Tumor-associated macrophages (TAMs) are important tumor-promoting cells in the breast tumor microenvironment. Preclinically TAMs stimulate breast tumor progression, including tumor cell growth, invasion and metastasis. TAMs also induce resistance to multiple types of treatment in breast cancer models. The underlying mechanisms include: induction and maintenance of tumor-promoting phenotype in TAMs, inhibition of CD8+ T cell function, degradation of extracellular matrix, stimulation of angiogenesis and inhibition of phagocytosis. Several studies reported that high TAM infiltration of breast tumors is correlated with a worse patient prognosis. Based on these findings, macrophage-targeted treatment strategies have been developed and are currently being evaluated in clinical breast cancer trials. These strategies include: inhibition of macrophage recruitment, repolarization of TAMs to an antitumor phenotype, and enhancement of macrophage-mediated tumor cell killing or phagocytosis. This review summarizes the functional aspects of TAMs and the rationale and current evidence for TAMs as a therapeutic target in breast cancer.

Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using ⁸⁹Zr-trastuzumab PET (for HER2-positive breast cancer) or ⁸⁹Zr-bevacizumab PET [for estrogen receptor (ER)–positive breast cancer] to determine in vivo degradation of client proteins caused by the novel HSP90 inhibitor NVP-AUY922. Experimental Design: Of note, 70 mg/m² NVP-AUY922 was administered intravenously in a weekly schedule to patients with advanced HER2 or ER-positive breast cancer. Biomarker analysis consisted of serial PET imaging with 2[18F]fluoro-2-deoxy-D-glucose (FDG), ⁸⁹Zr-trastuzumab, or ⁸⁹Zr-bevacizumab. Response evaluation was performed according to RECIST1.0. FDG, ⁸⁹Zr-trastuzumab, and ⁸⁹Zr-bevacizumab distributions were scored visually and quantitatively by calculating the maximum standardized uptake values (SUV_max). In blood samples, serial HSP70 levels, extracellular form of HER2 (HER2-ECD), and pharmacokinetic and pharmacodynamic parameters were measured. Results: Sixteen patients (ten HER2-positive and six ER-positive tumors) were included. One partial response was observed; seven patients showed stable disease. SUV_max change in individual tumor lesions on baseline versus 3 weeks ⁸⁹Zr-trastuzumab PET was heterogeneous and related to size change on CT after 8 weeks treatment (r² = 0.69; P = 0.006). Tumor response on ⁸⁹Zr-bevacizumab PET and FDG-PET was not correlated with CT response. Conclusions: NVP-AUY922 showed proof-of-concept clinical response in HER2-amplified metastatic breast cancer. Early change on ⁸⁹Zr-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT. Clin Cancer Res; 20(15); 3945–54. ©2014 AACR.

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 ).

Purpose of Review: Molecular imaging with positron emission tomography (PET) is a powerful tool to visualize breast cancer characteristics. Nonetheless, implementation of PET imaging into cancer care is challenging, and essential steps have been outlined in the international “imaging biomarker roadmap.” In this review, we identify hurdles and provide recommendations for implementation of PET biomarkers in breast cancer care, focusing on the PET tracers 2-[¹⁸F]-fluoro-2-deoxyglucose ([¹⁸F]-FDG), sodium [¹⁸F]-fluoride ([¹⁸F]-NaF), 16α-[¹⁸F]-fluoroestradiol ([¹⁸F]-FES), and [⁸⁹Zr]-trastuzumab. Recent Findings: Technical validity of [¹⁸F]-FDG, [¹⁸F]-NaF, and [¹⁸F]-FES is established and supported by international guidelines. However, support for clinical validity and utility is still pending for these PET tracers in breast cancer, due to variable endpoints and procedures in clinical studies. Summary: Assessment of clinical validity and utility is essential towards implementation; however, these steps are still lacking for PET biomarkers in breast cancer. This could be solved by adding PET biomarkers to randomized trials, development of imaging data warehouses, and harmonization of endpoints and procedures.