Potential clinical utility of 68Ga-DOTATATE PET/CT for detection and response assessment in cardiac sarcoidosis.

BACKGROUND: Somatostatin receptor is expressed in sarcoid granulomas, and preliminary clinical studies have shown that myocardial sarcoidosis can be identified on somatostatin receptor-targeted PET. We examined the potential clinical use of 68Ga-DOTATATE PET/CT for diagnosis and response assessment in cardiac sarcoidosis compared to 18F-FDG PET/CT. METHODS: Eleven cardiac sarcoidosis patients with 18F-FDG PET/CT were prospectively enrolled for cardiac 68Ga-DOTATATE PET/CT. The two PET/CT studies were interpreted independently and were compared for patient-level and segment-level concordance, as well as for the degree of radiotracer uptake. Follow-up 68Ga-DOTATATE PET/CT was performed in eight patients. RESULTS: Patient-level concordance was 91%: ten patients had multifocal DOTATATE uptake (active cardiac sarcoidosis) and one patient showed diffuse DOTATATE uptake. Segment-level agreement was 77.1% (Kappa 0.53 ± 0.07). The SUVmax-to-blood pool ratio was lower on 68Ga-DOTATATE PET/CT (3.2 ± 0.6 vs. 4.9 ± 1.5, P = 0.006 on paired t test). Follow-up 68Ga-DOTATATE PET/CT showed one case of complete response and one case of partial response, while 18F-FDG PET/CT showed four cases of response, including three with complete response. CONCLUSION: Compared to 18F-FDG PET/CT, 68Ga-DOTATATE PET/CT can identify active cardiac sarcoidosis with high patient-level concordance, but with moderate segment-level concordance, low signal-to-background ratio, and underestimation of treatment response.

Temporal Heterogeneity of Estrogen Receptor Expression in Bone-Dominant Breast Cancer: 18F-Fluoroestradiol PET Imaging Shows Return of ER Expression.

Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using (18)F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging.

Molecular Imaging of Pulmonary Inflammation in Users of Electronic and Combustible Cigarettes: A Pilot Study.

Electronic cigarette (EC) use has increased dramatically, particularly among adolescents and young adults, and, like cigarette use, can cause pulmonary inflammation and increase the risk of lung disease. Methods: This preliminary study used PET with 18F-6-(1/2)(2-fluoro-propyl)-4-methylpyridin-2-amine (18F-NOS) to quantify inducible nitric oxide synthase expression to characterize oxidative stress and inflammation in the lungs in vivo in 3 age- and sex-matched groups: 5 EC users, 5 cigarette smokers, and 5 controls who had never smoked or vaped. Results: EC users showed greater 18F-NOS nondisplaceable binding potential (BPND) than cigarette smokers (P = 0.03) and controls (P = 0.01), whereas BPND in cigarette smokers did not differ from that in controls (P > 0.1). 18F-NOS lung tissue delivery and inducible nitric oxide synthase distribution volume did not significantly differ among groups. Although there were no group differences in peripheral inflammatory biomarker concentrations, 18F-NOS BPND correlated with the proinflammatory cytokine tumor necrosis factor-α concentrations (rs = 0.87, P = 0.05) in EC users. Additionally, when EC users and cigarette smokers were pooled together, number of vaping episodes or cigarettes per day correlated with interleukin-6 levels (rs = 0.86, P = 0.006). Conclusion: This is the first PET imaging study to compare lung inflammation between EC and cigarette users in vivo. We found preliminary evidence that EC users have greater pulmonary inflammation than cigarette smokers and controls, with a positive association between pulmonary and peripheral measures of inflammation.

Preliminary Evaluation of 68Ga-P16-093, a PET Radiotracer Targeting Prostate-Specific Membrane Antigen in Prostate Cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising molecular target for imaging of prostate adenocarcinoma. 68Ga-P16-093, a small molecule PSMA ligand, previously showed equivalent diagnostic performance compared to 68Ga-PSMA-11 PET/CT in a pilot study of prostate cancer patients with biochemical recurrence (BCR). We performed a pilot study for further characterization of 68Ga-P16-093 including comparison to conventional imaging. PROCEDURES: Patients were enrolled into two cohorts. The biodistribution cohort included 8 treated prostate cancer patients without recurrence, who underwent 6 whole body PET/CT scans with urine sampling for dosimetry using OLINDA/EXM. The dynamic cohort included 15 patients with BCR and 2 patients with primary prostate cancer. Two patients with renal cell carcinoma were also enrolled for exploratory use. A dynamic PET/CT was followed by 2 whole body scans for imaging protocol optimization based on bootstrapped replicates. 68Ga-P16-093 PET/CT was compared for diagnostic performance against available 18F-fluciclovine PET/CT, 99mTc-MDP scintigraphy, diagnostic CT, and MRI. RESULTS: 68Ga-P16-093 deposited similar effective dose (0.024 mSv/MBq) and lower urinary bladder dose (0.064 mSv/MBq) compared to 68Ga-PSMA-11. The kidneys were the critical organ (0.290 mSv/MBq). While higher injected activities were preferable, lower injected activities at 74-111 MBq (2-3 mCi) yielded 80% retention in signal-to-noise ratio. The optimal injection-to-scan interval was 60 min, with acceptable delay up to 90 min. 68Ga-P16-093 PET/CT showed superior diagnostic performance over conventional imaging with overall patient-level lesion detection rate of 71%, leading to a change in management in 42% of the patients. CONCLUSIONS: Based on its favorable imaging characteristics and diagnostic performance in prostate cancer, 68Ga-P16-093 PET/CT merits further investigation in larger clinical studies.

The Development of 18F Fluorthanatrace: A PET Radiotracer for Imaging Poly (ADP-Ribose) Polymerase-1.

Fluorine 18 (18F) fluorthanatrace (18F-FTT) is a PET radiotracer for imaging poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1), an important target for a class of drugs known as PARP inhibitors, or PARPi. This article describes the stepwise development of this radiotracer from its design and preclinical evaluation to the first-in-human imaging studies and the initial validation of 18F-FTT as an imaging-based biomarker for measuring PARP-1 expression levels in patients with breast and ovarian cancer. A detailed discussion on the preparation and submission of an exploratory investigational new drug application to the Food and Drug Administration is also provided. Additionally, this review highlights the need and future plans for identifying a commercialization strategy to overcome the major financial barriers that exist when conducting the multicenter clinical trials needed for approval in the new drug application process. The goal of this article is to provide a road map that scientists and clinicians can follow for the successful clinical translation of a PET radiotracer developed in an academic setting. Keywords: Molecular Imaging-Cancer, PET, Breast, Genital/Reproductive, Chemistry, Radiotracer Development, PARPi, 18F-FTT, Investigational New Drug © RSNA, 2022.

Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET Images of Ovarian Cancer.

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of 18F-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of 18F-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing 18F-fluorthanatrace as a biomarker of response to PARPi therapy. Methods: Fourteen prospectively enrolled ovarian cancer patients were injected with 18F-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUVmax and SUVpeak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (n = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. Results:18F-fluorthanatrace blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. The total distribution volume from a reversible 2-tissue-compartment model and Logan reference tissue distribution volume ratio (DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (r = 0.76 and 0.83, respectively; P < 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUVmax and SUVpeak acquired from images with midpoints of 57.5, 110 ± 3, and 199 ± 4 min highly correlated with PARP-1 expression (mean ± SD, r ≥ 0.79; P < 0.05). Conclusion: Tumor SUVmax and SUVpeak at 55-60 min after injection and later and DVR from at least 60 min appear to be robust noninvasive measures of PARP-1 binding. 18F-fluorthanatrace uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.

18F-Fluoroestradiol PET Imaging in a Phase II Trial of Vorinostat to Restore Endocrine Sensitivity in ER+/HER2- Metastatic Breast Cancer.

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. We tested whether 18F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Methods: Patients with ER+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI. 18F-fluoroestradiol PET and 18F-FDG PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, and then 15 simultaneously. Eight patients had stable disease at week 8, and 6 of these 8 patients had more than 6 mo of stable disease. Higher baseline 18F-fluoroestradiol uptake was associated with longer progression-free survival. 18F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18F-FDG uptake did not show a significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACIs and AI dosing in patients with cancer resistant to AI alone showed clinical benefit (6 or more months without progression) in 4 of 10 evaluable patients. Higher 18F-fluoroestradiol PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of 18F-fluoroestradiol PET.

Association between serial dynamic contrast-enhanced MRI and dynamic 18F-FDG PET measures in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer.

PURPOSE: To investigate the relationship between changes in vascularity and metabolic activity measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and dynamic (18)F-FDG-positron emission tomography (PET) in breast tumors undergoing neoadjuvant chemotherapy. MATERIALS AND METHODS: PET and MRI examinations were performed in 14 patients with locally advanced breast cancer (LABC) before and after chemotherapy. Dynamic (18)F-FDG PET measures included (18)F-FDG transport rate constant from blood to tissue (K(1)) and metabolism flux constant (Ki). DCE-MRI measures included initial peak enhancement (PE), signal enhancement ratio (SER), and tumor volume. Spearman rank-order correlations were assessed between changes in PET and MRI parameters, and measures were compared between patients with and without pathologic complete response (pCR) by Mann-Whitney U-test. RESULTS: Changes in glucose delivery (PET K(1)) were closely correlated with changes in tumor vascularity as reflected by DCE-MRI SER (r = 0.83, P < 0.001). Metabolic changes in PET Ki showed moderate correlations with vascularity changes as reflected by SER (r = 0.71) and PE (r = 0.76), and correlated closely with MRI tumor volume (r = 0.79, P < 0.001). Decreases in K(1), Ki, SER, and PE were greater for patients with pCR compared to those with residual disease (P < 0.05). CONCLUSION: Dynamic (18)F-FDG PET and DCE-MRI tumor measures of tumor metabolism, vascularity, and volume were well correlated for assessing LABC response to neoadjuvant chemotherapy and significantly discriminated pathologic complete responders. Further work is necessary to assess the value of combined PET and MRI for evaluating tumor pharmacodynamics in response to novel therapy.

PennPET Explorer: Human Imaging on a Whole-Body Imager.

The PennPET Explorer, a prototype whole-body imager currently operating with a 64-cm axial field of view, can image the major body organs simultaneously with higher sensitivity than that of commercial devices. We report here the initial human imaging studies on the PennPET Explorer, with each study designed to test specific capabilities of the device. Methods: Healthy subjects were imaged with FDG on the PennPET Explorer. Subsequently, clinical subjects with disease were imaged with 18F-FDG and 68Ga-DOTATATE, and research subjects were imaged with experimental radiotracers. Results: We demonstrated the ability to scan for a shorter duration or, alternatively, with less activity, without a compromise in image quality. Delayed images, up to 10 half-lives with 18F-FDG, revealed biologic insight and supported the ability to track biologic processes over time. In a clinical subject, the PennPET Explorer better delineated the extent of 18F-FDG-avid disease. In a second clinical study with 68Ga-DOTATATE, we demonstrated comparable diagnostic image quality between the PennPET scan and the clinical scan, but with one fifth the activity. Dynamic imaging studies captured relatively noise-free input functions for kinetic modeling approaches. Additional studies with experimental research radiotracers illustrated the benefits from the combination of large axial coverage and high sensitivity. Conclusion: These studies provided a proof of concept for many proposed applications for a PET scanner with a long axial field of view.

Biodistribution, dosimetry, and temporal signal-to-noise ratio analyses of normal and cancer uptake of [68Ga]Ga-P15-041, a gallium-68 labeled bisphosphonate, from first-in-human studies.

INTRODUCTION: [68Ga]Ga-P15-041 ([68Ga]Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer that can be generator-produced. We undertook a Phase 0/I clinical trial to assess its potential for imaging bone metastases in prostate cancer including assessment of radiotracer biodistribution and dosimetry. METHODS: Subjects with prostate cancer and known or suspected osseous metastatic disease were enrolled into one of two arms: dosimetry or dynamic. Dosimetry was performed with 6 whole body PET acquisitions and urine collection spanning 3 h; normal organ dosimetry was calculated using OLINDA/EXM. Dynamic imaging included a 60 min acquisition over a site of known or suspected disease followed by two whole body scans. Bootstrapping and subsampling of the acquired list-mode data were conducted to recommend image acquisition parameters for future clinical trials. RESULTS: Up to 233 MBq (6.3 mCi) of [68Ga]Ga-P15-041 was injected into 12 enrolled volunteers, 8 in dosimetry and 4 in dynamic cohorts. Radiotracer accumulated in known bone lesions and cleared rapidly from blood and soft tissue. The highest individual organ dose was 0.135 mSv/MBq in the urinary bladder wall. The average effective dose was 0.0173 ± 0.0036 mSv/MBq. An average injected activity of 166.5 MBq (4.5 mCi) resulted in absorbed dose estimates of 22.5 mSv to the urinary bladder wall, 8.2 mSv to the kidneys, and an effective dose of 2.9 mSv. Lesion signal to noise ratios on images generated from subsampled data were significantly higher for injected activities above 74 MBq (2 mCi) and were also significantly higher for imaging at 90 min than at 180 min post-injection. CONCLUSIONS: Dosimetry estimates are acceptable and [68Ga]Ga-P15-041 uptake characteristics in patients with confirmed bone metastases support its continued development. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Use of [68Ga]Ga-P15-041 would not require cyclotron infrastructure for manufacturing and distribution, allowing for improved patient access to a promising PET bone imaging agent.

Breast Cancer 18F-ISO-1 Uptake as a Marker of Proliferation Status.

The σ2 receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide (18F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of 18F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether 18F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Methods: Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of 18F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of 18F-ISO-1 was quantitated by SUVmax and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Results: Tumor SUVmax (median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUVmax, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUVmax greater than the low-Ki-67 (<20%) group (P = 0.02). SUVmax exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46, P = 0.01, n = 29). Partial-volume-corrected SUVmax was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51, P = 0.02, n = 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (P > 0.05). Conclusion:18F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.

Correction to: a Phase 2 Study of 16α-[18F]-Fluoro-17ß-Estradiol Positron Emission Tomography (FES-PET) as a Marker of Hormone Sensitivity in Metastatic Breast Cancer (MBC).

Two data points from Table 1. (continued) were published in error. The corrected data in Table 1. (continued) are shown, in italic, below.

Quantitative imaging of estrogen receptor expression in breast cancer with PET and 18F-fluoroestradiol.

UNLABELLED: The PET compound (18)F-fluoroestradiol ((18)F-FES) has been developed and tested as an agent for the imaging of estrogen receptor (ER) expression in vivo. (18)F-FES uptake has been shown to correlate with ER expression assayed in vitro by radioligand binding; however, immunohistochemistry (IHC) rather than radioligand binding is used most often to measure ER expression in clinical practice. We therefore compared (18)F-FES uptake with ER expression assayed in vitro by IHC with both qualitative and semiquantitative measures. METHODS: Seventeen patients with primary or metastatic breast cancer were studied with dynamic (18)F-FES PET; cancer tissue samples, collected close to the time of imaging, were assayed for ER expression by IHC. For each tumor, partial-volume-corrected measures of (18)F-FES uptake were compared with ER expression measured by 3 different ER scoring methods: qualitative scoring (0-3+), the Allred score (0-10), and a computerized IHC index. RESULTS: There was excellent agreement (r = 0.99) between observers using IHC as well as the different methods of measuring ER content (P < 0.001). ER-negative tumors had (18)F-FES partial-volume-corrected standardized uptake values of less than 1.0, whereas ER-positive tumors had values above 1.1. Correlation coefficients for the different measures of ER content and the different measures of (18)F-FES uptake ranged from 0.57 to 0.73, with the best correlation being between the computerized IHC index and (18)F-FES partial-volume-corrected standardized uptake values. CONCLUSION: Our results showed good agreement between (18)F-FES PET and ER expression measured by IHC. (18)F-FES imaging may be a useful tool for aiding in the assessment of ER status, especially in patients with multiple tumors or for tumors that are difficult to biopsy.

Validation of gallbladder absorbed radiation dose reduction simulation: human dosimetry of [18F]fluortriopride.

BACKGROUND: [18F]Fluortriopride (FTP) was developed as a dopamine D3-selective radiotracer, thought to be important to neurobiological reward pathways and implicated in drug addiction, Parkinson's disease, and schizophrenia. Preclinical radiation dosimetry studies found the gallbladder wall received the highest dose. A gallbladder dose reduction intervention was simulated using a novel reduction model for healthy adults following fatty-meal consumption. The goals of this study were to assess whole body FTP human dosimetry and determine the feasibility of reducing absorbed dose to the gallbladder wall. RESULTS: Effective dose without a fatty meal was 0.022 ± 0.002 mSv/MBq (± standard deviation) with highest organ dose of 0.436 ± 0.178 mSv/MBq to the gallbladder wall (n = 10). Predicted gallbladder dose reduction with fatty meal consumed was 67.4% (n = 10). Meal consumption by four repeat volunteers decreased average gallbladder dose by 71.3% (n = 4) compared to the original ten volunteers. CONCLUSIONS: Observed effective doses were adequately low to continue studying FTP uptake in humans. Validated dosimetry simulations indicate up to a 71% reduction in gallbladder dose can be achieved by employing intrinsic physiology to contract the gallbladder via fatty meal ingestion. This methodology for predicting gallbladder absorbed dose reduction from fatty meal consumption can be applied to other radiopharmaceuticals and radiotherapies.

Dynamic and static approaches to quantifying 18F-FDG uptake for measuring cancer response to therapy, including the effect of granulocyte CSF.

UNLABELLED: The response of cancer to chemotherapy can be quantified using (18)F-FDG to indicate changes in tumor metabolism. Quantification using the standardized uptake value (SUV) is more feasible for clinical practice than is the metabolic rate of (18)F-FDG (MRFDG), which requires longer, dynamic scanning. The relationship between MRFDG and SUV depends in part on how each accounts for blood clearance of tracer. We tested whether chemotherapy and treatment with granulocyte colony-stimulating factor (CSF) changed the blood clearance curves and therefore affected the relationship between MRFDG and SUV. METHODS: Thirty-nine patients with locally advanced breast cancer underwent (18)F-FDG PET before and after chemotherapy, including granulocyte CSF. The area under the curve (AUC) for blood clearance was determined before and after therapy. MRFDGs were determined by graphical analyses, whereas SUVs were calculated using the standard formula normalized by body weight. MRFDG and SUVs were compared with each other and with tumor response. Paired percentage changes in MRFDG and SUV were also divided into tertiles based on pretherapy SUV to investigate differences in the relative sensitivity of SUV changes to MRFDG changes due to baseline tumor uptake. RESULTS: Despite a small but statistically significant 6% decrease in blood AUCs after therapy (P = 0.02), SUV and MRFDG did not differ significantly in slope (P = 0.53) or in correlation before and after therapy (r = 0.95 for both). Percentage changes in MRFDG and SUV between serial scans correlated with each other (r = 0.84) and with patient response (P

Estrogen Receptor Binding (18F-FES PET) and Glycolytic Activity (18F-FDG PET) Predict Progression-Free Survival on Endocrine Therapy in Patients with ER+ Breast Cancer.

PURPOSE: 18F-fluoroestradiol (FES) PET scans measure regional estrogen binding, and 18F-fluorodeoxyglucose (FDG) PET measures tumor glycolytic activity. We examined quantitative and qualitative imaging biomarkers of progression-free survival (PFS) in breast cancer patients receiving endocrine therapy. EXPERIMENTAL DESIGN: Ninety patients with breast cancer from an estrogen receptor-positive (ER+), HER2- primary tumor underwent FES PET and FDG PET scans prior to endocrine therapy (63% aromatase inhibitor, 22% aromatase inhibitor and fulvestrant, 15% other). Eighty-four had evaluable data for PFS prediction. RESULTS: Recursive partitioning with 5-fold internal cross-validation used both FES PET and FDG PET measures to classify patients into three distinct response groups. FDG PET identified 24 patients (29%) with low FDG uptake, suggesting indolent tumors. These patients had a median PFS of 26.1 months (95% confidence interval, 11.2-49.7). Of patients with more FDG-avid tumors, 50 (59%) had high average FES uptake, and 10 (12%) had low average FES uptake. These groups had median PFS of 7.9 (5.6-11.8) and 3.3 months (1.4-not evaluable), respectively. Patient and tumor features did not replace or improve the PET measures' prediction of PFS. Prespecified endocrine resistance classifiers identified in smaller cohorts did not individually predict PFS. CONCLUSIONS: A wide range of therapy regimens are available for treatment of ER+ metastatic breast cancer, but no guidelines are established for sequencing these therapies. FDG PET and FES PET may help guide the timing of endocrine therapy and selection of targeted and/or cytotoxic chemotherapy. A multicenter trial is ongoing for external validation. Clin Cancer Res; 23(2); 407-15. ©2016 AACR.

18F-Fluoroestradiol PET: Current Status and Potential Future Clinical Applications.

Estrogen receptor (ER) expression in breast cancer is associated with a more favorable prognosis and is necessary for a response to endocrine therapies. Traditionally, ER expression is assessed by in vitro assays on biopsied tumor tissue. However, recent advances have allowed in vivo evaluation of ER expression with (18)F-fluoroestradiol ((18)F-FES) PET. Clinical studies have demonstrated the use of (18)F-FES PET as a method for quantifying in vivo ER expression and have explored its potential as a predictive assay and method of assessing in vivo pharmacodynamic response to endocrine therapy. This review outlines the biology and pharmacokinetics of (18)F-FES, highlights the current experience with (18)F-FES in patient studies on breast cancer and other diseases, and discusses potential clinical applications and the possible future clinical use of (18)F-FES PET.

Blood flow and metabolism in locally advanced breast cancer: relationship to response to therapy.

UNLABELLED: Locally advanced breast cancer (LABC) is commonly treated with neoadjuvant chemotherapy followed by definitive surgery. The factors influencing the response of LABC to presurgical chemotherapy are incompletely understood. To characterize in vivo tumor biology in patients with LABC, we measured pretherapy blood flow and glucose metabolism in LABC, compared measurements with clinical and pathologic parameters, and examined blood flow and response to subsequent neoadjuvant chemotherapy. METHODS: Thirty-seven patients with newly diagnosed LABC underwent (18)F-FDG and (15)O-water PET imaging. Thirty-one of these patients underwent neoadjuvant chemotherapy, and response was evaluated by serial measurements of tumor size and pathologic examination after definitive surgery after chemotherapy. Tumor metabolism was estimated from graphic analysis of dynamic (18)F-FDG studies and was expressed as the metabolic rate of (18)F-FDG (MRFDG). Blood flow was estimated from dynamic images after bolus (15)O-water injection using a 1-compartment model. Tumor blood flow and metabolism were compared with clinical and pathologic parameters and with response to chemotherapy. RESULTS: Both blood flow and metabolism were significantly higher in tumor than in normal breast. Tumor blood flow and metabolism were correlated but highly variable. There were weak associations of metabolism with patient age and tumor grade and of blood flow with estrogen receptor status. There was a statistically significant trend for patients with a high MRFDG to have a poorer response to therapy (P = 0.001). Response was not significantly correlated with any other parameters. A low ratio of MRFDG to blood flow was the best predictor of macroscopic complete response (CR) (P = 0.02 vs. non-CR). Preliminary analysis of patient follow-up showed the ratio of MRFDG to blood flow to also be predictive of disease-free survival. CONCLUSION: Despite uniformly large tumor size, blood flow and metabolism in LABC are highly variable. High glucose metabolism predicts a poor response to neoadjuvant chemotherapy, and low MRFDG relative to blood flow is a predictor of CR. Further work is needed to elucidate the biologic mechanisms underlying these findings.

18F-FDG kinetics in locally advanced breast cancer: correlation with tumor blood flow and changes in response to neoadjuvant chemotherapy.

UNLABELLED: The aim of this study was to characterize the biologic response of locally advanced breast cancer (LABC) to chemotherapy using (15)O-water-derived blood flow measurements and (18)F-FDG-derived glucose metabolism rate parameters. METHODS: Thirty-five LABC patients underwent PET with (15)O-water and (18)F-FDG before neoadjuvant chemotherapy and 2 mo after the initiation of treatment. Kinetic analysis for (15)O-water was performed using a single tissue compartment model to calculate blood flow; a 2-tissue compartment model was used to estimate (18)F-FDG rate parameters K(1), k(2), k(3), and the flux constant, K(i). Correlations and ratios between blood flow and (18)F-FDG rate parameters were calculated and compared with pathologic tumor response. RESULTS: Although blood flow and (18)F-FDG transport (K(1)) were correlated before chemotherapy, there was relatively poor correlation between blood flow and the phosphorylation constant (k(3)) or the overall (18)F-FDG flux (K(i)). Blood flow and (18)F-FDG flux were more closely matched after chemotherapy, with changes in k(3) accounting for the increased correlation. These findings were consistent with a decline in both the K(i)/flow and k(3)/flow ratios with therapy. The ratio of (18)F-FDG flux to transport (K(i)/K(1)) after 2 mo of chemotherapy was predictive of ultimate response. CONCLUSION: The pattern of tumor glucose metabolism in LABC, as reflected by analysis of (18)F-FDG rate parameters, changes after therapy, even in patients with modest clinical responses. This may indicate a change in tumor "metabolic phenotype" in response to treatment. A low ratio of glucose metabolism (reflected by K(i)) to glucose delivery (reflected by K(1) and blood flow) after therapy is associated with a favorable response. Further work is needed to understand the tumor biology underlying these findings.

SUV varies with time after injection in (18)F-FDG PET of breast cancer: characterization and method to adjust for time differences.

UNLABELLED: The purpose of this study was to measure how (18)F-FDG PET standardized uptake values (SUVs) change over time in breast cancer and to examine the feasibility of a method to adjust for modest variations in the time of uptake measurement experienced in clinical practice. METHODS: (18)F-FDG PET was performed as 60-min dynamic imaging with an additional image acquired at approximately 75 min after injection. For 20 newly diagnosed, untreated, locally advanced breast cancer patients, both the maximum SUV and the average SUV within the lesion were calculated with and without correction for blood glucose concentration. A linear regression analysis of the portion of the time-activity curves starting at 27 min after injection was used to estimate the rate of SUV change per minute during the interval from 27 to 75 min. The rate of SUV change with time was compared with the instantaneous SUV obtained at different times from 27 to 75 min. RESULTS: In untreated breast cancer, (18)F-FDG SUV values changed approximately linearly after 27 min at a rate ranging from -0.02 to 0.15 per minute. In addition, the rate of SUV change was linearly correlated with the instantaneous SUV measured at different times after injection (r(2) ranged from 0.82 to 0.94; P < 0.001). Using this information, an empirical linear model of SUV variation with time from injection to uptake measurement was formulated. The comparison method was then applied prospectively to a second set of 20 locally advanced breast cancer lesions not included in the initial analysis. The average percent error using the method to adjust for time differences was 8% and 5% for maximum SUVs and average SUVs ranging from 2 to 12. CONCLUSION: In untreated breast cancer, the SUV at any time point approximately predicts the rate of change of SUV over time. A comparison method based on this finding appears feasible and may improve the usefulness of the SUV by providing a means of comparing SUV acquired at different times after injection.