[¹⁸F]F-FES PET for diagnosis, staging, and endocrine therapy prediction in ER-positive breast cancer: a systematic review and meta-analysis

Abstract

Background

This meta-analysis evaluates the diagnostic and staging accuracy of [¹⁸F]F-FES PET/CT, its ability to detect estrogen receptor (ER) positivity, and its effectiveness in predicting response to endocrine therapy in ER-positive (ER+) breast cancer. A systematic search of PubMed, Embase (OVID), and Web of Science databases was conducted for studies published between 2013 and June 2024. Studies involving ER + breast cancer patients who underwent

[¹⁸F]F-FES PET/CT were included. We analyzed the diagnostic accuracy, ER detection capability, and predictive ability for endocrine therapy response.

Results

Out of 189 studies initially identified, 21 met the inclusion criteria. For diagnosis and staging compared to [¹⁸F]F-FDG PET (10 studies), [¹⁸F]F-FES PET/CT demonstrated a sensitivity of 0.75 (95% CI: 0.62–0.85) and a false positive rate (FPR) of 0.27 (95% CI: 0.09–0.50). For ER detection (7 studies), sensitivity was 0.86 (95% CI: 0.71–0.94) with an FPR of 0.45 (95% CI: 0.19–0.73). For predicting response to endocrine therapy (12 studies), [¹⁸F]F-FES PET/CT showed a sensitivity of 0.79 (95% CI: 0.62–0.89) and an FPR of 0.58 (95% CI: 0.42–0.72).

Conclusions

[¹⁸F]F-FES PET/CT is valuable for diagnosing and staging ER + breast cancer, assessing ER status, and predicting response to endocrine therapy. Its implementation can improve treatment planning and patient outcomes in breast cancer management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13550-025-01205-x.

Introduction

Breast cancer is the most common malignant tumor affecting women worldwide and poses a significant threat to their health and wellbeing [1]. Among breast cancer subtypes, the estrogen receptor-positive (ER+) luminal subtype is the most prevalent, accounting for approximately 70% of all cases [2]. Endocrine therapy is the cornerstone of treatment for ER + breast cancer, often yielding favorable outcomes for patients who respond effectively [3]. Despite these advances, 3–10% of women are diagnosed with breast cancer at an advanced stage with distant metastases. Additionally, 30–40% of early-stage breast cancer patients eventually progress to advanced disease despite receiving standardized treatment, resulting in a five-year survival rate of less than 30% [4]. In recurrent and metastatic breast cancer, ER expression often changes compared to primary tumors, with a concordance rate ranging from 66 to 83%, and displays heterogeneity in its expression profile. Notably, obtaining biopsies from metastatic sites such as bone, lung, and liver in breast cancer patients can be invasive, costly, and fraught with potential complications, rendering pathological assessments challenging in clinical settings [5].

[¹⁸F]F-FDG PET/CT, based on the Warburg effect, has improved the accuracy of detecting distant metastases and recurrences in breast cancer, achieving a sensitivity of 95–100% while reducing false-positive rates by half compared to regular CT [6]. However, its uptake can be influenced by inflammatory or reactive processes, which can obscure the detection of true malignancy [7]. Moreover, while [¹⁸F]F-FDG PET/CT is invaluable for staging, it does not provide information about hormone receptor expression. Therefore, there is a critical need for an imaging technique that not only offers precise tumor staging but also accurately assesses functional ER status and endocrine therapy responsiveness.

The ER-targeting imaging agent 16α-¹⁸F-fluoro-17β-estradiol ([¹⁸F]F-FES) has been approved for clinical use in France and the United States, demonstrating high sensitivity (71–95%) and specificity (98%) in breast cancer. Unlike [¹⁸F]F-FDG, [¹⁸F]F-FES is less affected by inflammation and offers a similar safety profile [8]. Qualitative and quantitative studies have shown that [¹⁸F]F-FES PET/CT is a reliable, non-invasive alternative to biopsies, accurately assessing ER expression across multiple metastatic lesions. This advanced imaging modality aids in evaluating the extent of metastatic disease, guiding personalized treatment plans, predicting therapy efficacy, and overcoming the limitations of conventional assessments in multifocal disease management [9].

This systematic review and meta-analysis aim to comprehensively evaluate the diagnostic and staging accuracy of [¹⁸F]F-FES PET/CT, as well as its ability to assess ER expression and predict endocrine therapy response in ER-positive breast cancer. By analyzing the available evidence, we aim to clarify the potential role of [¹⁸F]F-FES PET/CT in guiding clinical decision-making and optimizing patient outcomes.

Materials and methods

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was approved by the Ethics Committee of Peking Union Medical College Hospital (Approval No. JS-2959). As the study involved no direct participant interaction, informed consent was waived.

Search Strategy

We systematically searched PubMed, Embase (OVID), MEDLINE, and Web of Science for English-language publications from January 2013 to June 2024. The search terms used were: ‘Breast Neoplasm’ OR ‘Breast Cancer’ AND ‘FES’ OR ‘Fluoroestradiol’ AND ’PET-CT.’ Additionally, we reviewed grey literature and reference lists of selected articles to identify further relevant studies.

Study selection

Two reviewers (Ying Xu and Ru Yao) independently screened titles and abstracts. Studies were included if they met the following criteria: (a) clinical trials, cohort, or case-control studies with English-language titles and abstracts; (b) use of [¹⁸F]F-FES PET/CT imaging for diagnosing metastatic breast cancer; (c) [¹⁸F]F-FES PET/CT used to identify ER status and predict endocrine therapy response in ER + breast cancer; (d) availability of raw data for calculation and analysis. Studies were excluded if they: (a) had a high risk of bias, (b) lacked full-text availability, (c) did not provide sufficient data for analysis, (d) reported duplicate data, or (e) were case reports, reviews, comments, letters, in vitro studies, non-human studies, or non-English texts.

Data extraction

Two reviewers (Ying Xu and Zhixin Hao) independently extracted data using a predesigned form. Information collected included author details, publication year, country, study design (clinical trials, prospective or retrospective cohort studies), sample size, patient characteristics (age, histology, staging, hormone receptor status, metastatic status, intervention), technical aspects of PET/CT, and summary statistics (sensitivity, specificity, positive and negative likelihood ratios).

Quality assessment

The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist was used to evaluate study quality [10]. Risk of bias was assessed in areas such as patient selection, index test, reference standard, and study flow/timing. Applicability concerns were evaluated for patient selection, index test, and reference standard. RevMan (version 5.3, The Cochrane Collaboration, Copenhagen) was used to generate risk of bias plots.

Statistical analysis

Statistical analyses were performed using Review Manager (RevMan, version 5.3) and R software (Version 4.2.2). Forest plots and hierarchical summary receiver operating characteristic (HSROC) plots were used to present pooled sensitivity and 1-specificity data. A random-effects model combined sensitivity and 1-specificity results with 95% confidence intervals (CIs). The threshold effect was assessed using Spearman’s correlation to detect systematic variation in diagnostic thresholds across studies. Heterogeneity was evaluated using the I² statistic and Cochran’s Q test. Publication bias was examined using funnel plots and Egger’s regression test. A two-sided p-value < 0.05 was considered statistically significant.

Results

Literature search

Our comprehensive database search identified a total of 189 articles, including 62 from PubMed, 70 from Embase and MEDLINE, 57 from Web of Science, and 5 from other sources. After removing 129 duplicates, 65 unique records remained. Screening these titles and abstracts against our inclusion criteria resulted in 35 studies. Following a full-text review and applying exclusion criteria, 14 studies were further excluded, leaving 21 studies for our qualitative analysis and systematic review, as shown in Fig. 1; Table 1. 10 studies focused on diagnosis and staging (Table 2), 7 on ER status assessment (Table 3), and 12 on predicting endocrine therapy response (Table 4).

Fig. 1.

Flow chart of study included and selection

Table 1.

Study, patient, and technical characteristics of included studies

Authors	Year	Country	Study design	Sample size	Patients’ characteristics	Intervention	Technical aspects
Gennari A et al. [11]	2024	Italy	Prospective cohort	125 patients	ER + HER2- MBC	Rapamycin, CDK4/6 inhibitors	Baseline FES PET/CT FES: 200MBq, 60 min SUVmax > 2
Matthew FC et al. [12]	2023	USA	Prospective cohort	13 patients 19 lesions	ILC	-	FDG and FES PET/CT Metastasis biopsy FES: 6mCi, 60 min SUVmax > 1.5
Ramsha I et al. [8]	2023	the Netherlands	Prospective cohort	16 patients 1051 lesions	ER + HER2- MBC	Rintodestrant	FDG and FES PET/CT FES: 200MBq, 60 min Visual assessment, SUVmax > 1.5
Gianluca B et al. [13]	2023	Germany	Prospective cohort	92 patients 2678 lesions	MBC	-	FDG and FES PET/CT FES: 200MBq, 60 min Visual assessment, TBR
Cheng L et al. [14]	2023	China	Retrospective study	38 patients	ER + MBC	Palbociclib Abemaciclib, AI/Ful	Baseline FES PET/CT FES: 222MBq, 60 min Visual assessment, SUVmax > 1.8
Peerapon K et al. [15]	2023	Thailand	Retrospective study	28 patients	ER + breast cancer	-	FDG and FES PET/CT FES: 111MBq, 60 min Visual assessment
Boers J et al. [16]	2020	the Netherlands	Prospective cohort	26 patients 382 lesions	ER + MBC	Letrozole and Palbociclib	FDG and FES PET/CT Metastasis biopsy FES: 200MBq, 60 min SUVmax > 2
Chae SY et al. [17]	2017	Korea	Prospective cohort	26 patients	Postmenopausal, primary breast cancer and neoadjuvant therapy	FEC or Letrozole	Baseline FES PET/CT Core-needle biopsy and surgery FES:111-222MBq, 90 min Visual assessment
Chae SY et al. [18]	2020	Korea	Prospective cohort	45 patients	ER+, recurrent or metastatic breast cancer	-	FDG and FES PET/CT Core-needle biopsy and surgery FES: 111-222MBq, 80–100 min Visual assessment
Gemigani ML et al. [19]	2013	USA	Prospective cohort	48 patients	I-IV stage breast cancer	-	Preoperative FES PET Serum estradiol levels were measured 46 patients underwent surgery FES: 185-296MBq, 90 min Visual assessment, SUVmax ≥ 1.5
Gupta M et al. [20]	2017	India	Prospective cohort	12 patients	ER- patients: 2 ER + patients: 10	-	Lesions biopsy FES: 200MBq, 60 min Visual assessment
Jager A et al. [21]	2020	USA	Prospective clinical trial	16 patients	Postmenopausal women with ER+, HER2- breast cancer	Elacestrant	FES PET/CT was performed at baseline and day 14 FES: 200MBq SUVmax ≥ 1.5
Jasper J.L et al. [9]	2022	the Netherlands	Prospective cohort	181 patients	Newly diagnosed non-rapidly progressive MBC of all subtypes	-	Baseline FES PET/CT Biopsy ER IHC FES: 200MBq, 60 min Visual assessment, SUVmax ≥ 1.5
Liu C et al. [22]	2019	China	Retrospective study	19 patients 238 lesions	ER + breast cancer	Fulvestrant	FDG and FES PET/CT FES: 222MBq, 60 min Visual assessment, SUVmax ≥ 1.8
Liu C et al. [23]	2022	China	Retrospective study	56 patients 551 lesions	ER + HER2- MBC	Palbociclib combined with endocrine therapy	Underwent FES PET/CT before the first regimen, CT or MRI every 2–3 months FES: 222MBq, 60 min Visual assessment, SUVmax ≥ 1.8
Park JH et al. [24]	2016	Korea	Prospective clinical trial	24 patients	Postmenopausal ER + HER2 + breast cancer of stages II–III	Letrozole plus Lapatinib	Baseline FDG and FES PET/CT Surgery FES: 148-222MBq, 60–90 min SUVmax > 5.5
Peterson LM et al. [25]	2014	USA	Prospective clinical trial	26 patients	ER + stage IV breast cancer (no prior treatment)	Endocrine therapy	FDG and FES PET/CT Biopsy FES: 6mCi, 60 min Visual assessment
Peterson LM et al. [26]	2021	USA	Prospective clinical trial	24 patients	MBC	HDACIs and endocrine therapy	FDG and FES PET/CT FES: 6mCi, 60 min Visual assessment, SUVmax ≥ 2.2
Ulaner GA et al. [27]	2020	USA	Prospective cohort	7 patients	ILC	-	FDG and FES PET/CT FES: 185MBq, 60 min
van Kruchten M et al. [28]	2015	the Netherlands	Retrospective evaluation of prospective clinical trials	19 patients 255 lesions	ER+, acquired endocrine-resistant advanced breast cancer	Oestradiol	FES PET/CT FES: 200MBq SUVmax ≥ 1.5
Yang Z et al. [29]	2013	China	Prospective cohort	18 patients	Stage II and III breast cancer undergoing NAC	Paclitaxel and Carboplatin	FDG and FES PET/CT before NAC FES: 178-222MBq, 60 min Visual assessment

Table 2.

Performance of [¹⁸F]F-FES PET in breast cancer diagnosis and staging in reference to [¹⁸F]F-FDG PET/CT

Study	TP	FP	FN	TN	Total	Sensitivity (95% CI)	1-Specificity (95% CI)
PetersonLM et al.2014	12	2	5	0	19	0.69(0.53–0.82)	0.83(0.194–0.99)
PetersonLM et al.2021	21	0	2	1	24	0.86(0.66–0.95)	0.50(0.094–0.91)
Liu C et al.2019	3	6	7	3	19	0.32(0.12–0.62)	0.65(0.336–0.87)
Ulaner GA et al.2020	6	1	0	0	7	0.93(0.42,1.00)	0.75(0.109–0.99)
Gupta M et al.2017	3	1	5	1	10	0.39(0.14–0.71)	0.50(0.094–0.91)
Chae SY et al.2020	25	2	11	1	39	0.69(0.53–0.82)	0.62(0.180–0.93)
Matthew FC et al.2023	13	2	1	3	19	0.90 (0.62,0.98)	0.42 (0.124,0.78)
Gianluca B et al.2023	77	2	10	3	92	0.88(0.79,0.93)	0.42 (0.124,0.78)
Ramsha I et al.2023	12	1	3	0	16	0.78(0.52,0.92)	0.75(0.109,0.99)
Peerapon K et al.2023	18	5	5	0	28	0.77(0.56,0.90)	0.92(0.378–0.99)
Summary Estimate	190	22	49	12	273	0.75(0.62–0.85)	0.59(0.421–0.99)

Table 3.

Performance of [¹⁸F]F-FES PET/CT in assessing breast cancer ER status

Study	TP	FP	FN	TN	Total	Sensitivity (95% CI)	1-Specificity (95% CI)
PetersonLM et al.2014	12	2	5	0	19	0.69(0.53–0.82)	0.83(0.194–0.99)
Chao SY et al.2020	31	9	0	4	44	0.77(0.616–0.87)	0.10(0.01–0.67)
Boers J et al.2020	23	1	0	1	25	0.94(0.75–0.99)	0.25(0.01–0.89)
Chao SY et al.2017	24	0	2	0	26	0.91(0.73–0.97)	0.50(0.25–0.75)
Peterson LM et al.2014	8	5	3	3	19	0.94(0.495-1.00)	0.58(0.22–0.88)
Gemigani ML et al.2013	34	2	6	6	48	0.93(0.79–0.98)	0.50(0.25–0.75)
Jasoer J.L et al.2022	125	10	7	39	181	0.92(0.86–0.96)	0.16(0.08–0.29)
Yang Z et al.2013	11	1	0	6	18	0.41(0.17–0.70)	0.94(0.49-1.00)
Summary Estimate	256	28	18	59	361	0.86(0.71–0.94)	0.45(0.19–0.73)

Table 4.

Performance of [¹⁸F]F-FES PET/CT in predicting breast cancer endocrine therapy response

Study	TP	FP	FN	TN	Total	Sensitivity (95% CI)	1-Specificity (95% CI)
Chao SY et al.2017	24	0	2	0	26	0.91(0.73–0.97)	0.50(0.02–0.98)
Boers J et al.2020	237	34	89	33	393	0.73(0.68–0.77)	0.51(0.39–0.62)
Jager A et al.2020	4	2	2	1	9	0.64(0.28–0.89)	0.62(0.18–0.93)
Peterson LM et al.2014	8	3	0	2	13	0.94(0.50-1.00)	0.58(0.22–0.88)
Peterson LM et al.2021	8	5	0	2	15	0.94(0.50-1.00)	0.69(0.33–0.91)
Liu C et al.2022	43	3	0	10	56	0.99(0.84-1.00)	0.25(0.09–0.53)
Park JH et al.2016	8	1	7	8	24	0.53(0.30–0.75)	0.15(0.03–0.50)
Yang Z et al.2013	4	8	6	0	18	0.41(0.17–0.70)	0.94(0.49-1.00)
van Kruchten M et al.2015	6	4	1	4	15	0.81(0.42–0.96)	0.50(0.21–0.79)
Gennari A et al.2024	85	28	9	3	125	0.90(0.82–0.95)	0.89(0.73–0.96)
Ramsha I et al.2023	8	4	0	4	16	0.94(0.50-1.00)	0.50(0.21–0.79)
Cheng L et al.2023	5	11	10	6	38	0.34(0.16–0.60)	0.64(0.40–0.82)
Summary Estimate	440	103	126	73	748	0.79(0.62–0.89)	0.58(0.42–0.72)

Study characteristics

Among the 21 selected publications from 2013 to 2024, most (n = 14) were published within the last five years (2019–2024) [8, 9, 11–29]. The studies originated from Asia (n = 9, 43%), North America (n = 6, 29%), and Europe (n = 6, 29%), involving patient populations ranging from 7 to 181 individuals and tumor lesion counts from 19 to over 1,000, as detailed in Table 1. Most studies employed a prospective cohort design (n = 12) or were clinical trials (n = 5), with a few retrospective studies (n = 4). The primary focus was on ER+/HER2- metastatic breast cancer, with some studies including invasive lobular breast cancer, primary breast cancer undergoing neoadjuvant therapy, or targeting postmenopausal patients. Interventions included mono-endocrine therapy, combinations with CDK inhibitors or EGFR inhibitors, and chemotherapy.

[¹⁸F]F-FES PET/CT was typically conducted at baseline alongside [¹⁸F]F-FDG PET/CT, without contrast-enhanced CT. The injected [¹⁸F]F-FES activity ranged from 111 MBq to 296 MBq, with an uptake time of 60–90 min. Interpretation of [¹⁸F]F-FES PET/CT results was mainly based on visual assessment or maximum standardized uptake value (SUVmax), with the SUVmax cut-off being 1.5 in most studies, and 1.8 or 2.2 in a few. Endocrine response was assessed using RECIST v1.1. Clinical benefit rates (CBR).

Quality assessment and risk of bias

The QUADAS assessment indicated a low or unclear risk of bias in most studies (n = 19), as shown in Fig. 2. However, two studies [9, 27] were identified as high risk due to incomplete patient inclusion, potentially limiting their findings. Another study [28] was also considered high risk due to inadequate study plan descriptions. Publication bias was assessed using a funnel plot (Supplementary Fig. 4) and Egger’s test (Supplementary Fig. 5). The p-values of the three meta-analyses (diagnostic capability, ER detection, and endocrine therapy response prediction) by Egger’s test were 0.27, 0.17, and 0.72, respectively, indicating no significant publication bias.

Fig. 2.

Risk of bias of included studies: each risk of bias item is presented as percentages. Green: low risk of bias; Yellow: unclear risk of bias; Red: high risk of bias

Diagnostic accuracy of [¹⁸F]F-FES PET/CT

Ten studies evaluated the diagnostic capability of [¹⁸F]F-FES PET/CT compared to [¹⁸F]F-FDG PET. Significant heterogeneity was observed (Q statistic = 146.59, p < 0.001, I² = 93.9%). The threshold effect p-value was 0.06, allowing pooling of summary statistics. Compared to [¹⁸F]F-FDG PET as the diagnostic standard, [¹⁸F]F-FES PET/CT demonstrated a pooled sensitivity of 0.75 (95% CI: 0.62–0.85) and a false positive rate (FPR) of 0.27 (95% CI: 0.09–0.50) (Table 2; Fig. 3), with an AUC of 0.553 (95% CI: 0.48–0.69) (Supplementary Fig. 1).

Fig. 3.

Forest plot of meta-analysis of effects of diagnostic ability

ER status detection accuracy of [¹⁸F]F-FES PET/CT

Eight studies assessed the ability of [¹⁸F]F-FES PET/CT to detect ER status, using ER positivity from IHC as the reference. Sensitivity ranged from 0.86 to 0.96, and specificity from 0.43 to 0.76, with no detectable threshold effect (p = 0.81). The pooled sensitivity was 0.86 (95% CI: 0.71–0.94) and the FPR was 0.45 (95% CI: 0.19–0.73) (Table 3; Fig. 4), with an AUC of 0.808 (95% CI: 0.757–0.859) from HSROC (Supplementary Fig. 2). Heterogeneity among the seven studies was significant (Q statistic = 55.62, p < 0.001, I² = 89.21%).

Fig. 4.

Forest plot of meta-analysis of the identification of estrogen receptor status

Predictive ability for endocrine therapy response

Twelve studies evaluated the predictive capability of [¹⁸F]F-FES PET/CT for endocrine therapy response (threshold effect p = 0.45). The pooled sensitivity was 0.79 (95% CI: 0.62–0.89), with an FPR of 0.58 (95% CI: 0.42–0.72) (Table 4; Fig. 5), and an AUC of 0.680 (95% CI: 0.64–0.72) (Supplementary Fig. 3). Significant heterogeneity was present among the nine studies (Q statistic = 145.20, p < 0.001, I² = 92.4%).

Fig. 5.

Forest plot of meta-analysis of predicting response to endocrine therapy

Discussion

Accurate staging of breast cancer is crucial for effective management and prognosis prediction. [¹⁸F]F-FDG PET/CT, which reflects the metabolic activity of tumor cells, is widely used in evaluating various cancers, including breast cancer. The NCCN guidelines recommend [¹⁸F]F-FDG PET/CT for assessing metastatic disease in newly diagnosed stage III and IV breast cancer patients. However, this modality has limitations: it can produce false positives due to infections or inflammatory processes and false negatives in subtypes like lobular breast cancer with low metabolic activity. Consequently, there is a need for alternative tracers with improved diagnostic accuracy.

[¹⁸F]F-FES, a novel PET radiopharmaceutical, was FDA-approved in 2020 for clinical use as an adjunct in biopsies for recurrent or metastatic breast cancer. It visualizes ER-positive breast lesions using a radioactive tracer linked to estradiol, which binds to estrogen receptors with high affinity, enabling accurate localization and characterization of ER-positive lesions. For patients with a history of ER-positive primary breast cancer, [¹⁸F]F-FES PET/CT offers a non-invasive alternative to biopsy, especially for newly detected metastatic sites with uncertain ER status [11]. Our systematic review included 21 studies, analyzing its role in diagnostic staging, ER detection, and endocrine therapy response prediction, with insights drawn from 10, 8, and 12 studies, respectively.

When compared to [¹⁸F]F-FDG PET/CT as the diagnostic benchmark, [¹⁸F]F-FES PET/CT showed a combined sensitivity of 0.75 (95% CI: 0.62–0.85) and a false positive rate (FPR) of 0.27 (95% CI: 0.09–0.50), with an AUC of 0.553 (95% CI: 0.448–0.659). These findings suggest that while [¹⁸F]F-FES PET/CT has certain sensitivity and a relatively low FPR, its overall diagnostic accuracy is limited. Furthermore, the included studies exhibit substantial heterogeneity, with variations in [¹⁸F]F-FES diagnostic prowess across different research endeavors. Notably, high physiological uptake in the liver poses challenges in detecting liver metastases, limiting its use in some patients [14]. Additionally, [¹⁸F]F-FES PET/CT primarily assesses ER expression and may not effectively identify ER-negative lesions [27]. Despite this, it has a distinct advantage in accurately identifying inflammatory lesions and shows comparable safety to [¹⁸F]F-FDG PET/CT. Different organs exhibit heterogeneity in the uptake of [¹⁸F]F-FES. Studies have highlighted its superior accuracy in detecting metastases in lymph nodes, bones, lungs, and soft tissues compared to [¹⁸F]F-FDG PET/CT [13]. In the context of bone metastases, [¹⁸F]F-FES PET/CT is capable of conducting functional detection of ER, thereby exhibiting greater sensitivity compared to traditional [¹⁸F]F-FDG PET/CT [30]. Moreover, the uptake of [¹⁸F]F-FES in patients with bone metastases surpasses that in patients with lymph node and lung metastases [31]. Studies have revealed that for the detection of metastatic lymph nodes, [¹⁸F]F-FES PET/CT can achieve sub-centimeter level detection with high sensitivity [32]. Nevertheless, in an alternative study, only patients with an axillary lymph node metastasis burden of four or more lymph node metastases demonstrated high 18F-FES uptake in the corresponding region [19]. Given the hepatic metabolic pathway of [¹⁸F]F-FES, it poses challenges in ascertaining the metastasis of abdominal lymph nodes, particularly those in proximity to the intestine [33]. The brain tissue presents a low background value for [¹⁸F]F-FES uptake, enabling the diagnosis of brain parenchymal and dural metastases via [¹⁸F]F-FES PET/CT [34]. In the context of special breast cancer types, such as lobular carcinoma, where [¹⁸F]F-FDG PET/CT tends to underestimate disease extent, [¹⁸F]F-FES PET/CT emerges as a potentially invaluable diagnostic tool for identifying metastatic lesions. This finding carries profound implications given the inferior prognosis associated with lobular carcinoma compared to ductal carcinoma. The differential sensitivity between [¹⁸F]F-FES and [¹⁸F]F-FDG PET may stem from the relatively lower expression of glucose transporters in lobular breast cancer versus ductal breast cancer [15, 27].

Currently, ER status in breast cancer metastases is assessed through biopsy followed by immunohistochemical analysis, which is invasive, technically challenging, and may not capture tumor heterogeneity. A notable proportion (14–40%) of patients experience changes in receptor status as the disease progresses, underscoring the need for repeated evaluations [35]. As a non-invasive tool, [¹⁸F]F-FES PET/CT allows repeated assessment of ER expression across multiple lesions, providing a comprehensive visualization of ER status. Our meta-analysis of eight studies demonstrated that [¹⁸F]F-FES PET/CT had high sensitivity for ER detection, with an AUC of 0.808, making it an effective tool for assessing ER status. Several studies have demonstrated a strong correlation between [¹⁸F]F-FES uptake and ER expression in breast cancer, with increased uptake observed in tumors exhibiting higher ER levels, leading to enhanced detection rates. In contrast, the diagnostic efficacy of [¹⁸F]F-FDG PET/CT is diminished in tumors with heightened ER expression owing to their reduced aggressiveness. Moreover, unlike [¹⁸F]F-FDG PET/CT, [¹⁸F]F-FES PET/CT is not affected by ESR1 mutations, ensuring accurate ER assessment [20, 26].

Endocrine therapy is a cornerstone treatment for patients with metastatic ER-positive/HER2-negative breast cancer. However, up to 30% of patients experience early treatment failure, highlighting the need for early identification of endocrine resistance [11]. Given the ability of [¹⁸F]F-FES PET/CT to assess ER status, it may also predict endocrine therapy response. Our analysis of 12 studies revealed a pooled sensitivity of 0.79 (95% CI: 0.62–0.89) for predicting therapy response, with an AUC of 0.680 (95% CI: 0.64–0.72). While highlighting the high sensitivity of [¹⁸F]F-FES PET in predicting therapeutic success, these findings also underscore a considerable false negative rate, indicating lower specificity. Notably, the AUC for predicting efficacy fell short of that for ER receptor assessment, potentially attributable to the heterogeneity across studies, which may stem from variations in endocrine therapeutic regimens. Studies suggest that patients with elevated baseline [¹⁸F]F-FES uptake exhibit extended PFS of more than 2 months compared to those with low or absent uptake. This heightened [¹⁸F]F-FES uptake aligns with robust ER expression, a prerequisite for favorable endocrine therapy response. Moreover, [¹⁸F]F-FES PET imaging offers a unique window into the modus operandi and integrity of ER blockade during selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) treatment. A study underscores a marked reduction (> 87%) in [¹⁸F]F-FES uptake among patients receiving a novel SERD [8]. Conversely, patients lacking or displaying partial lesion uptake of [¹⁸F]F-FES are less likely to derive benefit from CDK4/6 inhibitors combined with endocrine therapy. On the other hand, patients with 100% [¹⁸F]F-FES positive lesions uniformly achieved clinical benefits and significantly longer PFS (22.9 months vs. 5.3 months) [14]. The preponderance of reports investigating [¹⁸F]F-FES PET in the context of ER + endocrine therapy for breast cancer concurs that heightened [¹⁸F]F-FES uptake portends a more favorable prognosis than low or absent uptake. Mechanistic preclinical research further illuminates that CDK4/6 inhibitor-resistant cells exhibit augmented glucose metabolism, which may signify enhanced ER signaling pathway activation, potentially bolstering the efficacy of endocrine therapy inhibition [36].

This meta-analysis has several strengths. First, it employed a rigorous search strategy, spanning multiple databases and adhering to PRISMA guidelines. Second, it comprehensively evaluated [¹⁸F]F-FES PET/CT in breast cancer from three perspectives: diagnostic staging, ER detection, and endocrine therapy response prediction. Notably, to our knowledge, this is the first meta-analysis to consolidate evidence on the role of [¹⁸F]F-FES PET/CT in endocrine therapy efficacy for breast cancer.

However, there are limitations. Significant heterogeneity among studies posed challenges, and differences in PET imaging criteria and diagnostic cut-off values contributed to this variability. The sample sizes across studies varied, which might affect the overall findings. Additionally, while this analysis included a majority of prospective cohort studies, there were fewer randomized controlled trials (RCTs), which are the gold standard for high-quality evidence. Future RCTs are needed to validate these findings and strengthen the evidence base.

Conclusion

[¹⁸F]F-FES PET/CT is a valuable tool for the diagnostic staging and evaluation of endocrine therapy response in ER-positive breast cancer. By offering detailed insights into ER expression across both primary and metastatic lesions, this imaging modality can enhance treatment planning and improve patient outcomes.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

YX and FC: Data analysis and drafted the manuscript. ZH and RY: Revised the manuscript. BL and QS: Acquired data, and played an important role in interpreting the results. BP, LH and YZ: Designed the work that led to the submission.

Funding

This work was supported by the National High Level Hospital Clinical Research Funding (Grant No. 2022-PUMCH-A-165) and the Project for Post-Marketing Clinical Research of Innovative Drugs by Medical and Health Science and Technology Development Research Center of the National Health Commission (Grant No. WKZX2024CX103104).

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the Peking Union Medical University Hospital (No. JS-2959).

Consent for publication

Not applicable.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.