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. 2018 Nov-Dec;15(6):461-471.
doi: 10.21873/cgp.20105.

Evaluation of the Insulin-like Growth Factor Receptor Pathway in Patients with Advanced Breast Cancer Treated with Trastuzumab

Christos Christodoulou  1 , Georgios Oikonomopoulos  2 , Georgia Angeliki Koliou  3 , Ioannis Kostopoulos  4 , Vassiliki Kotoula  4   5 , Mattheos Bobos  5 , George Pentheroudakis  6 , George Lazaridis  7 , Maria Skondra  8 , Sofia Chrisafi  5 , Angelos Koutras  9 , Dimitrios Bafaloukos  10 , Evangelia Razis  11 , Kyriaki Papadopoulou  5 , Pavlos Papakostas  12 , Haralambos P Kalofonos  9 , Dimitrios Pectasides  8 , Pantelis Skarlos  13 , Konstantine T Kalogeras  5   14 , George Fountzilas  5   15
Affiliations

Evaluation of the Insulin-like Growth Factor Receptor Pathway in Patients with Advanced Breast Cancer Treated with Trastuzumab

Christos Christodoulou et al. Cancer Genomics Proteomics. 2018 Nov-Dec.

Abstract

Background: Trastuzumab is a monoclonal antibody against HER2-positive breast cancer. Despite improving the natural history of the disease, there is a number of patients who are resistant to it, whereas all patients will eventually develop resistance and disease will progress. Inconsistent preclinical data show that the IGF-R pathway may contribute to either de novo or acquired resistance to trastuzumab.

Materials and methods: In total, 227 trastuzumab-treated metastatic breast cancer patients were evaluated for IGF-1, IGF-1R, GLP-1R, Akt1, Akt2 Akt3 mRNA expression, and IGF-1Rα, IGF-1Rβ, IGF-2R protein expression.

Results: Only 139 patients were truly HER2-positive by central assessment. Among HER2-positive patients, high Akt2 and GLP-1R mRNA expression showed a trend towards higher and lower risk of progression, respectively (HR=1.83, 95%CI=0.90-3.72, p=0.094 and HR=0.62, 95%CI=0.36-1.06, p=0.079), while high Akt1 and GLP-1R mRNA expression presented a trend towards unfavorable survival (HR=1.67, 95%CI=0.93-2.99, p=0.086 and HR=1.67, 95%CI=0.94-2.96, p=0.080). Among HER2-negative patients, high GLP-1R mRNA expression and negative stromal IGF-1Rβ protein expression showed a trend towards worse survival (HR=2.31, 95%CI=0.87-6.13, p=0.094 and HR=2.03, 95%CI=0.94-4.35, p=0.071, respectively). In the multivariate analyses, HER2-positive patients with high Akt1 and GLP-1R mRNA expression had a worse survival (HR=1.86, 95%CI=1.01-3.43, p=0.045 and HR=1.83, 95%CI=0.99-3.41, p=0.055, respectively).

Conclusion: This study revealed a crosstalk between the IGF-R pathway and HER2. There was evidence that high Akt1 and GLP-1R mRNA expression might affect survival among HER2-positive metastatic breast cancer patients treated with trastuzumab.

Keywords: HER2-negative breast cancer; HER2-positive breast cancer; IGF-R; advanced breast cancer; trastuzumab.

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Figures

Figure 1
Figure 1. REMARK diagram.
Figure 2
Figure 2. Kaplan–Meier curves for survival according to Akt1 mRNA expression (A) and GLP-1R mRNA expression (B) (using the upper quartile as a cut-off) in HER2-positive patients. Comparisons were estimated using the log-rank test.
See this image and copyright information in PMC

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