Breast Cancer Research and Treatment

, Volume 123, Issue 2, pp 437–445 | Cite as

Monitoring serum HER2 levels during neoadjuvant trastuzumab treatment within the GeparQuattro trial

  • Isabell Witzel
  • Sibylle Loibl
  • Gunter von Minckwitz
  • Christoph Mundhenke
  • Jens Huober
  • Claus Hanusch
  • Stephan Henschen
  • Maik Hauschild
  • Tilmann Lantzsch
  • Hans Tesch
  • Kunibert Latos
  • Marianne Just
  • Jörn Hilfrich
  • Jana Barinoff
  • Christine zu Eulenburg
  • Marc Roller
  • Michael Untch
  • Volkmar Müller
Clinical trial


In the context of neoadjuvant therapy (NT) for breast cancer patients, different targeted therapy approaches are currently evaluated in clinical trials. Serum markers could help to monitor and optimize such treatment strategies. We investigated human epidermal growth factor receptor 2 serum (sHER2) levels in 175 breast cancer patients participating in the GeparQuattro trial. This study incorporated NT approaches and additional trastuzumab treatment for all patients with HER2-positive tumors. Human epidermal growth factor receptor 2 serum levels were measured by enzyme-linked immunosorbent assay (ELISA) before initiation of NT and after NT (pre-surgery) in a HER2-positive (n = 90) and a HER2-negative patient cohort (n = 85). Median pre-chemotherapy sHER2 levels were higher in patients with positive HER2 status of the primary tumor than in patients with negative HER2 status (14.9 ng/ml vs. 7.7 ng/ml, P < 0.001). A pre-chemotherapy sHER2 cut-off level of 10 ng/ml had the best sensitivity and specificity in discriminating between HER2-positive and HER2-negative primary tumors. In HER2-positive patients, we found a significant positive association between pathological complete remission (pCR) and elevated sHER2 levels (above 15 ng/ml, P = 0.045) and a decrease of sHER2 levels during NT (P = 0.02), which was also significant in multivariate analysis (OR = 3.29, 95% CI 1.001–10.89, P = 0.049). In HER2-negative patients, we observed no association between sHER2 levels and pCR (P > 0.05). Monitoring sHER2 levels in the presence of anti-HER2 treatment might be an adjunct to the clinical evaluation during NT.


Breast cancer Neoadjuvant therapy HER2 Serum 

Supplementary material

10549_2010_1030_MOESM1_ESM.ppt (62 kb)
Supplementary Fig 1: Disposition of patients (CONSORT diagram). (PPT 62 kb)


  1. 1.
    Kaufmann M, von Minckwitz G, Smith R, Valero V, Gianni L, Eiermann W, Howell A, Costa SD, Beuzeboc P, Untch M, Blohmer JU, Sinn HP, Sittek R, Souchon R, Tulusan AH, Volm T, Senn HJ (2003) International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations. J Clin Oncol 21:2600–2608CrossRefPubMedGoogle Scholar
  2. 2.
    von Minckwitz G, Raab G, Caputo A, Schutte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 23:2676–2685CrossRefGoogle Scholar
  3. 3.
    Untch M, Mobus V, Kuhn W, Muck BR, Thomssen C, Bauerfeind I, Harbeck N, Werner C, Lebeau A, Schneeweiss A, Kahlert S, von Koch F, Petry KU, Wallwiener D, Kreienberg R, Albert US, Luck HJ, Hinke A, Janicke F, Konecny GE (2009) Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. J Clin Oncol 27:2938–2945CrossRefPubMedGoogle Scholar
  4. 4.
    von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kuhn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M (2010) Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. Journal of Clinical Oncology 28(12):2015–2023CrossRefGoogle Scholar
  5. 5.
    Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kuhn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, von Minckwitz G (2010) Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. Journal of Clinical Oncology 28(12):2024–2031CrossRefPubMedGoogle Scholar
  6. 6.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182CrossRefPubMedGoogle Scholar
  7. 7.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712CrossRefPubMedGoogle Scholar
  8. 8.
    Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, Wickerham DL, Wolmark N (2000) HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92:1991–1998CrossRefPubMedGoogle Scholar
  9. 9.
    Codony-Servat J, Albanell J, Lopez-Talavera JC, Arribas J, Baselga J (1999) Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. Cancer Res 59:1196–1201PubMedGoogle Scholar
  10. 10.
    Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J (2001) Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 61:4744–4749PubMedGoogle Scholar
  11. 11.
    Hudelist G, Kostler WJ, Attems J, Czerwenka K, Muller R, Manavi M, Steger GG, Kubista E, Zielinski CC, Singer CF (2003) Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment. Br J Cancer 89:983–991CrossRefPubMedGoogle Scholar
  12. 12.
    Molina MA, Saez R, Ramsey EE, Garcia-Barchino MJ, Rojo F, Evans AJ, Albanell J, Keenan EJ, Lluch A, Garcia-Conde J, Baselga J, Clinton GM (2002) NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin.Cancer Res 8:347–353PubMedGoogle Scholar
  13. 13.
    Schwartz MK, Smith C, Schwartz DC, Dnistrian A, Neiman I (2000) Monitoring therapy by serum HER-2/neu. Int J Biol Markers 15:324–329PubMedGoogle Scholar
  14. 14.
    Mueller V, Witzel I, Luck HJ, Kohler G, von Minckwitz G, Mobus V, Sattler D, Wilczak W, Loning T, Jaenicke F, Pantel K, Thomssen C (2004) Prognostic and predictive impact of the HER-2/ neu extracellular domain (ECD) in the serum of patients treated with chemotherapy for metastatic breast cancer. Breast Cancer Res Treat 86:9–18CrossRefGoogle Scholar
  15. 15.
    Esteva FJ, Cheli CD, Fritsche H, Fornier M, Slamon D, Thiel R, Luftner D, Ghani F (2005) Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies. Breast Can Res 7:R436–R443CrossRefGoogle Scholar
  16. 16.
    Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676–3685CrossRefPubMedGoogle Scholar
  17. 17.
    Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422CrossRefPubMedGoogle Scholar
  18. 18.
    Tewari M, Krishnamurthy A, Shukla HS (2008) Predictive markers of response to neoadjuvant chemotherapy in breast cancer. Surg Oncol 17:301–311CrossRefPubMedGoogle Scholar
  19. 19.
    Lipton A, Ali SM, Leitzel K, Demers L, Chinchilli V, Engle L, Harvey HA, Brady C, Nalin CM, Dugan M, Carney W, Allard J (2002) Elevated serum her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20:1467–1472CrossRefPubMedGoogle Scholar
  20. 20.
    Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN (2002) Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20:1800–1808CrossRefPubMedGoogle Scholar
  21. 21.
    Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Kostler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A (2008) Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Cancer 113:1294–1301CrossRefPubMedGoogle Scholar
  22. 22.
    Hayes DF, Ethier S, Lippman ME (2006) New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK. Breast Cancer Res Treat 100:237–238CrossRefPubMedGoogle Scholar
  23. 23.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184CrossRefPubMedGoogle Scholar
  24. 24.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672CrossRefPubMedGoogle Scholar
  25. 25.
    Hall PS, Cameron DA (2009) Current perspective—trastuzumab. Eur J Cancer 45:12–18CrossRefPubMedGoogle Scholar
  26. 26.
    Ali SM, Leitzel K, Lipton A, Carney WP, Kostler WJ (2009) Value of serum human epidermal growth factor receptor 2 (HER2)/neu testing for early prediction of response to HER2/neu-directed therapies is still an open one and deserves further study in large prospective trials. J Clin Oncol 27(36):e273CrossRefPubMedGoogle Scholar
  27. 27.
    Payne RC, Allard JW, Anderson-Mauser L, Humphreys JD, Tenney DY, Morris DL (2000) Automated assay for HER-2/neu in serum. Clin Chem 46:175–182PubMedGoogle Scholar
  28. 28.
    Köstler WJ, Steger GG, Soleiman A, Schwab B, Singer CF, Tomek S, Brodowicz T, Krainer M, Wiltschke C, Horvat R, Jakesz R, Zielinski CC (2004) Monitoring of serum Her-2/neu predicts histopathological response to neoadjuvant trastuzumab-based therapy for breast cancer. Anticancer Res 24:1127–1130PubMedGoogle Scholar
  29. 29.
    Mazouni C, Hall A, Broglio K, Fritsche H, Andre F, Esteva FJ, Hortobagyi GN, Buzdar AU, Pusztai L, Cristofanilli M (2007) Kinetics of serum HER-2/neu changes in patients with HER-2-positive primary breast cancer after initiation of primary chemotherapy. Cancer 109:496–501CrossRefPubMedGoogle Scholar
  30. 30.
    Pallud C, Guinebretiere JM, Guepratte S, Hacene K, Neumann R, Carney W, Pichon MF (2005) Tissue expression and serum levels of the oncoprotein HER-2/neu in 157 primary breast tumours. Anticancer Res 25:1433–1440PubMedGoogle Scholar
  31. 31.
    Molina R, Filella X, Zanon G, Pahisa J, Alicarte J, Munoz M, Farrus B, Ballesta AM (2003) Prospective evaluation of tumor markers (c-erbB-2 oncoprotein, CEA and CA 15.3) in patients with locoregional breast cancer. Anticancer Res 23:1043–1050PubMedGoogle Scholar
  32. 32.
    Quaranta M, Daniele A, Coviello M, Savonarola A, Abbate I, Venneri MT, Paradiso A, Stea B, Zito A, Labriola A, Schittulli F (2006) c-erbB-2 protein level in tissue and sera of breast cancer patients: a possibly useful clinical correlation. Tumori 92:311–317PubMedGoogle Scholar
  33. 33.
    Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (2009) Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer. J Clin Oncol 27:1685–1693CrossRefPubMedGoogle Scholar
  34. 34.
    Fornier MN, Seidman AD, Schwartz MK, Ghani F, Thiel R, Norton L, Hudis C (2005) Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate. Ann Oncol 16:234–239CrossRefPubMedGoogle Scholar
  35. 35.
    Leary AF, Hanna WM, van de Vijver MJ, Penault-Llorca F, Ruschoff J, Osamura RY, Bilous M, Dowsett M (2009) Value and limitations of measuring HER-2 extracellular domain in the serum of breast cancer patients. J Clin Oncol 27:1694–1705CrossRefPubMedGoogle Scholar
  36. 36.
    Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H, Slamon DJ (2003) Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 95:142–153CrossRefPubMedGoogle Scholar
  37. 37.
    Köstler WJ, Schwab B, Singer CF, Neumann R, Rucklinger E, Brodowicz T, Tomek S, Niedermayr M, Hejna M, Steger GG, Krainer M, Wiltschke C, Zielinski CC (2004) Monitoring of serum Her-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res 10:1618–1624CrossRefPubMedGoogle Scholar
  38. 38.
    Bedard PL, de Azambuja E, Cardoso F (2009) Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. Curr Cancer Drug Targets 9:148–162CrossRefPubMedGoogle Scholar
  39. 39.
    Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramon y Cajal S, Arribas J, Baselga J (2007) Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99:628–638CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Isabell Witzel
    • 1
  • Sibylle Loibl
    • 3
  • Gunter von Minckwitz
    • 3
  • Christoph Mundhenke
    • 4
  • Jens Huober
    • 5
  • Claus Hanusch
    • 6
  • Stephan Henschen
    • 7
  • Maik Hauschild
    • 8
  • Tilmann Lantzsch
    • 9
  • Hans Tesch
    • 10
  • Kunibert Latos
    • 11
  • Marianne Just
    • 12
  • Jörn Hilfrich
    • 13
  • Jana Barinoff
    • 14
  • Christine zu Eulenburg
    • 2
  • Marc Roller
    • 3
  • Michael Untch
    • 15
  • Volkmar Müller
    • 1
  1. 1.Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of Medical Biometry and EpidemiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.German Breast Group, Forschungs GmbHNeu IsenburgGermany
  4. 4.Department of Gynecology and ObstetricsUniversity Medical Center KielKielGermany
  5. 5.Department of GynecologyUniversity of TübingenTübingenGermany
  6. 6.Department of Gynecology and ObstetricsRotkreuzklinikum München gGmbHMünchenGermany
  7. 7.Johanniter-Krankenhaus, Genthin-StendalStendalGermany
  8. 8.Frauenklinik Rheinfelden Betriebs GmbHRheinfeldenGermany
  9. 9.Krankenhaus St. Elisabeth und St. BarbaraHalleGermany
  10. 10.Onkologische Gemeinschaftspraxis am Bethanien-KrankenhausFrankfurtGermany
  11. 11.Katharinen-HospitalUnnaGermany
  12. 12.Onkologische SchwerpunktpraxisBielefeldGermany
  13. 13.Frauenklinik der Henriettenstiftung HannoverHannoverGermany
  14. 14.Deptartment of Gynecology & Gynecologic OncologyDr. Horst Schmidt KlinikWiesbadenGermany
  15. 15.Department of Gynecology and ObstetricsHELIOS Hospital Berlin-BuchBerlinGermany

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