PURPOSE Determining the estrogen receptor (ER) status is essential in metastatic breast cancer (MBC) management. Whole-body ER imaging with 16α-[18F]fluoro-17β-estradiol positron emission tomography ([18F]FES-PET) is increasingly used for this purpose. To establish the clinical validity of the [18F]FES-PET, we studied the diagnostic accuracy of qualitative and quantitative [18F]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 [18F]FES-PET evaluation and quantitative [18F]FES uptake in the corresponding metastasis. A review and meta-analysis regarding [18F]FES-PET diagnostic performance were performed. RESULTS Whole-body [18F]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 [18F]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 [18F]FES-PET to determine tumor ER status in MBC. In view of the high diagnostic accuracy of qualitatively assessed whole-body [18F]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 ).

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.

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 [18F]fluorodeoxyglucose PET ([18F]FDG-PET), oestrogen receptor (ER) expression using 16α-[18F]Fluoro-17β-oestradiol ([18F]FES)-PET and human epidermal growth factor receptor 2 (HER2) expression using PET with radiolabelled trastuzumab (HER2-PET). In early breast cancer, baseline [18F]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 [18F]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 [18F]FDG-PET and [18F]FES-PET can be used as biomarker to predict treatment response, in triple-negative and ER-positive breast cancer, respectively. Metabolic progression on repeated [18F]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) [18F]FDG-PET, [18F]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.