18F-Labeled Fluoroestradiol PET/CT: Current Status, Gaps in Knowledge, and Controversies-AJR Expert Panel Narrative Review.

PET/CT using 16α-[18F]-fluoro-17ß-estradiol (FES) noninvasively images tissues expressing estrogen receptors (ERs). FES has undergone extensive clinicopathologic validation for ER-positive breast cancer and in 2020 received FDA approval for clinical use as an adjunct to biopsy in patients with recurrent or metastatic ER-positive breast cancer. Clinical use of FES PET/CT is increasing but is not widespread in the United States. This AJR Expert Panel Narrative Review explores the present status and future directions of FES PET/CT, including image interpretation, existing and emerging uses, knowledge gaps, and current controversies. Specific controversies discussed include whether both FES PET/CT and FDG PET/CT are warranted in certain scenarios, whether further workup is required after negative FES PET/CT results, whether FES PET/CT findings should inform endocrine therapy selection, and whether immunohistochemistry should remain the stand-alone reference standard for determining ER status for all breast cancers. Consensus opinions from the panel include agreement with the appropriate clinical uses of FES PET/CT published by a multidisciplinary expert work group in 2023, anticipated expanded clinical use of FES PET/CT for staging ER-positive invasive lobular carcinomas and low-grade invasive ductal carcinomas pending ongoing clinical trial results, and the need for further research regarding the use of FES PET/CT for nonbreast malignancies expressing ER.

Abbreviated Breast MRI for Supplemental Screening in Patients With Dense Breasts: Comparison of Baseline Versus Subsequent-Round Examinations.

BACKGROUND. Abbreviated breast MRI (AB-MRI) achieves a higher cancer detection rate (CDR) than digital breast tomosynthesis when applied for baseline (i.e., first-round) supplemental screening of individuals with dense breasts. Limited literature has evaluated subsequent (i.e., sequential) AB-MRI screening rounds. OBJECTIVE. This study aimed to compare outcomes between baseline and subsequent rounds of screening AB-MRI in individuals with dense breasts who otherwise had an average risk for breast cancer. METHODS. This retrospective study included patients with dense breasts who otherwise had an average risk for breast cancer and underwent AB-MRI for supplemental screening between December 20, 2016, and May 10, 2023. The clinical interpretations and results of recommended biopsies for AB-MRI examinations were extracted from the EMR. Baseline and subsequent-round AB-MRI examinations were compared. RESULTS. The final sample included 2585 AB-MRI examinations (2007 baseline and 578 subsequent-round examinations) performed for supplemental screening of 2007 women (mean age, 57.1 years old) with dense breasts. Of 2007 baseline examinations, 1658 (82.6%) were assessed as BI-RADS category 1 or 2, 171 (8.5%) as BI-RADS category 3, and 178 (8.9%) as BI-RADS category 4 or 5. Of 578 subsequent-round examinations, 533 (92.2%) were assessed as BI-RADS category 1 or 2, 20 (3.5%) as BI-RADS category 3, and 25 (4.3%) as BI-RADS category 4 or 5 (p < .001). The abnormal interpretation rate (AIR) was 17.4% (349/2007) for baseline examinations versus 7.8% (45/578) for subsequent-round examinations (p < .001). For baseline examinations, PPV2 was 21.3% (38/178), PPV3 was 26.6% (38/143), and the CDR was 18.9 cancers per 1000 examinations (38/2007). For subsequent-round examinations, PPV2 was 28.0% (7/25) (p = .45), PPV3 was 29.2% (7/24) (p = .81), and the CDR was 12.1 cancers per 1000 examinations (7/578) (p = .37). All 45 cancers diagnosed by baseline or subsequent-round AB-MRI were stage 0 or 1. Seven cancers diagnosed by subsequent-round AB-MRI had a mean interval of 872 ± 373 (SD) days since prior AB-MRI and node-negative status at surgical axillary evaluation; six had an invasive component, all measuring 1.2 cm or less. CONCLUSION. Subsequent rounds of AB-MRI screening of individuals with dense breasts had lower AIR than baseline examinations while maintaining a high CDR. All cancers detected by subsequent-round examinations were early-stage node-negative cancers. CLINICAL IMPACT. The findings support sequential AB-MRI for supplemental screening in individuals with dense breasts. Further investigations are warranted to optimize the screening interval.

18F-Fluoroestradiol: Current Applications and Future Directions.

In the United States, breast cancer is the second leading cause of cancer death in all women and the leading cause of cancer death in Black women. The breast cancer receptor profile, assessed with immunohistochemical staining of tissue samples, allows prediction of outcomes and direction of patient treatment. Approximately 80% of newly diagnosed breast cancers are hormone receptor (HR) positive, which is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positive. Patients with ER-positive disease can be treated with therapies targeting the ER; however, the assessment of ER expression with immunohistochemical staining of biopsy specimens has several limitations including sampling error, false-negative results, challenging or inaccessible biopsy sites, and the inability to synchronously and serially assess all metastatic sites to identify spatial and/or temporal ER heterogeneity. In May 2020, after decades of research, the U.S. Food and Drug Administration approved the PET radiotracer fluorine 18 (18F) fluoroestradiol (FES) for clinical use in patients with ER-positive recurrent or metastatic breast cancer as an adjunct to biopsy. FES binds to the ER in the nucleus of ER-expressing cells, enabling whole-body in vivo assessment of ER expression. This article is focused on the approved uses of FES in the United States, including identification of a target lesion for confirmatory biopsy, in vivo assessment of biopsy-proven ER-positive disease, and evaluation of spatial and temporal ER heterogeneity. FES is an example of precision medicine that has been leveraged to optimize the care of patients with breast cancer. © RSNA, 2023 See the invited commentary by Fowler in this issue. Quiz questions for this article are available through the Online Learning Center.

Molecular Imaging of Steroid Receptors in Breast Cancer.

ABSTRACT: Steroid receptors regulate gene expression for many important physiologic functions and pathologic processes. Receptors for estrogen, progesterone, and androgen have been extensively studied in breast cancer, and their expression provides prognostic information as well as targets for therapy. Noninvasive imaging utilizing positron emission tomography and radiolabeled ligands targeting these receptors can provide valuable insight into predicting treatment efficacy, staging whole-body disease burden, and identifying heterogeneity in receptor expression across different metastatic sites. This review provides an overview of steroid receptor imaging with a focus on breast cancer and radioligands for estrogen, progesterone, and androgen receptors.

Theranostics in Neuroendocrine Tumors.

ABSTRACT: Neuroendocrine tumors (NETs) are rare tumors that develop from cells of the neuroendocrine system and can originate in multiple organs and tissues such as the bowels, pancreas, adrenal glands, ganglia, thyroid, and lungs. This review will focus on gastroenteropancreatic NETs (more commonly called NETs) characterized by frequent somatostatin receptor (SSTR) overexpression and pheochromocytomas/paragangliomas (PPGLs), which typically overexpress norepinephrine transporter. Advancements in SSTR-targeted imaging and treatment have revolutionized the management of patients with NETs. This comprehensive review delves into the current practice, discussing the use of the various Food and Drug Administration-approved SSTR-agonist positron emission tomography tracers and the predictive imaging biomarkers, and elaborating on 177Lu-DOTATATE peptide receptor radionuclide therapy including the evolving areas of posttherapy imaging practices and peptide receptor radionuclide therapy retreatment. SSTR-targeted imaging and therapy can also be used in patients with PPGL; however, this patient population has demonstrated the best outcomes from norepinephrine transporter-targeted therapy with 131I-metaiodobenzylguanidine. Metaiodobenzylguanidine theranostics for PPGL will be discussed, noting that in 2024 it became commercially unavailable in the United States. Therefore, the use and reported success of SSTR theranostics for PPGL will also be explored.

PET Imaging of Metabolism, Perfusion, and Hypoxia: FDG and Beyond.

ABSTRACT: Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and guide targeted treatment.

Pembrolizumab-induced vasculitis demonstrated by FDG-PET/CT.

A 76-year-old man with a history of malignant pleural mesothelioma treated with pembrolizumab underwent FDG-PET/CT for restaging. The images demonstrated FDG uptake overlying the right hepatic and splenic artery, which were new from the previous FDG-PET/CT 2.5 years prior before the patient started pembrolizumab, suspicious for vasculitis. A follow-up MRI supported the diagnosis with evidence of celiac, splenic, common hepatic, and right hepatic artery involvement. Pembrolizumab was discontinued and the patient received a short course of oral glucocorticoids. Subsequent FDG-PET/CT performed 14 months after initiation of treatment for vasculitis demonstrated resolution of vasculitis. Immune checkpoint inhibitors can cause vasculitis, which can be recognized on FDG-PET/CT and lead to appropriate treatment.

PET Imaging of Breast Cancer: Current Applications and Future Directions.

As molecular imaging use expands for patients with breast cancer, it is important for breast radiologists to have a basic understanding of molecular imaging, including PET. Although breast radiologists may not directly interpret such studies, basic knowledge of molecular imaging will enable the radiologist to better direct diagnostic workup of patients as well as discuss diagnostic imaging with the patient and other treating physicians. Several new tracers are now available to complement imaging glucose metabolism with FDG. Because it provides a noninvasive assessment of disease status across the whole body, PET offers specific advantages over tissue-based assays. Paired with targeted therapy, molecular imaging has the potential to guide personalized treatment of breast cancer, including guiding dosing during drug trials as well as predicting and assessing clinical response. This review discusses the current established applications of FDG, which remains the most widely used PET radiotracer for malignancy, including breast cancer, and highlights potential areas for expanded use based on recent research. It also summarizes research to date on the U.S. Food and Drug Administration (FDA)-approved PET tracer 16α-18F-fluoro-17ß-estradiol (FES), which targets ER, including the current guidelines from the Society of Nuclear Medicine and Molecular Imaging on the appropriate use of FES-PET/CT for breast cancer as well as areas of active investigation for other potential applications. Finally, the review highlights several of the most promising novel PET tracers that are poised for clinical translation in the near future.

Upstaging of Invasive Lobular Cancer With FES PET/CT.

ABSTRACT: A 78-year-old woman diagnosed with left breast invasive lobular carcinoma with left axillary nodal metastasis underwent 18 F-fluoroestradiol (FES) PET/CT imaging for further evaluation of indeterminate right axillary lymph nodes seen on staging 18 F-FDG PET/CT. 18 F-FES PET/CT revealed abnormal 18 F-FES-avid right axillary and bilateral cervical nodes, subsequently biopsy-proven metastases, upstaging the patient from stage II to IV and greatly changing patient management. This case demonstrates the value of 18 F-FES PET/CT in accurately staging metastatic invasive lobular carcinoma at diagnosis, an indication for which 18 F-FES PET/CT "may be appropriate" per current Society of Nuclear Medicine and Molecular Imaging guidelines.

Update on 18F-Fluoroestradiol.

18F-16α-Fluoroestradiol (18F-FES) is a radiolabeled estrogen analogue positron emission tomography (PET) imaging agent that binds to the estrogen receptor (ER) in the nucleus of ER-expressing cells. Proof-of-concept studies of 18F-FES demonstrated expected correlation between tumoral 18F-FES-positivity on PET-imaging and ER+ status assessed on biopsy samples by radioligand binding and immunohistochemistry. After decades of study, 18F-FES PET/CT gained clinical approval in 2016 in France and 2020 in the United States for use in patients with ER+ metastatic or recurrent breast cancer. ER+ as assessed by 18F-FES PET/CT has been shown to serve as a biomarker, identifying metastatic breast cancer patients who may respond to endocrine therapy and those who are unlikely to respond. In 2023, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published Appropriate Use Criteria for 18F-FES PET/CT, identifying four indications in which use of 18F-FES PET/CT was "appropriate": (1) To assess functional ER status in metastatic lesions unfavorable to biopsy or when biopsy is nondiagnostic, (2) To detect ER status when other imaging tests are equivocal or suspicious, and at (3) initial diagnosis of metastatic disease or (4) progression of metastatic disease, for considering endocrine therapy. This article reviews the foundations of 18F-FES imaging, including normal distribution, false positives, and false negatives, and describes the most up-to-date clinical uses as well as emerging research in breast cancer and other patient populations.

Feasibility and Accuracy of Ultrasound-Guided Core Needle Biopsy for Nipple Lesions: A Pilot Study.

BACKGROUND: Due to the superficial location, suspicious findings of the nipple-areolar complex (NAC) are not amenable to stereotactic or MRI-guided sampling and have historically necessitated surgical biopsy or skin-punch biopsy. There are limited reports of US-guided core biopsy of the nipple (US-CBN). OBJECTIVE: We report our nearly 3-year pilot experience with US-CBN at an academic breast imaging center. METHODS: An institutional review board-exempt and HIPAA-compliant retrospective review was performed. We assessed patient demographics, breast imaging characteristics, procedural data, pathology, and outcomes. RESULTS: Nine female patients aged 27 to 64 underwent US-CBN from January 2021 to October 2023. Initial imaging abnormalities included abnormal MRI enhancement, mammographic calcifications, and sonographic masses. After initial or second-look US, all imaging findings had sonographic correlates for biopsy specimens, the majority of which were sonographic masses (8/9). US-CBN was performed by 6 breast radiologists using a variety of devices. All biopsy specimen results were concordant with sonographic abnormalities, although 1 was considered discordant from the initial abnormality seen on MRI. There were no complications, and discomfort during the procedure was well-treated. Two patients (22%, 2/9) were diagnosed with malignancy. CONCLUSION: This pilot study demonstrated that US-CBN can be performed by a breast radiologist for definitive diagnosis of suspicious nipple abnormalities seen on breast imaging, avoiding surgery, and maintaining nipple integrity. In our population, 22% (2/9) of US-CBNs revealed malignancy.

Maximizing Mentorship Throughout Your Breast Imaging Career.

Unlike many other subspecialties in radiology, breast radiologists practice in a patient-facing and interdisciplinary environment where team building, communication, and leadership skills are critical. Although breast radiologists can improve these skills over time, strong mentorship can accelerate this process, leading to a more successful and satisfying career. In addition to providing advice, insight, feedback, and encouragement to mentees, mentors help advance the field of breast radiology by contributing to the development of the next generation of leaders. During the mentorship process, mentors continue to hone their listening, problem-solving, and networking skills, which in turn creates a more supportive and nurturing work environment for the entire breast care team. This article reviews important mentorship skills that are essential for all breast radiologists. Although some of the principles apply to all mentoring relationships, ensuring that every breast radiologist has the skills to be both an effective mentor and mentee is key to the future of the profession.

Male Breast Imaging Uncovers Lymphoma.

Background: A 36-year-old man presented with a palpable mass in the right axillary tail for four months. He was referred to breast imaging for diagnostic work-up. He does not have a family history of breast cancer. Aim: Breast imaging work-up for diagnosis of lymphoma is unusual and even more so in a male patient. Case presentation: After Breast Mammography and targeted Ultrasound of the axillary tail and axilla, Magnetic Resonance Imaging (MRI) was performed and suggested lymphoproliferative disorder. Excisional biopsy was performed after the breast MRI with removal of right axillary tissue measuring 15.0 × 5.5 × 2.0 cm and containing multiple lymph nodes. Excisional biopsy revealed Classic Hodgkin lymphoma of nodular sclerosis type. Staging [18F]-FDG PET/CT revealed early stage of disease. Conclusion: The presentation and diagnostic elements of Hodgkin Lymphoma are described in this case report emphasizing the significance of breast imaging in multiple populations.

Mammographic Breast Density: Current Assessment Methods, Clinical Implications, and Future Directions.

Mammographic breast density is widely accepted as an independent risk factor for the development of breast cancer. In addition, because dense breast tissue may mask breast malignancies, breast density is inversely related to the sensitivity of screening mammography. Given the risks associated with breast density, as well as ongoing efforts to stratify individual risk and personalize breast cancer screening and prevention, numerous studies have sought to better understand the factors that impact breast density, and to develop and implement reproducible, quantitative methods to assess mammographic density. Breast density assessments have been incorporated into risk assessment models to improve risk stratification. Recently, novel techniques for analyzing mammographic parenchymal complexity, or texture, have been explored as potential means of refining mammographic tissue-based risk assessment beyond breast density.

PSMA Uptake in a Subdural Hematoma.

ABSTRACT: An 81-year-old man with known metastatic prostate cancer with recent biochemical progression underwent a PSMA PET/CT ( 18 F-piflufolastat) for restaging. Review of the images demonstrated an acute or chronic left cerebral convexity subdural hematoma on CT with corresponding radiotracer activity throughout the collection on PET. Analysis of the patient's prior imaging showed that this subdural hematoma had significantly increased in size when compared with a head CT obtained 2 months prior. The patient was referred to a nearby emergency department and underwent repeat imaging and subdural drain placement. Unfortunately, the patient died secondary to rapid reaccumulation of subdural blood products after intervention.

Widespread micronodular hepatic metastases of neuroendocrine tumor detected by [68Ga]DOTATATE PET/CT.

Neuroendocrine tumors (NET) encompass a diverse, heterogeneous group of neoplasms that originate from the secretory cells of the neuroendocrine system. These neoplasms typically express the somatostatin receptor (SSTR), which can be targeted by molecular agents for imaging and therapy. This is particularly advantageous for imaging NETs that are indolent, slow-growing, and less well detected by [18F]FDG and for the detection of occult disease not easily identified by anatomic imaging. Herein, we present a case in which [68Ga]DOTATATE PET/CT was used to diagnose the etiology of biochemical recurrence in NET that was not apparent on MRI. The importance of understanding deviations from the normal biodistribution of the radiotracer is emphasized as key in interpreting nuclear medicine studies and establishing the diagnosis. Imaging the SSTR is of particular interest given the recent FDA approval of [68Cu]DOTATATE as a new and possibly more available molecular radiotracer.

Metabolic Positron Emission Tomography in Breast Cancer.

Metabolic PET, most commonly 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT), has had a major impact on the imaging of breast cancer and can have important clinical applications in appropriate patients. While limited for screening, FDG PET/CT outperforms conventional imaging in locally advanced breast cancer. FDG PET/CT is more sensitive than conventional imaging in assessing treatment response, accurately predicting complete response or nonresponse in early-stage cases. It also aids in determining disease extent and treatment response in the metastatic setting. Further research, including randomized controlled trials with FDG and other metabolic agents such as fluciclovine, is needed for optimal breast cancer imaging.

Other Novel PET Radiotracers for Breast Cancer.

Many novel PET radiotracers have demonstrated potential use in breast cancer. Although not currently approved for clinical use in the breast cancer population, these innovative imaging agents may one day play a role in the diagnosis, staging, management, and even treatment of breast cancer.

Prediction of 177Lu-DOTATATE Therapy Outcomes in Neuroendocrine Tumor Patients Using Semi-Automatic Tumor Delineation on 68Ga-DOTATATE PET/CT.

BACKGROUND: Treatment of metastatic neuroendocrine tumors (NET) with 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) results in favorable response only in a subset of patients. We investigated the prognostic value of quantitative pre-treatment semi-automatic 68Ga-DOTATATE PET/CT analysis in NET patients treated with PRRT. METHODS: The medical records of 94 NET patients who received at least one cycle of PRRT at a single institution were retrospectively reviewed. On each pre-treatment 68Ga-DOTATATE PET/CT, the total tumor volume (TTV), maximum tumor standardized uptake value for the patient (SUVmax), and average uptake in the lesion with the lowest radiotracer uptake (SUVmin) were determined with a semi-automatic tumor delineation method. Progression-free survival (PFS) and overall survival (OS) among the patients were compared based on optimal cutoff values for the imaging parameters. RESULTS: On Kaplan-Meier analysis and univariate Cox regression, significantly shorter PFS was observed in patients with lower SUVmax, lower SUVmin, and higher TTV. On multivariate Cox regression, lower SUVmin and higher TTV remained predictive of shorter PFS. Only higher TTV was found to be predictive of shorter OS on Kaplan-Meier and Cox regression analyses. In a post hoc Kaplan-Meier analysis, patients with at least one high-risk feature (low SUVmin or high TTV) showed shorter PFS and OS, which may be the most convenient parameter to measure in clinical practice. CONCLUSIONS: The tumor volume and lowest lesion uptake on 68Ga-DOTATATE PET/CT can predict disease progression following PRRT in NET patients, with the former also predictive of overall survival. NET patients at risk for poor outcomes following PRRT can be identified with semi-automated quantitative analysis of 68Ga-DOTATATE PET/CT.

Introduction to Radiopharmaceutical Therapy.

Radiopharmaceutical therapy (RPT) is a precision medicine modality in which administered radionuclides are preferentially taken up by target cells or nearby tissues and emit radiation from within the patient, leading to targeted cell death. Many radiopharmaceuticals are currently FDA-approved with multiple others under investigation. This manuscript will give a broad introduction to RPT including how to become an authorized user, patient evaluation pre- and post-treatment, dosing strategies, and the physical spaces needed to run an RPT clinic. RPT may seem daunting at first but is feasible. As approved radiopharmaceuticals and RPT uses increase, patients will benefit from greater access to these new and evolving treatment options.