Background: Breast cancer (BC) is a heterogeneous disease, in which estrogen receptor (ER) expression plays an important role in the majority of breast tumors. A clinical dilemma may arise when a metastasis biopsy to determine the ER status cannot be performed safely or when ER heterogeneity is suspected between tumor lesions. Whole-body ER imaging, such as 16α-¹⁸F-fluoro-17β-estradiol (¹⁸F-FES) positron emission tomography (PET), may have added value in these situations. However, the role of this imaging technique in routine clinical practice remains to be further determined. Therefore, we assessed the value of ¹⁸F-FES-PET by evaluating if the physician’s clinical dilemma that remained after standard workup was solved by the ¹⁸F-FES-PET scan. Methods: In this retrospective study, ¹⁸F-FES-PET scans, performed in patients with (suspected) ER+ metastatic BC with remaining clinical dilemma after standard workup, at the University Medical Center of Groningen between November 2009 and January 2019, were included. We investigated whether the physician’s clinical dilemma was solved, defined as 1) ¹⁸F-FES-PET provided a solution for the clinical dilemma, and/or 2) a treatment decision was based directly on the ¹⁸F-FES-PET. In addition, category of clinical dilemma, and rate of ¹⁸F-FES positive or negative PET scans were reported, and related to frequency of solved dilemmas. Results: One hundred ¹⁸F-FES-PET scans were performed in 83 patients. Clinical dilemma categories were: 1) inability to determine extent of (suspected) metastatic disease with standard workup (n = 52), 2) unclear ER status of the tumor (n = 31), and 3) inability to determine which primary tumor caused metastases (n = 17). Dilemmas were solved by ¹⁸F-FES-PET in 87/100 cases (87%). In 81/87 cases a treatment decision was made based directly on the ¹⁸F-FES-PET (treatment change: n = 51 cases; continuance: n = 30 cases). The frequency of solved dilemmas was not related to the clinical dilemma category (P = 0.334). However, the frequency of solved dilemmas was related to whether scans were ¹⁸F-FES positive (n = 63) or negative (n = 37; p<0.001). Conclusion: For various indications, the ¹⁸F-FES-PET scan can help to solve the vast majority of clinical dilemmas that may remain after standard workup. Therefore, the ¹⁸F-FES-PET scan has added value in BC patients presenting with a clinical dilemma.

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.

The SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC. Postmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [¹⁸F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose. Currently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45%, fulvestrant in 91%, and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [¹⁸F] FES-PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant). The oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270). NCT03455270. G1 Therapeutics, Inc. G1 Therapeutics. E.C. Dees: Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): H3Biosciences; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Cerulean; Research grant / Funding (institution): Meryx; Advisory / Consultancy, Research grant / Funding (institution): Novartis. P.G. Aftimos: Advisory / Consultancy: Boehringer Ingleheim; Advisory / Consultancy: Macrogenics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Amcure; Honoraria (self), Research grant / Funding (institution): Synthon; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Radius; Research grant / Funding (institution): Servier. C.W. Menke-van der Houven van Oordt: Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy: Novartis. E.G..E. De Vries: Research grant / Funding (institution): G1 Therapeutics; Advisory / Consultancy: NSABP; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): Nordic Nanovector; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Synthon. M.D. Pegram: Advisory / Consultancy: G1 Therapeutics. J. Xiao: Full / Part-time employment: G1 Therapeutics. C. Sipes: Full / Part-time employment: G1 Therapeutics. C. Li: Full / Part-time employment: G1 Therapeutics. J.A. Sorrentino: Full / Part-time employment: G1 Therapeutics. R. Malik: Full / Part-time employment: G1 Therapeutics. A.P. Beelen: Full / Part-time employment: G1 Therapeutics. All other authors have declared no conflicts of interest.

Background: Positron emission tomography (PET) with 16α-[¹⁸F]-fluoro-17β-estradiol ([¹⁸F]-FES) can visualize estrogen receptor (ER) expression, but it is challenging to determine the ER status of liver metastases, due to high physiological [¹⁸F]-FES uptake. We evaluated whether [¹⁸F]-FES-PET can be used to determine the ER status of liver metastases, using corresponding liver biopsies as the gold standard. Methods: Patients with metastatic breast cancer (n = 23) were included if they had undergone a [¹⁸F]-FES-PET, liver metastasis biopsy, CT-scan, and [¹⁸F]-FDG-PET. [¹⁸F]-FES-PET scans were assessed by visual and quantitative analysis, tracer uptake was correlated with ER expression measured by immunohistochemical staining and the effects of region-of-interest size and background correction were determined. Results: Visual analysis allowed ER assessment of liver metastases with 100% specificity and 18% sensitivity. Quantitative analysis improved the sensitivity. Reduction of the region-of-interest size did not further improve the results, but background correction improved ER assessment, resulting in 83% specificity and 77% sensitivity. Using separate thresholds for ER+ and ER− metastases, positive and negative predictive values of 100% and 75%, respectively, could be obtained, although 30% of metastases remained inconclusive. Conclusion: In the majority of liver metastases, ER status can be determined with [¹⁸F]-FES-PET if background correction and separate thresholds are applied.

Background: In metastatic breast cancer (MBC), [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography ([¹⁸F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [¹⁸F]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 [¹⁸F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [¹⁸F]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 [¹⁸F]FDG uptake (estimated geometric mean SUV_max 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [¹⁸F]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 [¹⁸F]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: [¹⁸F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [¹⁸F]FDG uptake, [¹⁸F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332).