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PET/MR imaging of the breast Andrew Sher, J.L. Vercher-Conejero, Raymond F. Muzic Jr., Norbert Avril, Donna Plecha

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Cite this article as: Andrew Sher, J.L. Vercher-Conejero, Raymond F. Muzic Jr., Norbert Avril, Donna Plecha, PET/MR imaging of the breast, Seminar in Roentgenology, http://dx. doi.org/10.1053/j.ro.2014.04.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

PET/MR Imaging of the Breast

Andrew Sher, J.L. Vercher-Conejero, Raymond F. Muzic, Jr., Norbert Avril and Donna Plecha

Department of Radiology University Hospitals Case Medical Center Case Center for Imaging Research Case Western Reserve University Cleveland, OH 44106, USA

Correspondence: Donna Plecha, M.D. Department of Radiology Case Western Reserve University University Hospitals Case Medical Center 11100 Euclid Avenue Cleveland, OH 44106

Words:

4076

Conflict of interest: There is no conflict of interest

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Abstract Breast cancer is one of the most common oncologic entities in the world. Survival is highly dependent on the stage at diagnosis, which in turn determines appropriate therapy. Mammography remains the mainstay of screening. Dynamic contrast enhanced breast MRI (DCE-MRI) and FDG-PET/CT have been added to the repertoire of tools to manage breast cancer patients. DCE-MRI is highly sensitive in detecting primary breast cancer, although not very specific. FDG-PET is highly specific but lacks sensitivity in small breast carcinomas and tumors with low metabolic activity. Recently, whole-body hybrid PET/MR has been developed and is currently being evaluated in clinical practice. Nevertheless, its precise role in imaging primary breast carcinomas has not been determined. This article will describe the current use of DCE-MRI and FDG-PET/CT in breast cancer.

Introduction Despite advances in the diagnosis and treatment of breast cancer it remains a major cause of morbidity and mortality. In the United States, approximately 232,000 new cases of breast cancer and 40,000 cancer deaths are expected in 2013 and one in eight women will develop breast cancer in her lifetime.1 Currently, mammography is the primary method of breast cancer screening,2 however extensive controversy exists regarding the timing, frequency, and schedule of such screening.3 Mammography has its limitations, with reported sensitivities ranging from 30% to 96%4,5 and is influenced by multiple factors including age and breast tissue density.6 Given the known limitations of mammography, alternative modalities have been explored to aid in the diagnosis of breast cancer, including dynamic contract enhanced magnetic resonance tomography (DCE-MRI), whole breast ultrasound and molecular breast imaging using positron emission tomography (PET). FDG-PET/CT has been used in breast cancer patient as a tool to diagnose breast cancer as well as to detect metastasis and recurrence. This article will review the current state of DCE-MRI and FDG-PET/CT in breast cancer patients and then delve into the potential utilization of PET-MR. MRI in Breast Cancer Breast MR imaging was first utilized in clinical practice beginning in the 1990s.7 With improvements in technology and access, there has been a rapid increase in its utilization with a recent study demonstrating a greater than 16-fold increase from 2000 to 2011.7 As a result of its 2  

adaptation and the need for standardization, the first edition of the American College of Radiology Breast Imaging Reporting and Data System MRI lexicon was published in 2003.8 However, the higher cost and lower specificity of breast MRI relative to mammography limits its use to select groups.9 The cost and the benefits of the exam have to be carefully balanced with its potential drawbacks to determine who should undergo the study. Given the physical, psychological and economical costs associated with breast cancer, high standards in MRI imaging are necessary to produce accurate, reproducible, and diagnostic images. Both morphologic and kinetic enhancement characteristics of breast lesions need to be considered. Additionally, the radiologist reading the breast MRI should have experience in the field, as up to a 50% call-back rate has been shown in community practice groups.10,11 Images need to be evaluated for enhancing lesions, and other sequences utilizing subtraction images and fat suppression should be incorporated in an attempt to separate benign from malignant disease. DCE-MRI has been shown to be advantageous for evaluating patients with newly diagnosed breast cancer, for monitoring response to treatment in patients undergoing neoadjuvant therapy, and in evaluating patients with metastatic axillary adenocarcinoma from an occult primary site.12 Cost-based analysis has shown MRI can be cost effective in high-risk groups.3 In contrast, patient stress can occur as a result of the MRI, which demonstrates a higher call-back and biopsy rate than mammography.

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The use of MRI can be divided into screening and

diagnostic purposes such as locoregional staging in newly diagnosed breast cancer. Screening Based on clinical evidence, the American Cancer Society (ACS) recommends the use of breast DCE-MRI for annual screening in high risk patients, defined as those with a lifetime risk of approximately 20-25% or greater, including women with a known or suspected BRCA mutation as well as women who were treated with chest radiation for Hodgkin disease.10 Compared to mammography, MRI has higher sensitivity and identifies smaller tumors. The sensitivity of MRI for malignancy is around 90%, with a specificity approaching 75%.13 Unenhanced MRI is insufficient for the detection of breast cancer14 and DCE-MRI is the standard of care, with enhancement curve characteristics assisting in the identification of malignancy. Despite advances in MR imaging, there remains overlap in benign and malignant contrast enhancement patterns, with benign lesions such as fibroadenomas, fibrocystic changes, and mastitis demonstrating contrast enhancement.13 Such overlap of enhancing features at least partially

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explains the low specificity of MRI breast imaging. Conversely, much value lies in the negative predictive value of a lack of enhancement, which approaches 95%.14 It has been shown that in high risk patients, cancers detected by MRI screening protocols are detected at an earlier stage when compared to those outside such a program.15 The breast cancers found with MRI results in detection of smaller cancers and the occurrence of fewer interval cancers.16 For intermediate and low-risk patients, there is limited evidence regarding the benefit of MRI screening. While the American College of Radiology (ACR) states that MRI may be justified in some women at intermediate risk (15-20%),17 the European Society of Breast Cancer Specialists (EUSOMA) working group of 2010 states that there is insufficient data to reach a conclusion14 and the American Cancer Society states that there is insufficient evidence to recommend for or against MRI screening.10 For average-risk/general population, no available data on screening exists. It has been estimated that given the low yearly incidence of breast cancer in the normal population and the low specificity of MRI, further biopsy or short-term follow-up rates would be increased by a factor of 3-5 compared to screening mammography in this population. As such, both the ACR and ACS currently do not recommend a screening breast MRI for asymptomatic, average-risk women.17,18 Locoregional Staging DCE-MRI may be useful to determine the extent of disease as well as the presence of multifocality and multicentricity in patients diagnosed with invasive carcinoma and ductal carcinoma in situ.18 Multiple meta-analyses and randomized studies have shown DCE-MRI in breast cancer patients to be more sensitive than conventional imaging for local staging, however it has not proven to have a significant benefit on outcome.14 While patients who had DCE-MRI had an increased rate of mastectomies and wider excisions, the rate of incomplete margins and re-excision rates did not change significantly.19,20 However, the reason for mastectomy is often a personal decision and cannot be definitely linked to the results of the DCE-MRI. A subset of patients where DCE-MRI has proven to be beneficial is in patients who present with axillary metastasis with an occult primary tumor not detected by conventional methods, including mammography or ultrasound. Identification of the primary tumor affects treatment planning, potentially resulting in a conventional lumpectomy and radiation to the primary tumor site while avoiding radiation of the whole breast. A meta-analysis of eight studies demonstrated a pooled sensitivity of 90% for occult tumor presenting as axillary metastasis.21 Although breast cancer patients presenting as axillary metastases with an occult primary comprise less than 1% 4  

of cases, in approximately two thirds of the cases the primary tumor is able to be detected with DCE-MRI.21 In patients newly diagnosed with breast cancer and a normal contralateral breast by conventional imaging and physical examination, the Society of Breast Imaging and ACR recommend DCE- MRI examination of the contralateral breast17 while the ACS makes no such recommendation.10 Screening of the contralateral breast has been shown to detect an occult cancer that is missed by mammography and clinical examination in 3-5% of women.22,23 Nevertheless, it is unclear how many of these lesions would become clinically significant or would be successfully treated with the adjuvant systemic therapy given for the primary cancer.16 Treatment response In the I-SPY/ACRIN 6657 trial, DCE-MRI was used before, during and after chemotherapy in 216 patients to evaluate treatment response. DCE-MRI was shown to be a stronger predictor of pathologic response to neoadjuvant chemotherapy than clinical assessment.24 This may be helpful in the future, avoiding unnecessary toxicity before completion of multiple courses of inappropriate chemotherapy.

FDG-PET in Breast Cancer Positron emission tomography (PET) using Fluorine-18 labeled fluorodeoxyglucose (FDG) enables the visualization of metabolic pathways within tissue via the consumption of glucose. Malignant tumors including breast cancer are generally characterized by an increased uptake of FDG. While FDG-PET/CT is able to differentiate a wide number of benign and malignant tumors, prior work has shown that the relative moderately increased glucose metabolism of primary breast cancer limits the sensitivity of FDG-PET in detecting small breast carcinomas,25 locoregional micrometastases, and non-enlarged malignant lymph nodes.26 In the United States, the Centers for Medicare and Medicaid Services guidelines do not cover FDG-PET or FDGPET/CT imaging for breast cancer in instances of initial diagnosis and/or staging of axillary lymph nodes. The modalities are covered for initial staging of distant metastatic disease, restaging, and monitoring response to treatment.27 Primary Tumor Visualization The feasibility of FDG-PET to study breast cancer was first shown in the early 1990s, where increased FDG uptake was seen in advanced stage primary tumors and axillary lymph node

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metastases.28 While early studies demonstrated that nearly all large primary breast cancers could be detected by FDG-PET, further studies demonstrated that smaller primary breast cancers were not visualized as the spatial resolution of the PET system and varying metabolic activity of different tumor types limited the diagnostic application of FDG-PET.29,30 With the introduction of combined PET and CT (PET/CT) into clinical practice in 2000,31 the ability to analyze both functional and anatomic information with accurate co-registration of images was developed. Initial studies found that combined PET/CT added incremental diagnostic confidence to PET in the majority of breast cancer patients and was able to detect more regions with malignancies than stand-alone CT.32 While overall diagnostic confidence increased, the ability of FDG-PET/CT to detect small primary malignancies (i.e. T1a and T1b) did not significantly improve, with a recent study demonstrating a sensitivity of 59% in such tumors.33 Given these limitations, FDG-PET/CT is not indicated for the initial diagnosis of primary breast cancer. Locoregional Staging The presence and extent of metastasis to locoregional lymph nodes has been proven to carry a high prognostic indication of recurrence and survival.34,35 As such, numerous studies have sought to delineate the utility of FDG-PET and FDG-PET/CT in locoregional nodal evaluation. The outcomes of these studies have demonstrated varying results. A single-center study of 167 consecutive breast cancer patients who underwent FDG-PET found axillary involvement in 68 of 72 patients resulting in a sensitivity of 94% and specificity of 86%.36 Conversely, a larger multicenter prospective study of 360 women with newly diagnosed breast cancer reported that FDGPET had moderate overall accuracy for detecting axillary metastases, but a relatively low sensitivity of 61% and specificity of 80%. FDG-PET often missed axillae with small and few nodal metastases, and the authors concluded that FDG-PET could not be recommended for axillary staging of patients with newly diagnosed breast cancer.29 Studies conducted with FDG-PET/CT have drawn similar conclusions. A 90-patient study in breast cancer patients sought to compare the diagnostic accuracy of FDG-PET/CT to ultrasound in the evaluation of axillary lymph nodes. While there was a statistically significant difference in FDG-PET/CT accuracy compared to ultrasound (75% vs. 62%, respectively), there was no statistically significant difference in the sensitivity of detection and the authors concluded that FDG-PET/CT could not act as a substitute for sentinel lymph node biopsy.37 Similarly, a recent retrospective study looking at the axillary lymph nodes in 349 T1 breast cancer patients found that FDG-PET/CT could not replace sentinel lymph node biopsy in this subgroup.38 Likewise, a study of 236 patients with clinically negative findings for axillary involvement who 6  

underwent FDG-PET/CT prior to sentinel node biopsy found that only 37% of patients with positive results of sentinel node biopsy had positive findings by PET.39 The spatial resolution of FDG-PET and its limited detection of micro-metastases and small tumor-infiltrated lymph nodes restricts the usage of FDG-PET and FDG-PET/CT in the locoregional staging of newly diagnosed breast cancer patients. Despite current trends of doing less invasive management of the axilla in breast cancer patients,40 the modality has not yet reached a diagnostic level that can replace histologic surgical staging as the standard of care in patient workup of newly diagnosed breast cancer.41 Treatment response Histopathology is often used as the reference standard to assess response to primary (neoadjuvant) chemotherapy in breast cancer. However, there is no single definition of histopathologic response and response criteria vary among studies. Most commonly, pathologic complete response (pCR) is defined by the absence of residual invasive tumor.42-44 A modified classification was suggested by Honkoop and colleagues who found no difference in survival for patients with scattered microscopic foci of residual tumor cells compared to those who achieved pathologic complete response.45 These two groups were combined in a response category “minimal residual disease” (MRD), versus all other patients classified as “gross residual disease” (GRD). A prospective multi-center trial in which 272 FDG-PET scans were performed in 104 patients confirmed the greater the reduction in tumor metabolic activity early in the course of therapy the more likely patients were to achieve histopathologic response.46 In histopathologic responders, the tumor metabolic activity measured as standardized uptake value (SUV) decreased by 50.5±18.4% after the first cycle of primary chemotherapy compared to 36.5±20.9% in nonresponders. Histopathologic non-responders were identified with a negative predictive value of 89.5% after the first cycle when using a relative decrease in SUV of less than 45% as cut-off. Correspondingly, the negative predictive value after the second cycle was 88.9% for a cut-off of 55% decrease in SUV. An important observation is that FDG-PET identified patients with low tumor metabolic activity prior to treatment who did not achieve histopathologic response. Twenty-four out of 104 breast carcinomas (23%) had a baseline SUV of less than 3.0 and none responded to chemotherapy. In another study, 115 women with newly diagnosed, large or locally advanced breast cancer underwent FDG-PET treatment monitoring.47 Analysis was based on different breast cancer 7  

subtypes: triple negative (ER-/PR-/HER2-), luminal (ER+ and/or PR+; HER2-) and HER2 positive (HER2+). Triple negative tumors presented the highest baseline metabolic activity with an SUV of 11.3 ± 8.5. The decrease in SUV after the first course of neoadjuvant chemotherapy was significantly higher in triple negative and HER2-positive subtypes (-45% ± 25% and -57% ± 30%, respectively) than in luminal one (-19% ± 35%). The decrease in SUV was a predictive factor of the pathological complete response only in HER2-positive tumors with an accuracy of 76%. Although this is an interesting and important observation, more studies are needed to better define the potential clinical role of FDG-PET treatment monitoring in the neoadjuvant setting. FDG-PET/MRI in Breast Cancer Hybrid PET/MR technology has recently been introduced, appearing in the clinical setting in 2007.48,49 Whether designed as a sequential or simultaneous system, the hybrid PET/MR produces high resolution anatomic, biological and functional imaging. Given the limited approved indications of FDG-PET/CT in breast cancer patients, it is understandable that the potential role of PET/MR in such patients remains to be determined. As described previously, dedicated breast MRI has been shown to be highly sensitive, detecting lesions that are occult to mammography, ultrasound and clinical breast exam, while lacking in specificity.50 Alternatively, FDG-PET/CT has been shown to have a higher specificity than MRI in detecting breast cancer recurrence.51 Iagaru et. al. studied 21 patients with known breast cancer and concluded that PET/CT and breast MRI should be considered as complimentary imaging tools.51 Goerres et. al. examined 32 patients with suspected locoregional breast cancer recurrence or suspected contralateral breast cancer and found that the combination of FDG-PET and breast MRI would result in a sensitivity and specificity of 93% and 94% respectively.52 Nevertheless, it has yet to be shown that FDG-PET can add specificity to MR in lesions that have previously been shown to have low detectability on FDG-PET, including those that lie below the spatial resolution of the system or have low metabolic activity.30

Technical Considerations Attenuation Correction Regardless of whether the hybrid PET/MRI system acquires images in a sequential or simultaneous fashion, dedicated MRI sequences are utilized for attenuation correction in PET, a necessary step to account for differences in the attenuation of photons by different tissues of the 8  

body. Precise and reproducible attenuation correction is necessary to determine accurate quantification of FDG activity (SUV). In PET/CT, attenuation coefficients of tissues at X-ray energies are obtained from the CT data itself, which directly provides data to allow for maps to 511 keV-photon attenuation coefficients.53 As MR images are determined by tissue hydrogen density and relaxation properties, the data cannot be directly converted into attenuation maps. Instead MR attenuation maps rely on automated tissue segmentation methods.54,55 Despite the differences in attenuation methods between PET/CT and PET/MR, initial studies to date have shown both overall good correlation between SUV values and similar detection rates between the two modalities.56-58 The most significant differences in SUV values tend to be seen in osseous lesions,59,60 likely explained by current segmentation models not accounting for bone attenuation.54,55

Patient positioning for breast PET/MR An obvious benefit of a hybrid PET/MR scanner is the reduction of misalignment issues that might occur secondary to different patient positioning between scans. Prior work has demonstrated that breast lesions can be detected more clearly with patients in prone position compared to supine.61,62 Therefore, successful hybrid PET/MR mammography must utilize a breast positioning device that is both PET and MR compatible, without affecting the image quality of either modality. The dedicated radiofrequency breast coil used for MR signal detection must be taken into account during PET imge reconstruction, as the annihilation photons emitted in positron decay will interact with and be absorbed and scattered by the coil.63,64 Such breast coils are currently under development and have been shown in early work on both phantom and patient studies to be compatible with PET and MR imaging without affecting either imaging modality when the attenuation is properly taken into account.65 Evaluation of Primary Breast Lesions No current, large scale data exists examining the ability of PET/MR to detect and evaluate primary breast cancer lesions. A recent study examined 36 breast cancer patients undergoing a dual-imaging protocol with PET/CT followed by PET/MR.66 The authors sought to assess the quality of PET data in terms of anatomic allocation and image contrast, as well as quantification of tracer activity. For the 25 primary tumors studied, the authors found no statistically significant difference in anatomic localization or tumor metabolic activity (SUV) between the two modalities, while describing slightly higher lesion contrast in the PET/MR images than in PET/CT images.66 9  

However, the study was limited by differences in PET scanner technology (e.g. Time-of-Flight vs. non-Time-of-Flight PET), bed-position length of scanning, and different uptake time of FDG from injection. Furthermore, given the objectives of the study, the patients were not scanned utilizing dedicated breast MR sequences via a breast coil and were not imaged in prone position, which has previously been shown to affect lesion detectability.61 While no studies have looked at the hybrid PET/MR imaging of breast cancer patients for the evaluation of primary lesions, so called PET/MR mammography, prior studies have examined the use of software fusion of MR with FDG-PET images acquired in prone positioning.62,67-69 Results have been inconsistent. Heusner et. al. found that while fused PET/MR images are as accurate as MR for the evaluation of local breast cancer, in only 1 patient of 27 would the combined images have changed surgical treatment and thus did not see a clinical benefit.67 Early work by Moy et. al. examined 23 patients with suspected or recurrent breast cancer and found that the fused datasets increased the specificity of MRI (from 52% to 95%) at the cost of decreased sensitivity (from 92% to 63%).69 Further work by the same group examined 36 breast cancer patients (90 lesions) and showed that the fusion of FDG-PET and MR data had a statistically significant increase in positive predictive value from 77% to 98% and in specificity from 53% to 97% compared to MR alone.68 The results are in agreement with earlier work by Walter et. al., who looked at non-fused FDG-PET and MRI images obtained in the prone position and found that if the two examinations were both positive, the diagnosis was correct in 95% of the patients.70 Part of the inconsistency between the current available data may be explained by differences in lesion definition between studies as well as differences in study populations, histopathological breast cancer subtypes, and breast positioning techniques.67,68

Future Advances of PET/MR in Breast Cancer It is expected that advances in hybrid PET/MR technology will continue and the utility of such imaging in breast cancer patients will evolve. One area of potential advancement in PET/MR is the development of new methods for accurate MR attenuation. Significant issues still need to be addressed, ranging from the lack of accurate correction for bone attenuation in clinically used software,54,55 to truncation artifacts and non-uniformities at the edge of the field of view, as well as motion artifact from patient respiration.71 Interesting work is already being done in these areas, ranging from the implementation of continuous table motion during a PET/MR scan72 to new attenuation algorithms which account for cortical bone via utilization of ultrashort-echo-time and fat-water discrimination via Dixon sequences.73 10  

It is worth mentioning the potential that new PET biomarkers hold for PET/MR imaging. Discovery and development of agents, including those that quantify receptor expression, cell proliferation, and angiogenesis, are active areas of research. These markers, in combination with the high soft-tissue contrast and spatial resolution of MRI, seek to improve staging information of patients and the evaluation of therapeutic effectiveness.26

Conclusion The evaluation of primary breast cancers with dedicated breast DCE-MRI has been shown to be highly sensitive. However given its high cost and relatively low specificity its utility remains only for specific clinical circumstances and high-risk patients. Due to the limited sensitivity and spatial resolution of FDG-PET in the detection of small primary breast tumors and treatmentnaive locoregional lymph node involvement, FDG-PET/CT is not recommended in the diagnosis or initial staging of early stage breast cancer. Rather, the strength of FDG-PET/CT lies in its high sensitivity and specificity in detecting the extent of metastatic disease, often being utilized when standard staging studies are equivocal or if a previously treated breast cancer patient becomes symptomatic for recurrence. The recent advent of hybrid PET/MRI systems has created a promising development in the diagnostic options of clinicians caring for breast cancer patients. Combining the high resolution and soft-tissue contrast provided by MRI with the high specificity of metabolic FDG-PET information, the potential exists for progress in the management of breast cancer patients. Early results comparing FDG-PET/MR with FDG-PET/CT in oncologic patients have shown hybrid PET/MR potentially contributes to clinical management more often than PET/CT.74 Furthermore, image quality, alignment, and confidence in lesion localization appear to be comparable between the two modalities.75,76 Quantification of FDG uptake between the two hybrid modalities has been shown repeatedly to be well correlated.77,78 The precise role of PET/MR in breast cancer management, like in many oncological processes, is yet to be determined. Perhaps the use of such a modality remains in the realm of research. Alternatively, breast PET/MR combined with whole-body PET/MR staging could offer a one-stop shop for the staging of breast cancer as well as measuring and/or predicting response to therapy. Advances in technology, including the development of new MR attenuation methodologies, scanner equipment, and the development of new PET radiotracers are constantly occurring and further delineating the role of PET/MR. Future prospective research

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trials targeted towards the comparison of PET/MR with today’s standard of care imaging for breast cancer patients will prove extremely worthwhile.

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Figure Legend: Figure 1: Known left-sided invasive ductal carcinoma in a 39 year old woman. Unenhanced axial (A) and sagittal (D) T1-weighted MR images of the breasts acquired for attenuation correction demonstrate no significant abnormality. Axial (B) and Sagittal (E) FDG-PET images demonstrate increased FDG uptake which on axial (C) and sagittal (F) fused FDG-PET/MRI images localizes to the superior-medial quadrant. FDG uptake noted within the lungs resolved and was inflammatory in nature. Figure 2: FDG-PET/CT of the same patient as Figure 1 demonstrates a soft-tissue mass in the superiormedial left breast on axial CT images (A). Axial FDG-PET (B) and fused FDG-PET/CT (C) images clearly demonstrate increased FDG uptake within the mass, corresponding to the known left-sided invasive ductal carcinoma. FDG uptake noted within the lungs resolved and was inflammatory in nature. Figure 3: Incidentally found right-sided lobular carcinoma in situ in the same patient as Figure 1. Unenhanced axial (A) and sagittal (D) T1-weighted MR images of the breasts acquired for attenuation correction are unremarkable. Axial (B) and Sagittal (E) FDG-PET images demonstrate increased FDG uptake which on axial (C) and sagittal (F) fused FDG-PET/MRI images localizes to the lateral-inferior quadrant, biopsy proven to be lobular carcinoma in situ.

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