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Journal of Cancer Research and Clinical Oncology
Published in: Journal of Cancer Research and Clinical Oncology 1/2006

01-01-2006 | Original Paper

Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/neu overexpressing metastatic breast cancer

Authors: Wolfgang J. Köstler, Gernot Hudelist, Werner Rabitsch, Klaus Czerwenka, Ruth Müller, Christian F. Singer, Christoph C. Zielinski

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2006

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Abstract

Purpose: Her-2/neu and the insulin-like growth factor-1 receptor (IGF-1R) share common postreceptor-signaling pathways, and pre-clinical models have implicated IGF-1R-signaling in resistance to treatment with the anti-Her-2/neu antibody trastuzumab. The present analysis was performed to evaluate the clinical relevance of IGF-1R expression within the context of trastuzumab-based therapy. Patients and methods: We performed immunohistochemical (IHC) analysis for IGF-1R expression in tumor specimens from 72 patients receiving trastuzumab-based treatment for Her-2/neu-overexpressing metastatic breast cancer at a single institution. IGF-1R status was evaluated using different cut-offs for positivity regarding staining intensity and staining pattern. IGF-1R positivity was then correlated with clinical patient and biological tumor characteristics and the clinical course of disease of patients under trastuzumab-based therapy. Results: No pattern or intensity of staining for IGF-1R correlated with any of the clinical or biological characteristics. Likewise, response, clinical benefit, progression-free and overall survival were independent of IGF-1R expression in both, univariate and multivariate analyses (all P>0.05). Conclusions: We conclude that IGF-1R expression is not a major predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu- overexpressing metastatic breast cancer.
Literature
Ahmad N, Keehn CA, Coppola D (2004) The expression of insulin-like growth factor-1 receptor correlates with Fuhrman grading of renal cell carcinomas. Hum Pathol 35:1132–1136CrossRefPubMed
Arbet-Engels C, Tartare-Deckert S, Eckhart W (1999) C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-1 receptor. J Biol Chem 274:5422–5428CrossRefPubMed
Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3
Balana ME, Labriola L, Salatino M, Movsichoff F, Peters G, Charreau EH, Elizalde PV (2001) Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insulin-like growth factor receptor in mammary tumor cells. Oncogene 20:34–47CrossRefPubMed
Berns EM, Klijn JG, van Staveren IL, Portengen H, Foekens JA (1992) Sporadic amplification of the insulin-like growth factor 1 receptor gene in human breast tumors. Cancer Res 52:1036–1039PubMed
Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377PubMed
Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, Friedlander RJ Jr, Gargiulo J, Strenger R, Vogel CL, Ryan PD, Ellis MJ, Nunes RA, Bunnell CA, Campos SM, Hallor M, Gelman R, Winer EP (2003) Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 21:2889–2895CrossRefPubMed
Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, Manola J, Younger J, Matulonis U, Bunnell CA, Partridge AH, Richardson PG, Clarke K, Shulman LN, Winer EP (2001) Clinical activity of trastuzumab and vinorelbine in women with HER2- overexpressing metastatic breast cancer. J Clin Oncol 19:2722–2730PubMed
Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H, Jimenez X, Johnson D, Apblett R, Kussie P, Bohlen P, Witte L, Hicklin DJ, Ludwig DL (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63:8912–8921PubMed
Camirand A, Lu Y, Pollak M (2002) Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med Sci Monit 8:BR521–526PubMed
Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1:707–717PubMed
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 17:2639–2648PubMed
Del Valle L, Enam S, Lassak A, Wang JY, Croul S, Khalili K, Reiss K (2002) Insulin-like growth factor I receptor activity in human medulloblastomas. Clin Cancer Res 8:1822–1830PubMed
Green S, Weiss GR (1992) Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239–253CrossRefPubMed
Happerfield LC, Miles DW, Barnes DM, Thomsen LL, Smith P, Hanby A (1997) The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue. J Pathol 183:412–417CrossRefPubMed
Hirsch FR, Langer CJ (2004) The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. Semin Oncol 31:75–82CrossRefPubMed
Hodak E, Gottlieb AB, Anzilotti M, Krueger JG (1996) The insulin-like growth factor 1 receptor is expressed by epithelial cells with proliferative potential in human epidermis and skin appendages: correlation of increased expression with epidermal hyperplasia. J Invest Dermatol 106:564–570CrossRefPubMed
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 89:983–991CrossRefPubMed
Ignatoski KM, Lapointe AJ, Radany EH, Ethier SP (1999) erbB-2 overexpression in human mammary epithelial cells confers growth factor independence. Endocrinology 140:3615–3622CrossRefPubMed
Jammes H, Peyrat JP, Ban E, Vilain MO, Haour F, Djiane J, Bonneterre J (1992) Insulin-like growth factor 1 receptors in human breast tumor: localization and quantification by histo-autoradiographic analysis. Br J Cancer 66:248–253PubMed
Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI (2004) Insulin-like growth factor-1 receptor signaling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814CrossRefPubMed
Koda M, Sulkowski S, Garofalo C, Kanczuga-Koda L, Sulkowska M, Surmacz E (2003) Expression of the insulin-like growth factor-1 receptor in primary breast cancer and lymph node metastases: correlations with estrogen receptors alpha and beta. Horm Metab Res 35:794–801CrossRefPubMed
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 Her-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res 10:1618–1624CrossRefPubMed
Kulik G, Weber MJ (1998) Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I. Mol Cell Biol 18:6711–6718PubMed
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr (1995) Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143–163CrossRefPubMed
Longo F, Mansueto G (2002) [Breast Cancer Conference Trastuzumab and capecitabine in the treatment of advanced breast cancer Milano, 6–7 June 2002]. Tumori 88:A1–10PubMed
Lu Y, Zi X, Pollak M (2004a) Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int J Cancer 108:334–341CrossRefPubMed
Lu Y, Zi X, Zhao Y, Pollak M (2004b) Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells. Biochem Biophys Res Commun 313:709–715CrossRefPubMed
Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-1 receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857CrossRefPubMed
Miller KD, Sisk J, Ansari R, Gize G, Nattam S, Pennington K, Monaco F, Sledge GW Jr (2001) Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. Oncology (Huntingt) 15:38–40
Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127CrossRefPubMed
Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ (1998) Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659–2671PubMed
Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518CrossRefPubMed
Remmele W, Schicketanz KH (1993) Immunohistochemical determination of estrogen and progesterone receptor content in human breast cancer Computer-assisted image analysis (QIC score) vs subjective grading (IRS). Pathol Res Pract 189:862–866PubMed
Salatino M, Schillaci R, Proietti CJ, Carnevale R, Frahm I, Molinolo AA, Iribarren A, Charreau EH, Elizalde PV (2004) Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity. Oncogene 23:5161–5174CrossRefPubMed
Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D (2000) Down-regulation of insulin-like growth factor-1 receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 89:506–513CrossRefPubMed
Scrimgeour AG, Blakesley VA, Stannard BS, LeRoith D (1997) Mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways are not sufficient for insulin-like growth factor I-induced mitogenesis and tumorigenesis. Endocrinology 138:2552–2558CrossRefPubMed
Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D’Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA (2001) Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19:2587–2595PubMed
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 235:177–182PubMedCrossRef
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792CrossRefPubMed
Slichenmyer WJ, Fry DW (2001) Anticancer therapy targeting the erbB family of receptor tyrosine kinases. Semin Oncol 28:67–79CrossRefPubMed
Smith BL, Chin D, Maltzman W, Crosby K, Hortobagyi GN, Bacus SS (2004) The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer
Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR (2001) AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 61:589–593PubMed
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 20:719–726CrossRefPubMed
Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB (2002) Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 95:2086–2095CrossRefPubMed
Weng LP, Smith WM, Brown JL, Eng C (2001) PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet 10:605–616CrossRefPubMed
Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62:4132–4141PubMed
Yamamoto K, Altschuler D, Wood E, Horlick K, Jacobs S, Lapetina EG (1992) Association of phosphorylated insulin-like growth factor-1 receptor with the SH2 domains of phosphatidylinositol 3-kinase p85. J Biol Chem 267:11337–11343PubMed
Yu H, Rohan T (2000) Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92:1472–1489CrossRefPubMed
Zhao H, Dupont J, Yakar S, Karas M, LeRoith D (2004) PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-1R expression in prostate cancer cells. Oncogene 23:786–794CrossRefPubMed
Metadata
Title
Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/neu overexpressing metastatic breast cancer
Authors
Wolfgang J. Köstler
Gernot Hudelist
Werner Rabitsch
Klaus Czerwenka
Ruth Müller
Christian F. Singer
Christoph C. Zielinski
Publication date
01-01-2006
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 1/2006
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-005-0038-8

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