Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas.

Abstract

AIMS:

A minority of patients with advanced sarcoma achieve prolonged progression free survival (PFS) with insulin growth factor type 1 receptor (IGF-1R) monoclonal antibody (Ab) therapy. A biomarker identifying those patients beforehand would be useful to select patients for the development of these agents.

METHODS:

This single centre series includes patients with unresectable or metastatic soft tissue sarcomas (STS), Ewing sarcoma (ES) and osteosarcoma treated with IGF-1R Ab (R1507, IMC-A12, SCH 717454 and CP-751.871) in the Centre Léon Bérard. Tumour samples were analysed by immunohistochemistry for expression of IGF-1R, insulin-like growth factor binding protein type 3 (IGFBP-3), Ki67, epidermal growth factor receptor (HER1) and human epidermal growth factor receptor 2 (HER2). Predictive factors for PFS and overall survival (OS) were investigated.

RESULTS:

All tumour samples had a positive IGF-1R immunostaining on 60% to 100% of tumour cells. IGFBP-3 immunostaining was observed in 12 (75%) samples with 5% to 100% of positive cells. IGF-1R immunostaining was nuclear (n=9, 56%), cytoplasmic (n=4, 25%), or nuclear +cytoplasmic (n=3, 19%). Neither IGFBP-3 expression, nor Ki67 was correlated to PFS. HER2 and HER1 staining were positive in 0 and 2 samples respectively (both primary resistant to IGF-1R Ab therapy). Exclusive intra-nuclear immunoreactivity for IGF-1R was significantly associated with a better PFS (p=0.01) and OS (p=0.007).

CONCLUSION:

Exclusive nuclear localisation of IGF-1R is an easily testable biomarker associated with a better PFS and OS for patients treated with IGF-1R Ab therapy. Nuclear localisation of IGF-1R in tumour cells might be a hallmark of pathway activation.

• Authors: Irène Asmane, Emmanuel Watkin, Laurent Alberti, Adeline Duc, Perrine Marec-Berard, Isabelle Ray-Coquard, Philippe Cassier, Anne-Valérie Decouvelaere, Dominique Ranchère, Jean-Emmanuel Kurtz, Jean-Pierre Bergerat, Jean-Yves Blay
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 48 Issue 16 Pg. 3027-35 (Nov 2012) ISSN: 1879-0852 [Electronic] England
• PMID: 22682017 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Biomarkers, Tumor
• IGFBP3 protein, human
• Insulin-Like Growth Factor Binding Protein 3
• Ki-67 Antigen
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, IGF Type 1

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (antagonists & inhibitors, immunology, metabolism)
• Biopsy
• Bone Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Child
• Disease-Free Survival
• ErbB Receptors (metabolism)
• Female
• France
• Humans
• Immunohistochemistry
• Insulin-Like Growth Factor Binding Protein 3 (metabolism)
• Kaplan-Meier Estimate
• Ki-67 Antigen (metabolism)
• Male
• Middle Aged
• Osteosarcoma (drug therapy, metabolism)
• Patient Selection
• Predictive Value of Tests
• Receptor, ErbB-2 (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, immunology, metabolism)
• Sarcoma (drug therapy, immunology, metabolism, mortality)
• Sarcoma, Ewing (drug therapy, metabolism)
• Time Factors
• Treatment Outcome
• Young Adult