Research Article: Comparison of the binding of the gastrin-releasing peptide receptor (GRP-R) antagonist 68Ga-RM2 and 18F-FDG in breast cancer samples

Date Published: January 15, 2019

Publisher: Public Library of Science

Author(s): Clément Morgat, Romain Schollhammer, Gaétan Macgrogan, Nicole Barthe, Valérie Vélasco, Delphine Vimont, Anne-Laure Cazeau, Philippe Fernandez, Elif Hindié, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0210905

Abstract

The Gastrin-Releasing Peptide Receptor (GRPR) is over-expressed in estrogen receptor (ER) positive breast tumors and related metastatic lymph nodes offering the opportunity of imaging and therapy of luminal tumors. 68Ga-RM2 binding and 18F-FDG binding in tumoral zones were measured and compared using tissue micro-imaging with a beta imager on 14 breast cancer samples (10 primaries and 4 associated metastatic lymph nodes). Results were then assessed against ER expression, progesterone receptor (PR) expression, HER2 over-expression or not and Ki-67 expression. GRPR immunohistochemistry (IHC) was also performed on all samples. We also retrospectively compared 68Ga-RM2 and 18F-FDG bindings to 18F-FDG SUVmax on the pre-therapeutic PET/CT examination, if available. 68Ga-RM2 binding was significantly higher in tumors expressing GRPR on IHC than in GRPR-negative tumors (P = 0.022). In ER+ tumors, binding of 68Ga-RM2 was significantly higher than 18F-FDG (P = 0.015). In tumors with low Ki-67, 68Ga-RM2 binding was also significantly increased compared to 18F-FDG (P = 0.029). Overall, the binding of 68Ga-RM2 and 18F-FDG displayed an opposite pattern in tumor samples and 68Ga-RM2 binding was significantly higher in tumors that had low 18F-FDG binding (P = 0.021). This inverse correlation was also documented in the few patients in whom a 18F-FDG PET/CT examination before surgery was available. Findings from this in vitro study suggest that GRPR targeting can be an alternative to 18F-FDG imaging in ER+ breast tumors. Moreover, because GRPR antagonists can also be labeled with lutetium-177 this opens new avenues for targeted radionuclide therapy in the subset of patients with progressive metastatic disease following conventional treatments.

Partial Text

The Gastrin-Releasing Peptide Receptor (GRPR, also named BB2) is a G-protein coupled receptor of the bombesin family. Its over-expression on the membrane of tumor cells offers the opportunity of a selective targeting, using suitable radiolabelled bioconjugates, for positron emission tomography (PET) imaging and targeted radionuclide therapy (TRT). Tumors that can be targeted with GRPR-based radiotracers are notably, prostate cancer, breast cancer, lung cancer and colorectal cancer among others [1]. We have recently studied, using immunohistochemistry, the expression of GRPR ina large series of primary breast cancers and found that GRPR was overexpressed in 83.2% of ER-positive tumors but only in 12% of ER-negative tumors (p < 0.00001) [2]. When examined in molecular subtypes, GRPR is over-expressed in 86.2% of luminal-A and 82.8% of luminal-B HER2 negative tumors while triple negative breast cancers and HER2-enriched phenotypes exhibit GRPR over-expression in only 7.8% and 21.3% of cases. Importantly, lymph nodes metastases of GRPR-positive tumors also showed GRPR overexpression [2]. The association between GRPR and ER has also been documented at mRNA level by Dalm and colleagues [3]. Recently, GRP-R antagonists radiolabelled for PET imaging, demonstrated promising results in breast cancer patients. For example, in a small pilot study that used 68Ga-SB3, metastases were successfully visualized in 4 out of 6 patients [4]. In another study, 68Ga-RM2 could image with high contrast 13/18 primary breast tumors and detected metastatic lesions [5]. In a more recent study conducted in 34 women with suspected breast cancer, a novel GRPR antagonist, 68Ga-NOTA-RM26, was able to delineate primary breast tumors in 29/34 patients and lymph nodes metastases in 15/18 patients with node-positive disease [6]. Comparison of breast cancer imaging using GRP-R based radioantagonists and 18F-FDG is now needed to elucidate the place of GRP-R in the complex landscape of breast cancer imaging. This in vitro study aimed to assess the binding of 18F-FDG and that of the GRPR antagonist 68Ga-RM2 on representative breast cancer samples. The correlation between GRP-R overexpression in breast cancer and estrogen receptor positivity at protein level or mRNA level has been recently highlighted [2,3]. Moreover, it has been documented that when the breast primary is GRPR-positive, lymph node metastases also show GRPR overexpression [2,3]. Several clinical pilot studies have illustrated, in vivo, the potential of GRP-R for breast cancer imaging using radiolabelled GRP-R antagonists such as 68Ga-SB3, 68Ga-RM2 or 68Ga-NOTA-RM26 [4,5,6]. In some of these studies it was shown that ER-positive tumors can be visualized with high contrast [5,6]. 18F-FDG PET/CT is also a valuable tool for staging of invasive breast cancer [10]. Highly 18F-FDG-avid tumors are generally Elston and Ellis grade 3, have a high proliferation index and negative hormone receptor status, while somewhat lower uptake can be encountered in low grade ER-positive tumors and in lobular carcinoma [10]. Indeed, imaging ER-positive breast tumors, especially the luminal-A phenotype, might be challenging using 18F-FDG PET/CT in some patients [11]. Therefore, how GRP-R imaging would perform compared to 18F-FDG in ER-positive breast cancer deserves investigation. We aimed to compare on breast cancer samples the binding of a radiolabelled GRP-R antagonist, 68Ga-RM2, to that of 18F-FDG in order to better understand the potential of GRP-R imaging as a first step before a clinical study comparing the two tracers was launched.   Source: http://doi.org/10.1371/journal.pone.0210905

 

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