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.

An Image-Rich Educational Review of Breast Pain.

Breast pain is extremely common, occurring in 70% to 80% of women. Most cases of breast pain are from physiologic or benign causes, and patients should be reassured and offered treatment strategies to alleviate symptoms, often without diagnostic imaging. A complete clinical history and physical examination is key for distinguishing intrinsic breast pain from extramammary pain. Breast pain without other suspicious symptoms and with a negative history and physical examination result is rarely associated with malignancy, although it is a common reason for women to undergo diagnostic imaging. When breast imaging is indicated, guidelines according to the American College of Radiology Appropriateness Criteria should be followed as to whether mammography, US, or both are recommended. This review article summarizes the initial clinical evaluation of breast pain and evidence-based guidelines for imaging. Additionally, the article reviews cyclical and noncyclical breast pain and provides an image-rich discussion of the imaging presentation and management of benign and malignant breast pain etiologies.

Multimodality imaging review of metastatic melanoma involving the breast.

Melanoma is among the most commonly reported non-mammary primary tumors to metastasize to the breast. Unfortunately, evidence of melanoma metastasis to any site portends a poor prognosis. Imaging studies can be useful in the early detection of metastatic melanoma which is essential for appropriate management of this disease. There have been very few previous studies on the imaging findings of metastatic melanoma especially across multiple imaging modalities. This review aims to describe these imaging features seen on mammography, ultrasound, magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography computed tomography (FDG PET/CT) using three case examples. Our findings, consistent with previous studies, describe melanoma metastases to the breast as largely non-specific, round or oval masses with circumscribed margins and homogeneous internal enhancement.

Attenuation correction and truncation completion for breast PET/MR imaging using deep learning.

Objective. Simultaneous PET/MR scanners combine the high sensitivity of MR imaging with the functional imaging of PET. However, attenuation correction of breast PET/MR imaging is technically challenging. The purpose of this study is to establish a robust attenuation correction algorithm for breast PET/MR images that relies on deep learning (DL) to recreate the missing portions of the patient's anatomy (truncation completion), as well as to provide bone information for attenuation correction from only the PET data.Approach. Data acquired from 23 female subjects with invasive breast cancer scanned with18F-fluorodeoxyglucose PET/CT and PET/MR localized to the breast region were used for this study. Three DL models, U-Net with mean absolute error loss (DLMAE) model, U-Net with mean squared error loss (DLMSE) model, and U-Net with perceptual loss (DLPerceptual) model, were trained to predict synthetic CT images (sCT) for PET attenuation correction (AC) given non-attenuation corrected (NAC) PETPET/MRimages as inputs. The DL and Dixon-based sCT reconstructed PET images were compared against those reconstructed from CT images by calculating the percent error of the standardized uptake value (SUV) and conducting Wilcoxon signed rank statistical tests.Main results. sCT images from the DLMAEmodel, the DLMSEmodel, and the DLPerceptualmodel were similar in mean absolute error (MAE), peak-signal-to-noise ratio, and normalized cross-correlation. No significant difference in SUV was found between the PET images reconstructed using the DLMSEand DLPerceptualsCTs compared to the reference CT for AC in all tissue regions. All DL methods performed better than the Dixon-based method according to SUV analysis.Significance. A 3D U-Net with MSE or perceptual loss model can be implemented into a reconstruction workflow, and the derived sCT images allow successful truncation completion and attenuation correction for breast PET/MR images.

Evaluation of a Deep Learning Reconstruction for High-Quality T2-Weighted Breast Magnetic Resonance Imaging.

Deep learning (DL) reconstruction techniques to improve MR image quality are becoming commercially available with the hope that they will be applicable to multiple imaging application sites and acquisition protocols. However, before clinical implementation, these methods must be validated for specific use cases. In this work, the quality of standard-of-care (SOC) T2w and a high-spatial-resolution (HR) imaging of the breast were assessed both with and without prototype DL reconstruction. Studies were performed using data collected from phantoms, 20 retrospectively collected SOC patient exams, and 56 prospectively acquired SOC and HR patient exams. Image quality was quantitatively assessed via signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and edge sharpness. Qualitatively, all in vivo images were scored by either two or four radiologist readers using 5-point Likert scales in the following categories: artifacts, perceived sharpness, perceived SNR, and overall quality. Differences in reader scores were tested for significance. Reader preference and perception of signal intensity changes were also assessed. Application of the DL resulted in higher average SNR (1.2-2.8 times), CNR (1.0-1.8 times), and image sharpness (1.2-1.7 times). Qualitatively, the SOC acquisition with DL resulted in significantly improved image quality scores in all categories compared to non-DL images. HR acquisition with DL significantly increased SNR, sharpness, and overall quality compared to both the non-DL SOC and the non-DL HR images. The acquisition time for the HR data only required a 20% increase compared to the SOC acquisition and readers typically preferred DL images over non-DL counterparts. Overall, the DL reconstruction demonstrated improved T2w image quality in clinical breast MRI.

Breast Imaging and Intervention during Pregnancy and Lactation.

Physiologic changes that occur in the breast during pregnancy and lactation create challenges for breast cancer screening and diagnosis. Despite these challenges, imaging evaluation should not be deferred, because delayed diagnosis of pregnancy-associated breast cancer contributes to poor outcomes. Both screening and diagnostic imaging can be safely performed using protocols based on age, breast cancer risk, and whether the patient is pregnant or lactating. US is the preferred initial imaging modality for the evaluation of clinical symptoms in pregnant women, followed by mammography if the US findings are suspicious for malignancy or do not show the cause of the clinical symptom. Breast MRI is not recommended during pregnancy because of the use of intravenous gadolinium-based contrast agents. Diagnostic imaging for lactating women is the same as that for nonpregnant nonlactating individuals, beginning with US for patients younger than 30 years old and mammography followed by US for patients aged 30 years and older. MRI can be performed for high-risk screening and local-regional staging in lactating women. The radiologist may encounter a wide variety of breast abnormalities, some specific to pregnancy and lactation, including normal physiologic changes, benign disorders, and malignant neoplasms. Although most masses encountered are benign, biopsy should be performed if the imaging characteristics are suspicious for cancer or if the finding does not resolve after a short period of clinical follow-up. Knowledge of the expected imaging appearance of physiologic changes and common benign conditions of pregnancy and lactation is critical for differentiating these findings from pregnancy-associated breast cancer. ©RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Molecular Classification of Breast Cancer.

Breast carcinomas classified based on traditional morphologic assessment provide useful prognostic information. Although morphology is still the gold standard of classification, recent advances in molecular technologies have enabled the classification of these tumors into four distinct subtypes based on its intrinsic molecular profile that provide both predictive and prognostic information. This article describes the association between the different molecular subtypes with the histologic subtypes of breast cancer and illustrates how these subtypes may affect the appearance of tumors on imaging studies.

Estrogen Receptor-Targeted and Progesterone Receptor-Targeted PET for Patients with Breast Cancer.

Estrogen receptor (ER)-targeted imaging with 16α-18F-fluoro-17ß-fluoroestradiol (18F-FES) has multiple proven clinical applications for patients with ER-positive breast cancer, including helping to select optimal patients for endocrine therapies, assessing ER status in lesions that are difficult to biopsy, and evaluating lesions with inconclusive results on other imaging tests. This has led to US Food and Drug Administration approval of 18F-FES PET for patients with ER-positive breast cancer. Newer progesterone receptor-targeted imaging agents are in clinical trials.

Breast Cancer Screening and Diagnosis: Recent Advances in Imaging and Current Limitations.

Breast cancer detection has a significant impact on population health. Although there are many breast imaging modalities, mammography is the predominant tool for breast cancer screening. The introduction of digital breast tomosynthesis to mammography has contributed to increased cancer detection rates and decreased recall rates. In average-risk women, starting annual screening mammography at age 40 years has demonstrated the highest mortality reduction. In intermediate- and high-risk women as well as in those with dense breasts, additional modalities, including MRI, ultrasound, and molecular breast imaging, can also be considered for adjunct screening to improve the detection of mammographically occult malignancy.

Molecular Breast Imaging and Positron Emission Mammography.

There is growing interest in application of functional imaging modalities for adjunct breast imaging due to their unique ability to evaluate molecular/pathophysiologic changes, not visible by standard anatomic breast imaging. This has led to increased use of nuclear medicine dedicated breast-specific single photon and coincidence imaging systems for multiple indications, such as supplemental screening, staging of newly diagnosed breast cancer, evaluation of response to neoadjuvant treatment, diagnosis of local disease recurrence in the breast, and problem solving. Studies show that these systems maybe especially useful for specific subsets of patients, not well served by available anatomic breast imaging modalities.

Summary: Appropriate Use Criteria for Estrogen Receptor-Targeted PET Imaging with 16α-18F-Fluoro-17ß-Fluoroestradiol.

PET imaging with 16α-18F-fluoro-17ß-fluoroestradiol (18F-FES), a radiolabeled form of estradiol, allows whole-body, noninvasive evaluation of estrogen receptor (ER). 18F-FES is approved by the U.S. Food and Drug Administration as a diagnostic agent "for the detection of ER-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer." The Society of Nuclear Medicine and Molecular Imaging (SNMMI) convened an expert work group to comprehensively review the published literature for 18F-FES PET in patients with ER-positive breast cancer and to establish appropriate use criteria (AUC). The findings and discussions of the SNMMI 18F-FES work group, including example clinical scenarios, were published in full in 2022 and are available at https://www.snmmi.org/auc Of the clinical scenarios evaluated, the work group concluded that the most appropriate uses of 18F-FES PET are to assess ER functionality when endocrine therapy is considered either at initial diagnosis of metastatic breast cancer or after progression of disease on endocrine therapy, the ER status of lesions that are difficult or dangerous to biopsy, and the ER status of lesions when other tests are inconclusive. These AUC are intended to enable appropriate clinical use of 18F-FES PET, more efficient approval of FES use by payers, and promotion of investigation into areas requiring further research. This summary includes the rationale, methodology, and main findings of the work group and refers the reader to the complete AUC document.

Novel Prognostic Staging System for Patients With De Novo Metastatic Breast Cancer.

PURPOSE: Given the heterogeneity and improvement in outcomes for metastatic breast cancer (MBC), we developed a staging system that refines prognostic estimates for patients with metastatic cancer at the time of initial diagnosis, de novo MBC (dnMBC), on the basis of survival outcomes and disease-related variables. METHODS: Patients with dnMBC (2010-2016) were selected from the National Cancer Database (NCDB). Recursive partitioning analysis (RPA) was used to group patients with similar overall survival (OS) on the basis of clinical T category, grade, estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2, histology, organ system site of metastases (bone-only, brain-only, visceral), and number of organ systems involved. Three-year OS rates were used to assign a final stage: IVA: >70%, IVB: 50%-70%, IVC: 25 to <50%, and IVD: <25%. Bootstrapping was applied with 1,000 iterations, and final stage assignments were made based on the most commonly occurring assignment. Unadjusted OS was estimated. Validation analyses were conducted using SEER and NCDB. RESULTS: At a median follow-up of 52.9 months, the median OS of the original cohort (N = 42,467) was 35.4 months (95% CI, 34.8 to 35.9). RPA stratified patients into 53 groups with 3-year OS rates ranging from 73.5% to 5.7%; these groups were amalgamated into four stage groups: 3-year OS, A = 73.2%, B = 61.9%, C = 40.1%, and D = 17% (log-rank P < .001). After bootstrapping, the survival outcomes for the four stages remained significantly different (log-rank P < .001). This staging system was then validated using SEER data (N = 20,469) and a separate cohort from the NCDB (N = 7,645) (both log-rank P < .001). CONCLUSION: Our findings regarding the heterogeneity in outcomes for patients with dnMBC could guide future revisions of the current American Joint Committee on Cancer staging guidelines for patients with newly diagnosed stage IV disease. Our findings should be independently confirmed.

Progesterone Receptor Gene Polymorphisms and Breast Cancer Risk.

The objective of this systematic review was to investigate the association between polymorphisms in the progesterone receptor gene (PGR) and breast cancer risk. A search of PubMed, Scopus, and Web of Science databases was performed in November 2021. Study characteristics, minor allele frequencies, genotype frequencies, and odds ratios were extracted. Forty studies met the eligibility criteria and included 75 032 cases and 89 425 controls. Of the 84 PGR polymorphisms reported, 7 variants were associated with breast cancer risk in at least 1 study. These polymorphisms included an Alu insertion (intron 7) and rs1042838 (Val660Leu), also known as PROGINS. Other variants found to be associated with breast cancer risk included rs3740753 (Ser344Thr), rs10895068 (+331G/A), rs590688 (intron 2), rs1824128 (intron 3), and rs10895054 (intron 6). Increased risk of breast cancer was associated with rs1042838 (Val660Leu) in 2 studies, rs1824128 (intron 3) in 1 study, and rs10895054 (intron 6) in 1 study. The variant rs3740753 (Ser344Thr) was associated with decreased risk of breast cancer in 1 study. Mixed results were reported for rs590688 (intron 2), rs10895068 (+331G/A), and the Alu insertion. In a pooled analysis, the Alu insertion, rs1042838 (Val660Leu), rs3740753 (Ser344Thr), and rs10895068 (+331G/A) were not associated with breast cancer risk. Factors reported to contribute to differences in breast cancer risk associated with PGR polymorphisms included age, ethnicity, obesity, and postmenopausal hormone therapy use. PGR polymorphisms may have a small contribution to breast cancer risk in certain populations, but this is not conclusive with studies finding no association in larger, mixed populations.

Nuclear Receptor Imaging In Vivo-Clinical and Research Advances.

Nuclear receptors are transcription factors that function in normal physiology and play important roles in diseases such as cancer, inflammation, and diabetes. Noninvasive imaging of nuclear receptors can be achieved using radiolabeled ligands and positron emission tomography (PET). This quantitative imaging approach can be viewed as an in vivo equivalent of the classic radioligand binding assay. A main clinical application of nuclear receptor imaging in oncology is to identify metastatic sites expressing nuclear receptors that are targets for approved drug therapies and are capable of binding ligands to improve treatment decision-making. Research applications of nuclear receptor imaging include novel synthetic ligand and drug development by quantifying target drug engagement with the receptor for optimal therapeutic drug dosing and for fundamental research into nuclear receptor function in cells and animal models. This mini-review provides an overview of PET imaging of nuclear receptors with a focus on radioligands for estrogen receptor, progesterone receptor, and androgen receptor and their use in breast and prostate cancer.

Molecular Breast Imaging in the Screening Setting.

Early detection of breast cancer through screening mammography saves lives. However, the sensitivity of mammography for breast cancer detection is reduced in women with dense breast tissue. Imaging modalities for supplemental breast cancer screening include MRI, whole breast US, contrast-enhanced mammography, and molecular breast imaging (MBI). Molecular breast imaging with 99mTc-sestamibi is a functional imaging test to identify metabolically active areas in the breast with positioning analogous to mammography. Since 2011, there have been six large, published studies of screening MBI as a supplement to mammography involving over 6000 women from four different institutions. A multicenter, prospective clinical trial of 3000 women comparing breast cancer detection using screening digital breast tomosynthesis alone or in combination with MBI recently completed enrollment. This review focuses on the current evidence of MBI use for supplemental breast cancer screening, the strengths and limitations of MBI, and recent technological advances.

Gadolinium-based contrast agent attenuation does not impact PET quantification in simultaneous dynamic contrast enhanced breast PET/MR.

PURPOSE: Simultaneous PET/MR imaging involves injection of a radiopharmaceutical and often also includes administration of a gadolinium-based contrast agent (GBCA). Phantom model studies indicate that attenuation of annihilation photons by GBCAs does not bias quantification metrics of PET radiopharmaceutical uptake. However, a direct comparison of attenuation-corrected PET values before and after administration of GBCA has not been performed in patients imaged with simultaneous dynamic PET/MR. The purpose of this study was to investigate the attenuating effect of GBCAs on standardized uptake value (SUV) quantification of 18 F-fluorodeoxyglucose (FDG) uptake in invasive breast cancer and normal tissues using simultaneous PET/MR. METHODS: The study included 13 women with newly diagnosed invasive breast cancer imaged using simultaneous dedicated prone breast PET/MR with FDG. PET data collection and two-point Dixon-based MR attenuation correction sequences began simultaneously before the administration of GBCA to avoid a potential impact of GBCA on the attenuation correction map. A standard clinical dose of GBCA was intravenously administered for the dynamic contrast enhanced MR sequences obtained during the simultaneous PET data acquisition. PET data were dynamically reconstructed into 60 frames of 30 s each. Three timing windows were chosen consisting of a single frame (30 s), two frames (60 s), or four frames (120 s) immediately before and after contrast administration. SUVmax and SUVmean of the biopsy-proven breast malignancy, fibroglandular tissue of the contralateral normal breast, descending aorta, and liver were calculated prior to and following GBCA administration. Percent change in the SUV metrics were calculated to test for a statistically significant, non-zero percent change using Wilcoxon signed-rank tests. RESULTS: No statistical change in SUVmax or SUVmean was found for the breast malignancies or normal anatomical regions during the timing windows before and after GBCA administration. CONCLUSIONS: GBCAs do not significantly impact the results of PET quantification by means of additional attenuation. However, GBCAs may still affect quantification by affecting MR acquisitions used for MR-based attenuation correction which this study did not address. Corrections to account for attenuation due to clinical concentrations of GBCAs are not necessary in simultaneous PET/MR examinations when MR-based attenuation correction sequences are performed prior to GBCA administration.

PET Imaging of Estrogen Receptors Using 18F-Based Radioligands.

In vivo molecular imaging of estrogen receptor alpha (ER) can be performed via positron emission tomography (PET) using ER-specific radioligands, such as 16α-[18F]fluoro-17ß-estradiol (18F-FES). 18F-FES is a radiopharmaceutical recently approved by the United States Food and Drug Administration for use with PET imaging to detect ER+ lesions in patients with recurrent or metastatic breast cancer as an adjunct to biopsy. 18F-FES PET imaging has been used in clinical studies and preclinical research to assess whole-body ER protein expression and ligand binding function across multiple metastatic sites, to demonstrate inter-tumoral and temporal heterogeneity of ER expression, to quantify the pharmacodynamic effects of ER antagonist treatment, and to predict endocrine therapy response. 18F-FES PET has also been studied for imaging ER in endometrial and ovarian cancer. This chapter details the experimental protocol for 18F-FES PET imaging of ER in preclinical tumor xenograft models. Consistent adherence to key methodologic details will facilitate obtaining meaningful and reproducible 18F-FES PET preclinical imaging results, which could yield additional insight for clinical trials regarding imaging biomarkers and oncologic therapy.

Clinical advances in PET-MRI for breast cancer.

Imaging is paramount for the early detection and clinical staging of breast cancer, as well as to inform management decisions and direct therapy. PET-MRI is a quantitative hybrid imaging technology that combines metabolic and functional PET data with anatomical detail and functional perfusion information from MRI. The clinical applicability of PET-MRI for breast cancer is an active area of research. In this Review, we discuss the rationale and summarise the clinical evidence for the use of PET-MRI in the diagnosis, staging, prognosis, tumour phenotyping, and assessment of treatment response in breast cancer. The continued development and approval of targeted radiopharmaceuticals, together with radiomics and automated analysis tools, will further expand the opportunity for PET-MRI to provide added value for breast cancer imaging and patient care.