Abstract
IntroductionWe sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes.Patients and MethodsArchival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers.ResultsAfter a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035).ConclusionAberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.
Highlights
We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes
Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer
Precursor polypeptide cleavage leads to the presence of two IGF1R isoforms: Isoform alpha (IGF1R-alpha), which is preferentially expressed in many cancers and is able to bind to insulin, IGF1 and IGF2, and isoform-beta (IGF1R-beta), which binds exclusively to insulin [10]
Summary
We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes. Classification of early breast cancer according to these criteria leads to five distinct immunophenotypical subtypes, namely the luminal A, luminal B, luminal-HER2, HER2-enriched and triplenegative tumor types, each one comprising a different constellation of markers [3]. This classification was validated by large-scale genome analysis [4,5] that demonstrated the differential gene expression signature for each immunophenotypical subtype. The insulin and insulin-like growth factor receptor (IGFR) mediated molecular pathways have recently emerged as important effectors of neoplastic transformation and proliferation in various malignancies [6,7,8], including breast cancer [9]. IGF2R, on the other hand, binds only to IGF2, is structurally distinct in the sense that it lacks an intracellular tyrosine kinase domain, and is deprived from the ability to transduce mitogenic signals, acting mainly as a ‘‘buffer’ for IGF2 bioactivity [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
