, Joshua J, Roman JJ, Pecorelli S, et al. Selection of HER-2/neu-positive tumor cells in early stage cervical cancer: implications for Herceptin-mediated therapy. Gynecol Oncol. 2003;91(1):231–40. Epub 2003 Oct 8.

    Article  PubMed  CAS  Google Scholar 

  70. Berchuck A, Rodriguez G, Kamel A, Soper JT, Clarke-Pearson DL, Bast RC Jr. Expression of epidermal growth factor receptor and HER-2/neu in normal and neoplastic cervix, vulva, and vagina. Obstet Gynecol. 1990;76(3 Pt 1):381–7. Epub 1990 Sep 11.

    PubMed  CAS  Google Scholar 

  71. Tebes S, Cardosi R, Hoffman M. Paget’s disease of the vulva. Am J Obstet Gynecol. 2002;187(2):281–3; discussion 283–4. Epub 2002 Aug 24.

    Article  PubMed  Google Scholar 

  72. Richter CE, Hui P, Buza N, Silasi DA, Azodi M, Santin AD, et al. HER-2/NEU overexpression in vulvar Paget disease: the Yale experience. J Clin Pathol. 2010;63(6):544–7. Epub 2010 Apr 27.

    Article  PubMed  CAS  Google Scholar 

  73. Noguchi S. Predictive factors for response to docetaxel in human breast cancers. Cancer Sci. 2006;97(9):813–20. Epub 2006 Jun 30.

    Article  PubMed  CAS  Google Scholar 

  74. Jung M, Koo JS, Moon YW, Park BW, Kim SI, Park S, et al. Overexpression of class III beta tubulin and amplified HER2 gene predict good response to paclitaxel and trastuzumab therapy. PloS One. 2012;7(9):e45127. Epub 2012 Oct 3.

    Article  PubMed  CAS  Google Scholar 

  75. Garcia-Velasco A, Mendiola C, Sanchez-Munoz A, Ballestin C, Colomer R, Cortes-Funes H. Prognostic value of hormonal receptors, p53, ki67 and HER2/neu expression in epithelial ovarian carcinoma. Clin Transl Oncol. 2008;10(6):367–71. Epub 2008 Jun 19.

    Article  PubMed  CAS  Google Scholar 

  76. Miyamoto A, Akasaka K, Oikawa H, Akasaka T, Masuda T, Maesawa C. Immunohistochemical study of HER2 and TUBB3 proteins in extramammary Paget disease. Am J Dermatopathol. 2010;32(6):578–85. Epub 2010 Jun 11.

    Article  PubMed  Google Scholar 

  77. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443–6. Epub 2000 Mar 31.

    Article  PubMed  CAS  Google Scholar 

  78. Spiridon CI, Guinn S, Vitetta ES. A comparison of the in vitro and in vivo activities of IgG and F(ab’)2 fragments of a mixture of three monoclonal anti-Her-2 antibodies. Clin Cancer Res. 2004;10(10):3542–51. Epub 2004 May 27.

    Article  PubMed  CAS  Google Scholar 

  79. Tamura K, Shimizu C, Hojo T, Akashi-Tanaka S, Kinoshita T, Yonemori K, et al. FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol. 2011;22(6):1302–7. Epub 2010 Nov 27.

    Article  PubMed  CAS  Google Scholar 

  80. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008;26(11):1789–96. Epub 2008 Mar 19.

    Article  PubMed  CAS  Google Scholar 

  81. Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10(17):5650.x–5.x. Epub 2008 Mar 19.

    Article  Google Scholar 

  82. Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94(2):259–67. Epub 2006 Jan 13.

    Article  PubMed  CAS  Google Scholar 

  83. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72. Epub 2005 Oct 21.

    Article  PubMed  CAS  Google Scholar 

  84. El-Sahwi K, Bellone S, Cocco E, Cargnelutti M, Casagrande F, Bellone M, et al. In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer. 2010;102(1):134–43. Epub 2009 Nov 19.

    Article  PubMed  CAS  Google Scholar 

  85. Jewell E, Secord AA, Brotherton T, Berchuck A. Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J Gynecol Cancer. 2006;16(3):1370–3. Epub 2006 Jun 29.

    Article  PubMed  CAS  Google Scholar 

  86. Villella JA, Cohen S, Smith DH, Hibshoosh H, Hershman D. HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int J Gynecol Cancer. 2006;16(5):1897–902. Epub 2006 Oct 3.

    Article  PubMed  CAS  Google Scholar 

  87. Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet. 2008;102(2):128–31. Epub 2008 Jun 17.

    Article  PubMed  CAS  Google Scholar 

  88. Alessandro S. Evaluation of carboplatin/paclitaxel with and without trastuzumab (Herceptin) in uterine serous cancer. http://www.clinicaltrials.gov/ct2/show/NCT01367002?id=NCT01367002&rank=1. Accessed 2013 Mar 14.

  89. Mullen P, Cameron DA, Hasmann M, Smyth JF, Langdon SP. Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. Mol Cancer Ther. 2007;6(1):93–100. Epub 2007 Jan 24.

    Article  PubMed  CAS  Google Scholar 

  90. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer cell. 2002;2(2):127.x–37.x. Epub 2007 Jan 24.

    Article  Google Scholar 

  91. Jackson JG, St Clair P, Sliwkowski MX, Brattain MG. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res. 2004;64(7):2601–9. Epub 2004 Apr 3.

    Article  PubMed  CAS  Google Scholar 

  92. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 2004;64(7):2343–6. Epub 2004 Apr 3.

    Article  PubMed  CAS  Google Scholar 

  93. Takai N, Jain A, Kawamata N, Popoviciu LM, Said JW, Whittaker S, et al. 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growth. Cancer. 2005;104(12):2701–8. Epub 2005 Nov 3.

    Article  PubMed  CAS  Google Scholar 

  94. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. Epub 2012 Oct 2.

    Article  PubMed  CAS  Google Scholar 

  95. Barok M, Tanner M, Koninki K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 2011;306(2):171.x–9.x. Epub 2012 Oct 2.

    Article  CAS  Google Scholar 

  96. Liu B, Nash J, Runowicz C, Swede H, Stevens R, Li Z. Ovarian cancer immunotherapy: opportunities, progresses and challenges. J Hematol Oncol. 2010;3:7. Epub 2010 Feb 12.

    Article  PubMed  CAS  Google Scholar 

  97. Yigit R, Massuger LF, Figdor CG, Torensma R. Ovarian cancer creates a suppressive microenvironment to escape immune elimination. Gynecol Oncol. 2010;117(2):366.x–72.x. Epub 2010 Feb 12.

    Article  CAS  Google Scholar 

  98. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137–48. Epub 2004 Aug 17.

    Article  PubMed  CAS  Google Scholar 

  99. Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology (Williston Park). 2009;23(6):488–96. Epub 2009 Jun 24.

    Google Scholar 

  100. Leslie M. Immunology. Regulatory T cells get their chance to shine. Science. 2011;332(6033):1020–1. Epub 2011 May 28.

    Article  PubMed  CAS  Google Scholar 

  101. Boyman O, Krieg C, Letourneau S, Webster K, Surh CD, Sprent J. Selectively expanding subsets of T cells in mice by injection of interleukin-2/antibody complexes: implications for transplantation tolerance. Transpl Proc. 2012;44(4):1032–4. Epub 2012 May 9.

    Article  CAS  Google Scholar 

  102. Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest. 2012;122(3):1066–75. Epub 2012 Feb 14.

    Article  PubMed  CAS  Google Scholar 

  103. Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer. 2001;1(2):118–29. Epub 2002 Mar 22.

    Article  PubMed  CAS  Google Scholar 

  104. Gelderman KA, Blok VT, Fleuren GJ, Gorter A. The inhibitory effect of CD46, CD55, and CD59 on complement activation after immunotherapeutic treatment of cervical carcinoma cells with monoclonal antibodies or bispecific monoclonal antibodies. Lab Invest. 2002;82(4):483–93. Epub 2002 Apr 16.

    Article  PubMed  CAS  Google Scholar 

  105. Gorter A, Blok VT, Haasnoot WH, Ensink NG, Daha, Fleuren GJ. Expression of CD46, CD55, and CD59 on renal tumor cell lines and their role in preventing complement-mediated tumor cell lysis. Lab Invest. 1996;74(6):1039–49. Epub 1996 Jun 1.

    PubMed  CAS  Google Scholar 

  106. Niehans GA, Cherwitz DL, Staley NA, Knapp DJ, Dalmasso AP. Human carcinomas variably express the complement inhibitory proteins CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), and CD59 (protectin). Am J Pathol. 1996;149(1):129–42. Epub 1996 Jul 1.

    PubMed  CAS  Google Scholar 

  107. Gelderman KA, Lam S, Gorter A. Inhibiting complement regulators in cancer immunotherapy with bispecific mAbs. Expert Opin Biol Ther. 2005;5(12):1593–601. Epub 2005 Dec 2.

    Article  PubMed  CAS  Google Scholar 

  108. Bellone S, Roque D, Cocco E, Gasparrini S, Bortolomai I, Buza N, et al. Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy. Br J Cancer. 2012;106(9):1543–50. Epub 2012 Apr 26.

    Article  PubMed  CAS  Google Scholar 

  109. Lang SA, Hackl C, Moser C, Fichtner-Feigl S, Koehl GE, Schlitt HJ, et al. Implication of RICTOR in the mTOR inhibitor-mediated induction of insulin-like growth factor-I receptor (IGF-IR) and human epidermal growth factor receptor-2 (Her2) expression in gastrointestinal cancer cells. Biochimi Biophys Acta. 2010;1803(4):435–42. Epub 2010 Feb 2.

    Article  CAS  Google Scholar 

  110. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 2011;29(23):3126–32. Epub 2011 Jul 7.

    Article  PubMed  CAS  Google Scholar 

  111. Andre F, Campone M, O’Regan R, Manlius C, Massacesi C, Sahmoud T, et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol. 2010;28(34):5110–5. Epub 2010 Oct 27.

    Article  PubMed  CAS  Google Scholar 

  112. Kim JW, Kim HP, Im SA, Kang S, Hur HS, Yoon YK, et al. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 2008;272(2):296–306. Epub 2008 Sep 9.

    Article  PubMed  CAS  Google Scholar 

  113. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13(16):4909–19. Epub 2007 Aug 19.

    Article  PubMed  CAS  Google Scholar 

  114. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99(8):628–38. Epub 2007 Apr 19.

    Article  PubMed  CAS  Google Scholar 

  115. Wilken JA, Badri T, Cross S, Raji R, Santin AD, Schwartz P, et al. EGFR/HER-targeted therapeutics in ovarian cancer. Futur Med Chem. 2012;4(4):447–69. Epub 2012 Mar 16.

    Article  CAS  Google Scholar 

  116. Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin Biol Ther. 2002;2(1):3–24. Epub 2002 Jan 5.

    Article  PubMed  CAS  Google Scholar 

  117. Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci. 2007;32(3):517–30. Epub 2007 May 31.

    Article  PubMed  CAS  Google Scholar 

  118. Munster PN, Srethapakdi M, Moasser MM, Rosen N. Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells. Cancer Res. 2001;61(7):2945–52. Epub 2001 Apr 18.

    PubMed  CAS  Google Scholar 

  119. Munster PN, Marchion DC, Basso AD, Rosen N. Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3′-kinase-AKT-dependent pathway. Cancer Res. 2002;62(11):3132–7. Epub 2002 May 31.

    PubMed  CAS  Google Scholar 

  120. Schoffelen R, van der Graaf WT, Franssen G, Sharkey RM, Goldenberg DM, McBride WJ, et al. Pretargeted 177Lu radioimmunotherapy of carcinoembryonic antigen-expressing human colonic tumors in mice. J Nucl Med. 2010;51(11):1780–7. Epub 2010 Nov 6.

    Article  PubMed  Google Scholar 

  121. Stillebroer AB, Boerman OC, Desar IM, Boers-Sonderen MJ, van Herpen CM, Langenhuijsen JF, et al. Phase 1 radioimmunotherapy study with lutetium 177-labeled anti-carbonic anhydrase IX monoclonal antibody girentuximab in patients with advanced renal cell carcinoma. Eur Urol. 2012. Epub 2012 Sep 18.

  122. Behe M, Alt K, Deininger F, Buhler P, Wetterauer U, Weber WA, et al. In vivo testing of 177Lu-labelled anti-PSMA antibody as a new radioimmunotherapeutic agent against prostate cancer. In Vivo. 2011;25(1):55–9. Epub 2011 Feb 2.

    PubMed  CAS  Google Scholar 

  123. Heyerdahl H, Abbas N, Brevik EM, Mollatt C, Dahle J. Fractionated therapy of HER2-expressing breast and ovarian cancer xenografts in mice with targeted alpha emitting 227Th-DOTA-p-benzyl-trastuzumab. PloS One. 2012;7(8):e42345. Epub 2012 Aug 11.

    Article  PubMed  CAS  Google Scholar 

  124. Ray GL, Baidoo KE, Keller LM, Albert PS, Brechbiel MW, Milenic DE. Pre-clinical assessment of Lu-labeled trastuzumab targeting HER2 for treatment and management of cancer patients with disseminated intraperitoneal disease. Pharmaceuticals (Basel). 2011;5(1):1–15. Epub 2012 Jan 10.

    Article  CAS  Google Scholar 

  125. Areva Med LLC. Safety study of 212Pb-TCMC-trastuzumab radio immunotherapy. http://www.clinicaltrials.gov/ct2/show/NCT01384253. Accessed 2013 Mar 14.

  126. Chu CS, Boyer J, Schullery DS, Gimotty PA, Gamerman V, Bender J, et al. Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission. Cancer Immunol Immunother. 2012;61(5):629–41. Epub 2011 Oct 25.

    Article  PubMed  CAS  Google Scholar 

  127. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med. 1982;155(4):1063–74. Epub 1982 Apr 1.

    Article  PubMed  CAS  Google Scholar 

  128. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56(5):641–8. Epub 2006 Sep 9.

    Article  PubMed  CAS  Google Scholar 

  129. Baxevanis CN, Papamichail M, Perez SA. Toxicity profiles of HER2/neu peptide anticancer vaccines: the picture from phase/I and II clinical trials. Expert Rev Vaccines. 2012;11(6):637–40. Epub 2012 Aug 10.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No sources of funding were used to prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, LSOG 305, P.O. Box 208063, New Haven, CT, 06520-8063, USA

    Diana P. English, Dana M. Roque & Alessandro D. Santin

Authors
  1. Diana P. English
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dana M. Roque
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandro D. Santin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro D. Santin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

English, D.P., Roque, D.M. & Santin, A.D. HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies. Mol Diagn Ther 17, 85–99 (2013). https://doi.org/10.1007/s40291-013-0024-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-013-0024-9

Keywords

Search

Navigation