**1. Introduction**

Breast cancer (BC) is the most frequently diagnosed malignancy among women worldwide [1]. In the Netherlands, 16,000 women are newly diagnosed with BC annually, most of whom have stage I (40.4%) or stage II (32.6%) disease, whereas 9.6% patients have stage III and 4.6% stage IV [2]. For stage IIB/III (advanced T-stage disease often with nodal involvement) or locoregional recurrent disease, curative treatment generally consists of surgery, radiotherapy and (neoadjuvant or adjuvant) systemic therapy (i.e., chemo-, endocrine and targeted therapy) [3]. In the case of metastatic disease without

**Citation:** Iqbal, R.; Mammatas, L.H.; Aras, T.; Vogel, W.V.; van de Brug, T.; Oprea-Lager, D.E.; Verheul, H.M.W.; Hoekstra, O.S.; Boellaard, R.; Menke-van der Houven van Oordt, C.W. Diagnostic Performance of [18F]FDG PET in Staging Grade 1–2, Estrogen Receptor Positive Breast Cancer. *Diagnostics* **2021**, *11*, 1954. https://doi.org/10.3390/ diagnostics11111954

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Academic Editors: Lioe-Fee de Geus-Oei and F.H.P. van Velden

Received: 9 September 2021 Accepted: 16 October 2021 Published: 21 October 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

curative options, burdensome locoregional as well as systemic therapy should be avoided in order to maintain quality of life. On the other hand, identification of oligometastatic disease may improve the chance of (prolonged disease free) survival by including these sites in the local therapy plan [4]. Therefore, accurate pre-operative staging is essential to identify locoregionally affected lymph nodes and (distant) metastases, as it will affect treatment choices.

The initial work-up for BC includes physical examination, mammography, ultrasound and magnetic resonance imaging (MRI) of the breast and axilla, to assess the extent of locoregional disease [3]. Standard staging procedures detect (distant) metastases in approximately 7% and 8–21% of clinical stage IIB and III patients, respectively, and in 33% of those presenting with locoregional recurrences [5–7]. Furthermore, 10–25% will develop recurrences within 2 years, suggesting, at least in part, missed (occult) metastases at presentation [8]. According to (inter)national guidelines, staging is often performed with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography accompanied by a low-dose CT scan for attenuation correction (FDG PET) [3,9,10]. In addition to this, a diagnostic computed tomography (CT) scan of the thorax and abdomen is often performed [3,9]. For primary staging of clinical stage II/III BC, the sensitivity and specificity of FDG PET to identify lymph node involvement and distant metastases is 63–100% and 98–100%, respectively [5,11], and in recurrent disease, it is 90% and 81%, respectively [12].

However, FDG uptake of BC can be quite variable, due to various underlying biological features [11–18]. FDG uptake is often lower in lobular BC (vs. ductal BC) [15,16,18,19], in low-intermediate grade (vs. high grade) [12–18] tumors and in ER-positive tumors, compared to triple negative tumors (ER-/PR-/HER2-) [11,13,15–17,20–23]. Alternatively, triple negative BC (ER-/PR-/HER2-), a more aggressive phenotype, shows higher FDG uptake than ER+/PR+ and HER2- BC [20]. Thus, these biological factors can affect the FDG avidity of lesions potentially limiting the accuracy of FDG PET/CT for the staging of grade 1–2 ER+ BC [16].

Although there are data that FDG uptake (usually expressed as standard uptake value (SUV)) is lower in low grade ER+ BC than in other types of BC and that staging might be suboptimal [24,25], no study has specifically investigated the extent to which this affects the staging of BC. Therefore, the primary aim of this study was to retrospectively investigate the diagnostic performance of FDG PET in staging patients with grade 1–2 ER + BC. The secondary aims were to study whether the level of tracer uptake in the primary tumor was associated with the accuracy of staging, and to investigate which histopathological features might predict the accuracy of FDG PET.

#### **2. Materials and Methods**
