Abstract
Purpose
High serum human epidermal growth factors receptor-2 (HER2) extracellular domain (ECD) has been identified as an independent prognostic indicator of poor prognosis in metastatic breast cancer. However, its prognostic value in primary operable breast cancer was still controversial. We aim to investigate the correlation between serum HER2 ECD levels and tissue HER2 status, the association between serum HER2 ECD levels and clinicopathological characteristics, and their impacts on disease-free survival (DFS) and overall survival (OS) in primary operable breast cancer.
Methods
Two hundred and fifty-two primary operable breast cancer patients pretreated from 2002 to 2009 in Sun Yat-Sen University Cancer Center were enrolled in this study. Serum HER2 ECD was measured by chemiluminescent assay, and tissue HER2 status was accessed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) assay.
Results
There was a significant correlation between serum HER2 ECD levels and HER2 tissue status (P < 0.001, R = 0.36). High serum HER2 ECD levels (≥15 ng/mL) were significantly associated with age (≥35 years) (P = 0.028), postmenopausal status (P < 0.001), stage III (P < 0.001), tumor size (≥2 cm) (P < 0.001), lymph node involvement (P < 0.001), negative estrogen receptor (P = 0.005), and progesterone receptor status (P = 0.001). Multivariate analysis showed that high serum HER2 ECD level was an independent prognostic factor of worse DFS (P = 0.014) and OS (P = 0.014) in primary operable breast cancer patients.
Conclusion
Serum HER2 ECD level can reflect tissue HER2 status and can be an independent prognostic indicator for primary operable breast cancer patients.
Similar content being viewed by others
References
Ali SM, Leitzel K, Chinchilli VM, Engle L, Demers L, Harvey HA, Carney W, Allard JW, Lipton A (2002) Relationship of serum HER-2/neu and serum CA 15-3 in patients with metastatic breast cancer. Clin Chem 48:1314–1320
Berns EM, Foekens JA, van Staveren IL, van Putten WL, de Koning HY, Portengen H, Klijn JG (1995) Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159:11–18
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
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 (1996) 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
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648
Colomer R, Montero S, Lluch A, Ojeda B, Barnadas A, Casado A, Massuti B, Cortes-Funes H, Lloveras B (2000) Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 6:2356–2362
Fehm T, Maimonis P, Katalinic A, Jager WH (1998) The prognostic significance of c-erbB-2 serum protein in metastatic breast cancer. Oncology 55:33–38
Fergenbaum JH, Garcia-Closas M, Hewitt SM, Lissowska J, Sakoda LC, Sherman ME (2004) Loss of antigenicity in stored sections of breast cancer tissue microarrays. Cancer Epidemiol Biomarkers Prev 13:667–672
Ferrero-Pous M, Hacene K, Bouchet C, Le Doussal V, Tubiana-Hulin M, Spyratos F (2000) Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. Clin Cancer Res 6:4745–4754
Fontana X, Ferrari P, Namer M, Peysson R, Salanon C, Bussiere F (1994) C-erb-B2 gene amplification and serum level of c-erb-B2 oncoprotein at primary breast cancer diagnosis. Anticancer Res 14:2099–2104
Garcia-Caballero T, Grabau D, Green AR, Gregory J, Schad A, Kohlwes E, Ellis IO, Watts S, Mollerup J (2010) Determination of HER2 amplification in primary breast cancer using dual-colour chromogenic in situ hybridization is comparable to fluorescence in situ hybridization: a European multicentre study involving 168 specimens. Histopathology 56:472–480
Gusterson BA, Gelber RD, Goldhirsch A, Price KN, Save-Soderborgh J, Anbazhagan R, Styles J, Rudenstam CM, Golouh R, Reed R et al (1992) Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin Oncol 10:1049–1056
Haerslev T, Jacobsen G, Zedeler K (1995) Proliferating cell nuclear antigen (pcna) and C-erbb-2 oncoprotein in breast-carcinoma with correlations to histopathological parameters and prognosis. Oncol Rep 2:99–105
Hammond ME, Hayes DF, Wolff AC (2011) Clinical Notice for American Society of Clinical Oncology-College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol 29:e458
Imoto S, Kitoh T, Hasebe T (1999) Serum c-erB-2 levels in monitoring of operable breast cancer patients. Jpn J Clin Oncol 29:336–339
Isola JJ, Holli K, Oksa H, Teramoto Y, Kallioniemi OP (1994) Elevated erbB-2 oncoprotein levels in preoperative and follow-up serum samples define an aggressive disease course in patients with breast cancer. Cancer 73:652–658
Jensen BV, Johansen JS, Price PA (2003) High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer. Clin Cancer Res 9:4423–4434
Kath R, Hoffken K, Otte C, Metz K, Scheulen ME, Hulskamp F, Seeber S (1993) The neu-oncogene product in serum and tissue of patients with breast carcinoma. Ann Oncol 4:585–590
Kong SY, Kang JH, Kwon Y, Kang HS, Chung KW, Kang SH, Lee DH, Ro J, Lee ES (2006) Serum HER2 concentration in patients with primary breast cancer. J Clin Pathol 59:373–376
Kostler 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 HER2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res 10:1618–1624
Krainer M, Brodowicz T, Zeillinger R, Wiltschke C, Scholten C, Seifert M, Kubista E, Zielinski CC (1997) Tissue expression and serum levels of HER2/neu in patients with breast cancer. Oncology 54:475–481
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 HER2 extracellular domain in the serum of breast cancer patients. J Clin Oncol 27:1694–1705
Limentani SA, Brufsky AM, Erban JK, Jahanzeb M, Lewis D (2007) Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer. J Clin Oncol 25:1232–1238
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 HER2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20:1467–1472
Ludovini V, Gori S, Colozza M, Pistola L, Rulli E, Floriani I, Pacifico E, Tofanetti FR, Sidoni A, Basurto C, Rulli A, Crino L (2008) Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival. Ann Oncol 19:883–890
Mazouni C, Hall A, Broglio K, Fritsche H, Andre F, Esteva FJ, Hortobagyi GN, Buzdar AU, Pusztai L, Cristofanilli M (2007) Kinetics of serum HER2/neu changes in patients with HER2-positive primary breast cancer after initiation of primary chemotherapy. Cancer 109:496–501
Menard S, Balsari A, Casalini P, Tagliabue E, Campiglio M, Bufalino R, Cascinelli N (2002) HER2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. Clin Cancer Res 8:520–525
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 23:1043–1050
Molina R, Auge JM, Escudero JM, Filella X, Zanon G, Pahisa J, Farrus B, Munoz M, Velasco M (2010) Evaluation of tumor markers (HER2/neu oncoprotein, CEA, and CA 15.3) in patients with locoregional breast cancer: prognostic value. Tumour Biol 31:171–180
Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M et al (1994) C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260–1266
Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, Fisher ER, Lippman ME, Wickerham DL, Wolmark N (1998) erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90:1361–1370
Pallud C, Guinebretiere JM, Guepratte S, Hacene K, Neumann R, Carney W, Pichon MF (2005) Tissue expression and serum levels of the oncoprotein HER2/neu in 157 primary breast tumours. Anticancer Res 25:1433–1440
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 353:1659–1672
Press MF, Bernstein L, Thomas PA, Meisner LF, Zhou JY, Ma Y, Hung G, Robinson RA, Harris C, El-Naggar A, Slamon DJ, Phillips RN, Ross JS, Wolman SR, Flom KJ (1997) HER2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol 15:2894–2904
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 92:311–317
Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, Addo FK, Murphy B, Ingle JN, Perez EA (2002) Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 94:855–857
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CJ, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Rastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684
Salvadori B, Pinzani P, Distante V, Casella D, Bianchi S, Paglierani M, Vezzosi V, Neumann R, Cataliotti L, Pazzagli M, Orlando C (2005) Comparison of pre- and postsurgical concentrations of blood HER2 mRNA and HER2 extracellular domain reflects HER2 status in early breast cancer. Clin Chem 51:254–256
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 HER2/neu oncogene. Science 235:177–182
Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez RP, Piccart-Gebhart MJ (2007) 2-Year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36
Stal O, Sullivan S, Wingren S, Skoog L, Rutqvist LE, Carstensen JM, Nordenskjold B (1995) C-erbB-2 expression and benefit from adjuvant chemotherapy and radiotherapy of breast cancer. Eur J Cancer 31A:2185–2190
Sugano K, Ushiama M, Fukutomi T, Tsuda H, Kitoh T, Ohkura H (2000) Combined measurement of the c-erbB-2 protein in breast carcinoma tissues and sera is useful as a sensitive tumor marker for monitoring tumor relapse. Int J Cancer 89:329–336
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726
Yuan P, Xu BH, Zhang C, Qi J (2003) Serum HER2/neu level and related factors in patients with breast cancer]. Zhonghua Zhong Liu Za Zhi 25:573–574
Acknowledgments
We thank all the patients who participate in this study. Grant support is given by Key Program of National Natural Science Foundation of China (31030061); Natural Science Foundation of Guangdong Province, China (9151008901000124); Science and Technology Planning Project of Guangzhou, China (10C32060205).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Yanan Kong and Shuqin Dai contributed equally to this article.
Rights and permissions
About this article
Cite this article
Kong, Y., Dai, S., Xie, X. et al. High serum HER2 extracellular domain levels: correlation with a worse disease-free survival and overall survival in primary operable breast cancer patients. J Cancer Res Clin Oncol 138, 275–284 (2012). https://doi.org/10.1007/s00432-011-1095-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-011-1095-9