Abstract P4-15-20: Insulin-like growth factor receptor-1 (IGF-1R) expression is highly correlated with HER2 amplification on circulating epithelial tumor cells (CETCs) in breast cancer - this may be the reason for resistance to trastuzumab
Authors: Zimon Dorothea , Pizon Monika , Pachmann Ulrich , Pachmann Katharina 
Published: May 2015

Abstract
Background: HER2 status has been the most extensively studied biomarker in circulating epithelial tumor cells of breast cancer patients. HER2 status can change during recurrence of disease and HER2 overexpression is a mandatory requirement to administer anti-HER2-directed drugs. Nevertheless, 70% of patients with HER2-positive breast cancers develop intrinsic or secondary resistance to trastuzumab. This resistance has been associated with the activation of an alternative signalling pathway such as the insulin-like growth factor (IGF) pathway. Therefore we investigated the expression of IGF-IR on the CETCs in addition to HER2 amplification in breast cancer patients to identify patients who might benefit from a combined targeted therapy against HER2 and IGF-IR.
Methods: CETCs were determined from blood of 30 breast cancer patients. The number of vital CETCs and the expression of IGF-IR were investigated using the maintrac® approach. Fluorescence in situ hybridisation was used for analysis of HER2 amplification in CETCs.
Results: CETCs could be detected in all breast cancer patients. The number of CETCs ranged from 4 to 163 in 100 µl of cell suspension. IGF-IR expression on the surface of CETCs was detected in all patients. Setting a cut-off 30% positive cells as HER2 positive in 75% of patients HER2 positive CETCs were observed irrespective of the status in the primary tumor. In contrast, only 6% of patients changed their HER2 status from positive tissue to negative CETCs. A statistically high correlation was found between the percentage of IGF-IR positive and HER2 positive CETCs. A statistically significant association was found between IGF-IR expression or HER2 amplification and ER/PR receptor status. The higher frequency of HER2 amplified circulating tumor cells might be due to the difference in preparation steps between tissue and blood borne cells and one of the reasons for trastuzumab resistance and for the response of some HER2 negative patients to trastuzumab. Re-evaluation of HER2 status in CETCs could be a valid strategy with potential clinical applications.
Conclusion:
Our results demonstrate a parallel expression of IGF-IR and HER2 amplification in CETCs. IGF-IR may be involved in the development of resistance to trastuzumab and may be an important potential therapeutic target in breast cancers with HER2 positive circulating tumor cells. Combining targeting of IGF-IR and HER2 may be a rational approach to improve response to trastuzumab in the sub-group of CETCs that express both, HER2 and IGF-IR.
Citation Format: Dorothea Zimon, Monika Pizon, Ulrich Pachmann, Katharina Pachmann. Insulin-like growth factor receptor-1 (IGF-1R) expression is highly correlated with HER2 amplification on circulating epithelial tumor cells (CETCs) in breast cancer - this may be the reason for resistance to trastuzumab [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-20.