Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET

I F Antunes; G A P Hospers; J W A Sijbesma; A S Boerema; A van Waarde; A W J M Glaudemans; R A J O Dierckx; E G E de Vries; E F J de Vries

doi:10.1007/s11307-020-01496-7

Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET

Mol Imaging Biol. 2020 Oct;22(5):1218-1225. doi: 10.1007/s11307-020-01496-7.

Authors

I F Antunes¹, G A P Hospers², J W A Sijbesma³, A S Boerema³, A van Waarde³, A W J M Glaudemans³, R A J O Dierckx³, E G E de Vries², E F J de Vries³

Affiliations

¹ Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. i.farinha.antunes@umcg.nl.
² Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
³ Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Abstract

Purpose: Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo.

Procedures: Male athymic nude mice were subcutaneously (sc) inoculated with 10⁶ SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[¹⁸F]-fluoro-17β-estradiol ([¹⁸F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry.

Results: All treatments led to smaller tumors than vehicle-treated tumors. Higher [¹⁸F]FES maximum standardize tumor uptake (SUV_max) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses.

Conclusion: FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

Keywords: Crosstalk; Estrogen receptor; Human epidermal growth factor receptor; Imaging; Positron emission tomography; [18F]FES.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Weight
Cell Line, Tumor
Cell Proliferation
Humans
Mice, Nude
Positron-Emission Tomography*
Receptor Cross-Talk*
Receptor, ErbB-2 / metabolism*
Receptors, Estrogen / metabolism*
Tomography, X-Ray Computed
Tumor Burden
Xenograft Model Antitumor Assays

Substances

Receptors, Estrogen
ERBB2 protein, human
Receptor, ErbB-2