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Intrapatient heterogeneity of estrogen receptor (ER) expression on 16α-[ 18 F]fluoro-17β-estradiol ([ 18 F]FES) PET is related to outcome in patients with ER-positive metastatic breast cancer (MBC), but a validated and practical method to support clinical decision-making is lacking. Therefore, the [ 18 F]FES PET heterogeneity score (i.e., percentage of [ 18 F]FES-positive metastases) was validated as a prognostic factor for endocrine therapy response and survival in a large cohort of patients with newly diagnosed MBC. Furthermore, we explored 2 less laborious methods to predict the [ 18 F]FES PET heterogeneity score. Methods: Patients with ER-positive MBC included in the IMPACT-MBC study, who received baseline [ 18 F]FES and [ 18 F]FDG PET and first-line endocrine therapy, were included in this subanalysis. ER homogeneous (100% [ 18 F]FES-positive lesions) and ER heterogeneous (both [ 18 F]FES-positive and [ 18 F]FES-negative lesions) MBC was distinguished by manual segmentation of all lesions on [ 18 F]FES PET and related to progression-free survival (PFS) and overall survival (OS). In addition, the positive predictive value of the visual assessment and the 5-largest-lesions assessment to predict homogeneous MBC in all lesions on [ 18 F]FES PET was determined. Results: From the 102 MBC patients eligible for the present retrospective subanalysis, 46 had ER homogeneous MBC and 56 had ER heterogeneous MBC. Differences were found between ER homogeneous and ER heterogeneous MBC for median PFS (19.8 vs. 15.0 mo; hazard ratio, 0.63; 95% CI, 0.41-0.96; P = 0.03) and median OS (62.5 vs. 34.7 mo; hazard ratio, 0.65; 95% CI, 0.38-1.08; P = 0.09). Twenty-one (38%) of 61 patients with ER homogeneous MBC by visual analysis and 37 (45%) of 83 patients with ER homogeneous MBC by the 5-largest-lesions method had ER heterogeneous MBC by manual segmentation of all lesions on [ 18 F]FES PET (positive predictive value, 0.66 and 0.55, respectively). Conclusion: Patients with ER-positive homogeneous MBC showed a trend toward superior PFS and OS compared with patients with ER heterogeneous MBC. This analysis confirmed and validated the prognostic value of the [ 18 F]FES PET heterogeneity score for endocrine therapy response and survival in a large cohort of MBC patients. The less laborious visual and 5-largest-lesions methods were inferior compared with assessment based on the [ 18 F]FES PET heterogeneity score in all lesions., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Understanding which patients with human epidermal growth factor receptor 2 (HER2)-negative or -low metastatic breast cancer (MBC) benefit from HER2-targeted strategies is urgently needed. We assessed the whole-body heterogeneity of HER2 expression on 89 Zr-trastuzumab PET (HER2 PET) and the diagnostic performance of HER2 PET in a large series of patients, including HER2-negative and -low MBC. Methods: In the IMPACT-MBC study, patients with newly diagnosed and nonrapidly progressive MBC of all subtypes were included. Metastasis HER2 status was determined by immunohistochemistry and in situ hybridization. 89 Zr-trastuzumab uptake was quantified as SUV max and SUV mean HER2 immunohistochemistry was related to the quantitative 89 Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, uptake heterogeneity, and qualitative scan evaluation. A prediction algorithm for HER2 immunohistochemistry positivity based on uptake was developed. Results: In 200 patients, 89 Zr-trastuzumab uptake was quantified in 5,163 metastases, including 186 biopsied metastases. With increasing HER2 immunohistochemistry status, uptake was higher (geometric mean SUV max of 7.0, 7.6, 7.3, and 17.4 for a HER2 immunohistochemistry score of 0, 1, 2, or 3+, respectively; P < 0.001). High uptake exceeding 14.6 (90th percentile) was observed in one third of patients with a HER2-negative or -low metastasis biopsy. The algorithm performed best when lesion site and size were incorporated (area under the curve, 0.86; 95% CI, 0.79-0.93). Conclusion: HER2 PET had good diagnostic performance in MBC, showing considerable whole-body HER2 heterogeneity and uptake above background in HER2-negative and -low MBC. This provides novel insights into HER2-negative and -low MBC compared with standard HER2 immunohistochemistry on a single biopsy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: In metastatic breast cancer (MBC), [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [ 18 F]FDG uptake in corresponding metastases., Patients and Methods: Patients with non-rapidly progressive MBC of all subtypes prospectively underwent a baseline histological metastasis biopsy and [ 18 F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [ 18 F]FDG uptake was expressed as maximum standardized uptake value (SUV max ) and results were expressed as geometric means., Results: Of 200 patients, 188 had evaluable metastasis biopsies, and 182 of these contained tumor. HER2 positivity and Ki-67 ≥ 20% were correlated with higher [ 18 F]FDG uptake (estimated geometric mean SUV max 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [ 18 F]FDG uptake was lowest in ER-positive/HER2-negative BC and highest in HER2-positive BC (geometric mean SUV max 6.8 and 10.0, respectively; p = 0.0058). Although [ 18 F]FDG uptake was lower in invasive lobular carcinoma ( n = 31) than invasive carcinoma NST ( n = 146) (estimated geometric mean SUV max 5.8 versus 7.8; p = 0.014), the metastasis detection rate was similar., Conclusions: [ 18 F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [ 18 F]FDG uptake, [ 18 F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332).

Molecular imaging, such as positron emission tomography (PET), is increasingly used as biomarker to predict and assess treatment response in breast cancer. The number of biomarkers is expanding with specific tracers for tumour characteristics throughout the body and this information can be used to aid the decision-making process. These measurements include metabolic activity using [ 18 F]fluorodeoxyglucose PET ([ 18 F]FDG-PET), oestrogen receptor (ER) expression using 16α-[ 18 F]Fluoro-17β-oestradiol ([ 18 F]FES)-PET and human epidermal growth factor receptor 2 (HER2) expression using PET with radiolabelled trastuzumab (HER2-PET). In early breast cancer, baseline [ 18 F]FDG-PET is frequently used for staging, but limited subtype-specific data reduce its usefulness as biomarker for treatment response or outcome. Early metabolic change on serial [ 18 F]FDG-PET is increasingly used in the neo-adjuvant setting as dynamic biomarker to predict pathological complete response to systemic therapy, potentially allowing de-intensification or step-up intensification of treatment. In the metastatic setting, baseline [ 18 F]FDG-PET and [ 18 F]FES-PET can be used as biomarker to predict treatment response, in triple-negative and ER-positive breast cancer, respectively. Metabolic progression on repeated [ 18 F]FDG-PET appears to precede progressive disease on standard evaluation imaging; however, subtype-specific studies are limited and more prospective data are needed before implementation in clinical practice. Even though (repeated) [ 18 F]FDG-PET, [ 18 F]FES-PET and HER2-PEt all show promising results as biomarkers to predict therapy response and outcome, for eventual integration into clinical practice, future studies will have to clarify at what timepoint this integration has to optimally take place., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial ( NCT03147040 ), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml -1 min -1 ) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8 + T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials., (© 2023. The Author(s).)

Purpose: Determining the estrogen receptor (ER) status is essential in metastatic breast cancer (MBC) management. Whole-body ER imaging with 16α-[ 18 F]fluoro-17β-estradiol positron emission tomography ([ 18 F]FES-PET) is increasingly used for this purpose. To establish the clinical validity of the [ 18 F]FES-PET, we studied the diagnostic accuracy of qualitative and quantitative [ 18 F]FES-PET assessment to predict ER expression by immunohistochemistry in a metastasis., Methods: In a prospective multicenter trial, 200 patients with newly diagnosed MBC underwent extensive workup including molecular imaging. For this subanalysis, ER expression in the biopsied metastasis was related to qualitative whole-body [ 18 F]FES-PET evaluation and quantitative [ 18 F]FES uptake in the corresponding metastasis. A review and meta-analysis regarding [ 18 F]FES-PET diagnostic performance were performed., Results: Whole-body [ 18 F]FES-PET assessment predicted ER expression in the biopsied metastasis with good accuracy: a sensitivity of 95% (95% CI, 89 to 97), a specificity of 80% (66 to 89), a positive predictive value (PPV) of 93% (87 to 96), and a negative predictive value (NPV) of 85% (72 to 92) in 181 of 200 evaluable patients. Quantitative [ 18 F]FES uptake predicted ER immunohistochemistry in the corresponding metastasis with a sensitivity/specificity of 91%/69% and a PPV/NPV of 90%/71% in 156 of 200 evaluable patients. For bone metastases, PPV/NPV was 92%/81%. Meta-analysis with addition of our data has increased diagnostic performance and narrowed the 95% CIs compared with previous studies with a sensitivity/specificity of both 86% (81 to 90 and 73 to 93, respectively)., Conclusion: In this largest prospective series so far, we established the clinical validity of [ 18 F]FES-PET to determine tumor ER status in MBC. In view of the high diagnostic accuracy of qualitatively assessed whole-body [ 18 F]FES-PET, this noninvasive imaging modality can be considered a valid alternative to a biopsy of a metastasis to determine ER status in newly MBC (ClinicalTrials.gov identifier: NCT01957332).