Introduction
According to GLOBOCAN 2020, female breast cancer (BC) was the leading cause of cancer incidence worldwide (2.3 million new cases, corresponding to 11.7% of all cancers) and it was the fifth leading cause of cancer mortality (685,000 deaths) [
5].
The histology of the majority of diagnosed BC (75–80%) is no special type (NST) that corresponds to invasive ductal carcinoma (IDC) in the previous nomenclature; the second most common histology (10–15%) is invasive lobular carcinoma (ILC). Up to 5% of BC is considered “special types” due to distinctive characteristics as well as particular cellular and molecular behaviours. These “special types” include medullary, apocrine, neuroendocrine, mucinous, tubular, and metaplastic carcinomas [
6‐
11]. BC is a heterogeneous disease with different biological subtypes depending on the expression of hormone receptors (HR), including oestrogen receptors (ER) and/or progesterone receptors (PR), and the levels of the human epidermal growth factor receptor 2 (HER2). There are four main subtypes of BC, although different classifications exist with small differences between them: Luminal A-like (HR + /HER2 − and low-grade/low proliferation), Luminal B-like (HR + /HER2 − and high-grade/high proliferation) – luminal-like correspond to 65% of cases, HER2 + (HR + or − /HER2 +) in 15–20%, and triple negative (HR − /HER2 −) in 10–15%.
BC usually disseminates loco-regionally to the ipsilateral axillary lymph nodes but can also spread loco-regionally to ipsilateral internal mammary or supraclavicular lymph nodes (up to stage N3c) [
12,
13]. However, dissemination to contralateral axillary, internal mammary, or supraclavicular lymph nodes or to ipsilateral or contralateral cervical lymph nodes is regarded as distant metastasis (or stage M1). BC can potentially spread to any organ, but the most common sites are the skeleton, liver, lung, and brain. Different from NST, metastatic ILC more commonly features sclerotic bone metastases (sometimes of miliary type without FDG uptake) and metastases to the gastrointestinal tract and serosa. Factors associated with the presence of distant metastases at an earlier stage are younger age at diagnosis and triple-negative tumours [
14,
15]. Each subtype has different biological behaviour in terms of survival, recurrence, and typical patterns of metastatic spread [
16‐
19]. For example, bone metastases are more common in patients with HR + BC, whereas visceral metastases occur more often in HR- tumours [
20]. In this regard, triple-negative breast cancers (TNBC) present with visceral metastases more often, predominantly intrapulmonary [
17,
21,
22]. The HER2-enriched subtypes usually metastasize to the lung, liver, and brain and less often to the skeleton [
23].
The 8th edition of the American Joint Committee on Cancer (AJCC) includes two staging systems: (1) the anatomic stage, which includes the characteristics of the primary tumour (T), nodal status (N), and distant metastasis (M), and is then further subdivided into clinical and pathologic anatomic stage, and (2) the prognostic stage, adding tumour grade, HR status, HER2 expression, and multigene panel testing results to the anatomic stage [
12].
Currently, there is extensive evidence that 2-[
18F]FDG PET/CT can be useful in BC management, including initial staging, assessing neoadjuvant systemic treatment response, assessing treatment response in the metastatic setting, searching for loco-regional or metastatic recurrence, and re-staging after therapy, as well as radiation therapy (RT) planning. The 2-[
18F]FDG avidity of BC is related to the histologic type, receptor status (ER, PR, and HER2), tumour grade, proliferation index (Ki-67 index), and tumour size. It has been demonstrated that, in general, (1) NST histology has higher 2-[
18F]FDG avidity than ILC, (2) TNBC has higher 2-[
18F]FDG avidity than ER + tumours, and (3) grade 3 cancers have higher 2-[
18F]FDG avidity than lower-grade malignancies [
24‐
27]. 2-[
18F]FDG uptake is also related to microvasculature density for delivering nutrients (and 2-[
18F]FDG), glucose transporter 1 (GLUT1) for transportation of the tracer into the cell, hexokinase for tracer entering into glycolysis, number of viable neoplastic cells per volume, number of lymphocytes, and hypoxia-inducible factor 1-alpha (HIF-1a) upregulation of GLUT1 [
28]. Consequently, high 2-[
18F]FDG uptake correlates with tumour aggressiveness and is associated with a worse prognosis [
3,
29‐
31]. A retrospective study reported that 2-[
18F]FDG PET/CT was more likely to reveal unsuspected distant metastases in patients with stage III NST (22%) compared to patients with stage III ILC (11%) [
32].
Considering there are limited data about 2-[
18F]FDG specifically in the ILC subtype, the recommendations written in this document are applicable to NST. In the “
Other developments and future applications” section, radiopharmaceuticals other than 2-[
18F]FDG are referred to and those may be more useful to study patients with ILC. We recognize the need to have guideline/recommendations about the lobular subtype, and this may be a future project.
Several studies have documented 2-[
18F]FDG PET/CT’s utility compared to other imaging modalities including bone scan and contrast-enhanced CT (ceCT). However, the superiority of 2-[
18F]FDG PET/CT is still unclear in comparison with whole-body magnetic resonance imaging (wbMRI) [
33‐
36].
In Table
2, we observe that baseline 2-[
18F]FDG PET/CT enabled overall upstaging, when compared with conventional imaging modalities, in more than 19% of patients from IIB onwards: stage IIB (19%), IIIA (34%), IIIB (41%), and IIIC (35%). The percentage of stage modification due to 2-[
18F]FDG PET findings is weaker in stage IIA patients but not negligible (13% in Table
2). Three studies from Table
2 also evaluated the percentage of upstaging based on the identification of distant metastasis only (meaning the exclusion of regional lymph node metastasis) and revealed staging modification in 10% of patients initially staged IIB, 20% in stage IIIA, 25% in stage IIIB, and 32% in stage IIIC [
37‐
39].
These same authors showed that 2-[
18F]FDG PET/CT can provide valuable information for nodal staging in around a quarter of patients, leading to upstaging in 17–24% of patients (mainly due to the identification of N3 disease) [
37‐
39]. In one study, modifications included downstaging in 16% of patients [
38].
A prospective and randomized clinical trial published in 2023 analyzed 369 patients with NST BC stage IIB (25%) or III (75%) staged with 2-[
18F]FDG PET/CT or conventional imaging (bone scan, CT of the chest/abdomen and pelvis) [
40]. 2-[
18F]FDG PET/CT identified more distant metastases than conventional modalities, resulting in upstaging to stage IV for 12% more patients (23% vs 11%). Consequently, this led to changes in therapy decision and reduction in the number of patients initially considered for combined modality therapy (chemotherapy, surgical resection, and radiotherapy) aimed at curative intent [
40].
As referred to above, despite the commonly reported upstaging after 2-[
18F]FDG PET/CT due to the identification of N3 or distant metastases, Cochet et al. [
38] also evaluated the percentage of downstaging. This prospective study compared staging with conventional imaging and 2-[
18F]FDG PET/CT in 142 patients. They observed that 21% of patients were upstaged after 2-[
18F]FDG PET/CT (including 8% whose stage changed from stage II/III to stage IV—detailed in Table
2) and 16% were downstaged (including 3% that were initially classified as stage IV, but changed to stage II/III), with high or medium impact on clinical management in 13% of patients (mainly because the intent to treat was modified from curative to palliative or vice-versa) [
38].
A systematic review and meta-analysis from 2021 analyzed the impact of 2-[
18F]FDG PET (3 studies), PET/CT (25 studies), and PET/MRI (1 study) and found a pooled 25% change in staging that resulted in an 18% change in management [
41]. Literature shows a better diagnostic accuracy of 2-[
18F]FDG PET/CT to detect distant metastases of NST BC compared to the combination of conventional imaging, due to its higher sensitivity (97–99% vs 56–75%) and specificity (95–99% vs 88–99%), as summarized in Table
3.
Table 2
Percentage of upstaging after 2-[
18F]FDG PET/CT compared to conventional modalities for each initial TNM stage according to the 7th and 8th editions of the AJCC Cancer Staging Manual (adapted from [
34])
Stage | TNM (based on conventional imaging) | Groheux et al. [ 37] Prospective, n = 254, 86% NST | Cochet et al. [ 38] Prospective, n = 142, 90% NST | Riedl et al. [ 14] Retrospective, n = 134, 92% NST | Ulaner et al. [ 42] Retrospective, n = 232 TNBC, 94% NST | Ulaner et al. [ 43] Retrospective, n = 238, 86% NST | Lebon et al. [ 44] Retrospective, n = 107, 85% NST | Ko et al. [ 39] Retrospective, n = 195, 88% NST | Overall metastasis range (mean) | Distant metastasis range (mean) |
I | T1N0M0 | NA | NA | 5 | 0 | NA | [8] | NA | 0–8 (4) | NA |
IIA | T0N1M0 T1N1M0 T2N0M0 | 4.5 [2.3] | 36 [9] | 5 | 5 | 4 | [11] | 24 [0] | 4–36 (13) | 2–9 (6) |
IIB | T2N1M0 T3N0M0 | 16.1 [10.7] | 18 [7] | 17 | 15 | 14 | [15] | 39 [13] | 14–39 (19) | 7–13 (10) |
IIIA | T1N2M0 T2N2M0 T3N1M0 T3N2M0 | 31.7 [17.5] | 33 [0] | 31 | 17 | 24 | [44] | 54 [22] | 17–54 (34) | 18–22 (20) |
IIIB | T4N0M0 T4N1M0 T4N2M0 | 51.4 [36.5] | 32 [21] | 50 | 57 | 27 [17] | 24–57 (41) | 17–37 (25) |
IIIC | AnyT N3M0 | 47.1 [47.1] | 13 [13] | 50 | 33 | 37 [37] | 13–50 (35) | 13–47 (32) |
Table 3
Diagnostic accuracy of 2-[18F]FDG PET/CT and conventional imaging to detect distant metastases of BC
Sensitivity (%) | 97* 99” 97.5ª | 56* 57” 75.4ª |
Specificity (%) | 95* 95” 98.8ª | 91* 88” 98.7ª |
Positive predictive value (%) | 95.4ª | 93.4ª |
Positive likelihood ratios | 21” | 4.8” |
Negative predictive value (%) | 99.4ª | 94.3ª |
Negative likelihood ratios | 0.02” | 0.49” |
Overall, several studies have demonstrated a good diagnostic accuracy of 2-[
18F]FDG PET/CT to detect distant metastases, compared to conventional imaging, in particular due to its high sensitivity (Table
2 and
3).
Additionally, 2-[
18F]FDG PET/CT seems to play a role in the context of personalized medicine, emerging as a useful imaging modality for response assessment, allowing for early identification of non-responding tumours, providing information regarding adverse therapeutic effects, and defining the right moment to implement changes in therapeutic approach or shift to a subsequent line of treatment with benefits of disease control and cost-effectiveness [
48,
49].
2-[18F]FDG PET/CT preparation and acquisition
Patient preparation should follow the “FDG PET/CT EANM procedural guidelines for tumour imaging version 2.0” and the American “Society of Nuclear Medicine and Molecular Imaging (SNMMI) procedure guideline for tumor imaging with
18F-FDG PET/CT 1.0” [
50,
51]. Several studies have shown that the metabolic flare reaction occurs between 7 and 10 days after the start of endocrine therapy, and this effect has been observed not only with tamoxifen, but also with fulvestrant and anti-aromatases [
52,
53]. Therefore, it is recommended to perform 2-[
18F]FDG PET/CT after this time interval [
53,
54]. Based on routine clinical practice, our expert consensus panel suggests performing 2-[
18F]FDG PET/CT at least 10 days (15 days if possible) after the last dose of systemic therapy (chemotherapy or endocrine therapy) to avoid the effects of the flare phenomenon or stunning reaction. This is an expert opinion-based recommendation, and not based on scientific evidence yet. Interruption of ongoing targeted therapy for therapeutic evaluation is not recommended [
55]. Because of the inflammatory effect, the recommendation is to wait at least 3 months after the end of radiotherapy to search for a recurrence in the radiotherapy field.
It is also important to report whether the patient is/was taking corticosteroids when scanned; has received growth factors; was treated with radiation therapy with specification of the treated volumes or recently underwent invasive procedures, including biopsy or surgery, because it will influence 2-[
18F]FDG uptake; and has implications in image interpretation [
50].
It is recommended that patients fast for at least 4 h before radiopharmaceutical administration and be properly hydrated, serum glucose level should be < 200 mg/dl, and patients should rest in a quiet and warm environment during the 2-[
18F]FDG-uptake time that should last 60 min (± 5 min) before image acquisition. Concurrent ceCT imaging can be considered to improve lesion detection on CT, mainly when evaluating response to treatment in patient with metastatic disease. Additionally, it may enable easier comparative imaging with follow-up CT scans. If intravenous contrast administration is performed, kidney function and history of contrast allergy should be verified before the injection and, in such cases, measures (i.e. reinforced hydration and specific medications) should be taken according to radiological protocols [
56] as well as local guidelines and regulations.
The standard 2-[18F]FDG PET/CT starts after bladder voiding. The patient is usually in the supine position with the arms above the head, and the acquisition includes the mid-thighs to the skull.
When RT planning is considered, and to better evaluate breasts, a flat table-top and an additional scan in the prone hanging breast position may be used in the imaging acquisition [
50,
57]. It is recommended to use support devices for the arms and knees to improve patient comfort and reproducibility. It is important to remember that positioning may be modified and adapted, and analgesic medication may be offered, when necessary, to improve patient comfort.
Ideally, patients should undergo a pre-treatment PET scan (baseline study) and a scan after the end of treatment (final study), performed on the same PET scanner, to evaluate response to therapy; interim PET scan may also be helpful to direct response adapted treatment protocols [
58] and should be performed with the same PET scanner used in the baseline study.
False positive findings
The most common cause of false positive 2-[
18F]FDG-PET findings in the breast and surrounding tissues are due to (1) benign lesions that include a wide range of diagnoses such as fibroadenoma, intraductal papilloma, as well as reactive, hyperplastic, and metaplastic processes, such as fibrocystic changes and apocrine metaplasia; (2) infection and inflammation (mastitis, fat necrosis, fungal infection, granulomatous processes, such as tuberculosis and sarcoidosis, ruptured breast implant or silicone-related reaction); (3) post-surgery (seroma, muscle uptake); and (4) physiologic (e.g. brown fat activation, lactational changes result in diffuse increased uptake in the breasts) [
59,
60].
In addition, changes in metabolic activity at non-cancer sites related to cancer treatments and other medical conditions and interventions may cause imaging misinterpretation at extramammary sites. Some examples include the following: (1) recent vaccinations, particularly to COVID-19, which can result in increased uptake in axillary, subpectoral, and neck nodes; (2) bone marrow repopulation in relation to systemic therapy or granulocyte colony-stimulating factor; (3) inflammation and/or immune-related adverse events such as mucositis, colitis, pneumonitis, thyroiditis, pancreatitis, adrenalitis, and hypophysitis; (4) systemic inflammatory diseases, in particular granulomatosis, sarcoidosis, and sarcoid-like reactions; (5) osteonecrosis of the jaw; (6) fracture and post-procedural inflammation.
False negative findings
Common causes of false negative 2-[
18F]FDG-PET findings are as follows [
26,
59,
60]: (1) small lesions measuring ≤ 10 mm (or 4–5 mm in digital PET scanners [
61]), (2) low-grade tumours, (3) certain histologic subtypes (e.g. lobular, tubular, carcinoma in situ, and neuroendocrine differentiation), (4) low tumour cell density (in necrotic tissue, fibrotic scar, cystic lesions, and mucinous component), (5) artefacts (for example lesions located close to prosthetic devices, or adjacent to areas of high 2-[
18F]FDG accumulation, such as activated brown fat or bone marrow, brain, myocardium, bladder), (6) suboptimal technique (e.g. elevated blood glucose or 2-[
18F]FDG injection without adequate fasting), (7) PET/CT procedure (e.g. patient movement or breathing artefacts), and (8) recent or ongoing therapy.
Incidental breast findings with 2-[18F]FDG uptake and additional procedures
When a 2-[
18F]FDG-avid breast lesion is incidentally detected in a study performed for reasons other than BC, further characterization with diagnostic mammography and/or breast US should be performed because these lesions are malignant in 30–40% of cases [
62,
63]. Several aetiologies have been described, including unsuspected BC, lymphoma, and metastases [
59,
64‐
67].
In the context of breast metastases, the most common aetiologies of non-mammary cancers include haematopoietic malignancies (50%), epithelial cancers (23%), such as lung and gastrointestinal adenocarcinomas and squamous cell carcinomas, and melanomas (21%) [
68].
A systematic review and meta-analysis from 2019 [
63] concluded that the pooled prevalence of focal incidental breast uptake on 2-[
18F]FDG PET/CT in women was 0.61%, and in this group of patients, the pooled prevalence of malignancy was 38.7%, with invasive ductal carcinoma being the most commonly detected cancer. In case of focal incidental breast uptake without a known correlate, irrespective of CT appearance, the patient should undergo further evaluation with physical examination, breast imaging, and possible biopsy.
Summary box nº 1 • 2-[18F]FDG PET/CT should be reported according to PERCIST or to the EORTC PET response criteria [ 69‐ 71] (III-92%/C-85%)• In patients on immunotherapy, 2-[18F]FDG PET/CT should be reported according to the respective EANM guidelines [ 72] (IV-100%/D-92%)• Quantitative features are imaging biomarkers and valuable tools for prognostication (I-92%/A-92%) |
Metabolic therapy response assessment should be performed according to either the European Organisation for Research and Treatment in Cancer (EORTC) PET response criteria or PET Response Criteria in Solid Tumors (PERCIST) [
69‐
71,
73]. For patients with BC undergoing immunotherapy, the recently published EANM/SNMMI/AZZSNM guideline is recommended for response assessment [
72].
The use of quantitative 2-[
18F]FDG PET/CT as an imaging biomarker has proven to be a valuable tool in treatment response assessment and prognostication [
74,
75], with an important predictive role in the prognosis of patients with locally advanced or metastatic BC [
58,
76‐
79]. Such metrics include the standardized uptake values (SUV) using either the body weight (SUVbw) or the lean body mass (SUL) for normalization, metabolically active tumour volume (MATV or MTV), and total lesion glycolysis (TLG), defined as MATV × SUVmean. In this regard, in a meta-analysis by Diao et al., metrics such as the maximum standardized uptake value (SUVmax—maximal voxel intensity in a defined volume of interest) in the primary tumour were related to a higher risk of recurrence or disease progression in this group of patients. Furthermore, SUVmax showed significant prognostic value in patients with NST [
80]. Prospective studies have shown that SUV, MTV, and TLG correlated with response to treatment and prognosis [
81,
82].
Pak et al
. demonstrated in their meta-analysis that volumetric parameters obtained from 2-[
18F]FDG PET/CT were significant prognostic factors for outcome in patients with BC. They concluded that patients with a high MTV and TLG from the primary tumour have a higher risk of adverse events and patients with a high TLG from whole-body tumour burden have a higher risk of death, therefore suggesting that these volumetric parameters should be routinely used when reporting scans [
83].
However, no specific cut-off values for these metrics can be recommended currently, as these values differ widely among the data published [
78]. To overcome this limitation, compliance with harmonizing standards, such as the EANM Research GmbH (EARL) or American College of Radiology (ACR)/Intersocietal Accreditation Commission (IAC) accreditation, aiming at using 2-[
18F]FDG PET/CT as a quantitative imaging biomarker [
84‐
86], is recommended.
Summary of indications for 2-[18F]FDG PET/CT in no special type breast cancer
In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. 2-[18F]FDG PET/CT is possibly useful in patients with clinical stage IIA (T1N1 or T2N0), but there are not enough data to recommend its routine use.
Whenever possible, quantitative features (such as SUV, MTV, and TLG) should be evaluated and included in the report, because there is robust evidence indicating that these are important imaging biomarkers and valuable prognostic parameters.
When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on EARL or ACR/IAC certified PET/CT scanners, and scans should be reported either according to PERCIST, EORTC PET response criteria, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2 + tumours.
2-[18F]FDG PET/CT is also useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse.
The concise summary of the 2-[
18F]FDG PET/CT indications according to the clinical scenario defined in this guideline is presented in Table
5 below. Recommendations with level of evidence/grade of recommendation I/A or II/B are highlighted in bold. The remaining recommendations, particularly the ones scored as III/C need further investigation. In our opinion, it would be particularly useful to have more evidence about the role of 2-[
18F]FDG PET/CT in assessing response to therapy in the metastatic setting and in RT planning in different clinical scenarios. We consider this the first attempt to define and organize 2-[
18F]FDG PET/CT indications for patients with NST BC, but future work is needed to clarify scenarios still lacking robust scientific evidence.
Table 5
Summary of the 2-[18F]FDG PET/CT recommendations according to the clinical scenario
Baseline staging | Stage I | • Not recommended (II/B) |
Stage IIA | • May be useful in clinical stage IIA (T1N1 or T2N0), but there is not enough data (III/C) |
Stage IIB and stages III | • Baseline staging of stage IIB (preferably before surgery) and stage III (including inflammatory BC) (II/B) • 2-[18F]FDG PET/CT can be done instead of, and not in combination with, conventional imaging modalities for staging (II/B) • Baseline treatment planning may improve RT planning (III/C) |
Stage IV | • Can be useful for determining the extent of metastatic disease (outside the brain) and improving treatment planning (III/C) • 2-[18F]FDG PET/CT can be done instead of, and not in addition to separate conventional imaging modalities (II/B) |
Assessment of treatment response | Non-metastatic breast cancer | • May be used to assess early metabolic response, particularly in TNBC and HER2 + (II/B) |
Metastatic breast cancer | • May play a role in monitoring treatment response (III/C) • May be particularly useful to assess bone metastases and enable early response to treatment evaluation (III/C) |
Assessment of recurrence | • Useful to detect the site and extent of recurrence when conventional imaging methods are equivocal (I/A) • 2-[18F]FDG PET/CT can be recommended: o In patients with signs or symptoms suggestive of metastatic disease (I/A) o In patients with rising serum tumour markers (II/B) o To guide the site of biopsy (IV/D) o To improve RT planning (III/C) • Can substitute CT and/or bone scan in the detection of bone metastases (II/B) |
Declarations
Conflict of interest
Gary Cook: research grant from Breast Cancer Now and he was a previous member of their scientific advisory board.
Gary Ulaner: Consultant/Advisory Board/Research Funding – GE Healthcare, Lantheus, ImaginAb, Point Biopharma
Heather Jacene: Blue Earth Diagnostics, honoraria and research support; Consulting, advanced accelerator applications, spectrum dynamics, royalties: Cambridge University Press; all are not related to the work presented in this manuscript.
Philip Poortmans: medical advisor of Sordina IORT Technologies S.p.A., not related to the work presented in this manuscript.
Ritse Mann: research grants from/with Beckton and Dickinson, Siemens, Bayer Healthcare, Screenpoint medical, Koning, and PA Imaging, and is a medical advisor to Screenpoint, Bayer, Guerbet, and BD. All are unrelated to the work in this manuscript.
Fatima Cardoso: Personal financial interest in form of consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, Touchime.
Institutional financial support for clinical trials from: Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, Eisai, Fresenius GmbH, Genentech, Gilead, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Tesaro, Tigris, Wilex, Wyeth.
All the other authors declare no conflict of interest.
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