(Radiographics. 2002;22:5-17.)
© RSNA, 2002
Detection of Locoregional and Distant Recurrences in Breast Cancer Patients by Using FDG PET1
William B. Eubank, MD,
David A. Mankoff, MD, PhD,
Hubert J. Vesselle, MD, PhD,
Janet F. Eary, MD,
Erin K. Schubert, BA,
Lisa K. Dunnwald, BS,
Skyler K. Lindsley, MD,
Julie R. Gralow, MD,
Mary M. Austin-Seymour, MD,
Georgianna K. Ellis, MD and
Robert B. Livingston, MD
1 From the Department of Radiology (S-113-RAD), Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108-1597 (W.B.E.); and the Department of Radiology (W.B.E., D.A.M., H.J.V., J.F.E.), Division of Nuclear Medicine (D.A.M., H.J.V., J.F.E., E.K.S., L.K.D.), Department of Radiation Oncology (S.K.L., M.M.A.S.), and Division of Medical Oncology (J.R.G., G.K.E., R.B.L.), University of Washington School of Medicine, Seattle. Received March 12, 2001; revision requested May 21 and received June 25; accepted July 2. Supported in part by grants CA42045 and CA72064 from the National Institutes of Health. Address correspondence to W.B.E. (e-mail: weubank@u.washington.edu).
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Abstract
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Cases of recurrence of breast cancer can pose considerable diagnostic and therapeutic challenges for the oncologic team. The prognosis and management decisions are based on knowledge of the true extent of disease. Conventional staging methods, including physical examination, assessment of levels of tumor markers, cross-sectional imaging, and bone scintigraphy, may not reliably demonstrate the extent of disease in all cases. Physical examination and cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging) can be problematic because (a) the sequelae of previous surgery and radiation therapy can be difficult to distinguish from recurrent neoplasms and (b) early metastatic disease (small lesions) can be difficult to distinguish from benign lesions that are too small to characterize. Positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) can help clarify inconclusive findings from physical examination and cross-sectional imaging. FDG PET is more sensitive than CT in detection of lymphatic spread of disease to locoregional and mediastinal nodes. Metastases at distant sites including the lung, bone, and the liver are also readily detected at FDG PET. FDG PET has been proved accurate in restaging cases of recurrent breast cancer and will likely aid in directing therapy in these cases.
© RSNA, 2002
Index Terms: Breast neoplasms, diagnosis, 00.32 • Breast neoplasms, metastases, **.332 • Breast neoplasms, PET, 00.12163 • Breast neoplasms, radionuclide studies, 00.12163, 00.12166 • Fluorine, radioactive, 00.12163, 00.12166
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LEARNING OBJECTIVES FOR TEST 1
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After reading this article and taking the test, the reader will be able to:
- Discuss the benefits and role of FDG PET in conjunction with conventional methods for staging locoregional or distant recurrences in patients with breast cancer.
- List common pathways of spread of disease and risk factors in patients with recurrence of breast cancer.
- Describe tracers other than FDG used for in vivo PET of tumor physiology.
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Introduction
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Recurrence of disease at locoregional and distant sites occurs frequently in women who have undergone primary treatment for breast cancer. Locoregional recurrence occurs in up to 35% of patients by 10 years after mastectomy or breast-conserving therapy (1–4). The clinical course of patients with recurrent breast cancer varies and is largely dependent on the extent of disease dissemination and the biologic aggressiveness of the tumor. Accurate staging of recurrences is critical for therapeutic planning. In general, systemic therapy is used at almost all disease stages; however, isolated locoregional disease or single sites of metastatic recurrence are also treated with surgery and radiation therapy (5,6). Estimation of the extent of disease is often a challenging task. Clinical symptoms, tumor markers, and physical examination results may not be reliable for the determination of recurrence, particularly among patients who have previously undergone surgery and irradiation (7). Findings from cross-sectional examinations like computed tomography (CT) or magnetic resonance (MR) imaging can often be inconclusive, particularly with regard to determining the status of lymph nodes and in anatomic areas previously treated with surgery or radiation (8).
Several studies have shown that positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) is a highly accurate method for restaging cases of suspected breast cancer recurrence (9,10). Large areas can be surveyed; this ability is advantageous because sites of recurrent disease can be extensive and separated by large anatomic distances. FDG PET provides metabolic information that can complement the information from morphologic imaging by increasing sensitivity and specificity in the evaluation of potential sites of disease (8). Hathaway et al (11) demonstrated the benefit of combined FDG PET and MR imaging for determination of axillary recurrence versus postsurgical scarring among patients previously treated with axillary lymph node dissection.
FDG PET is frequently used at our institution to help stage recurrent or metastatic breast cancer. Most of these patients are referred for FDG PET to better characterize disease extent, to clarify equivocal findings at cross-sectional imaging, or to assess the response to ongoing therapy. From this experience, we present cases showing representative patterns of spread of disease among patients with recurrent breast cancer. These cases illustrate the usefulness of FDG PET in recurrent or metastatic breast cancer, especially in assessing spread to the axillary, supraclavicular, internal mammary (IM), and mediastinal nodes. Specific topics discussed are FDG PET technique, locoregional spread of breast cancer—lymphatic mechanisms, locoregional recurrence, intrathoracic recurrences, extrathoracic recurrences, and other PET tracers.
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FDG PET Technique
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FDG PET was performed with an Advance scanner (GE Medical Systems, Waukesha, Wis). FDG was prepared by using the method of Hamacher et al (12) and had a radiochemical purity of greater than 99% and a specific activity of greater than 20 Ci/mmol (740 GBq/mmol). The patients fasted for at least 4 hours before the examination. A blood sample for determination of glucose level was obtained before FDG administration (concentrations were 66–118 mg/dL [3.7–6.6 mmol/L]) to ensure euglycemia. One milligram of lorazepam (Wyeth-Ayerst Laboratories, Philadelphia, Pa) was administered intravenously to decrease background muscular uptake, especially in the neck muscles. Beginning approximately 45 minutes after intravenous injection of FDG (mean dose, 9.8 mCi [0.363 GBq]; dose range, 6.6–10.8 mCi [0.244–0.400 GBq]), whole-body imaging was performed with the patient in the supine position. All images were acquired in the two-dimensional high-sensitivity mode with 35 imaging planes covering an axial field of view of 15 cm (4.0-mm axial full width at half maximum at the center of the tomograph) and in-plane intrinsic resolution of 4–5 mm (13,14).
One of two protocols was used. For patients with suspected widespread disease, the emission scan survey consisted of five adjacent 15-cm axial fields of view (7 minutes per field of view) extending from the inferior pelvis to the superior thorax. More detailed imaging in anatomic areas of interest was later performed with 15-cm axial field-of-view emission scans (15–25 minutes per field of view) followed by transmission scans (25–50 minutes per field of view). Transmission scans were performed with a rotating germanium-68 rod source. More recently, segmentation of the transmission scan has allowed shorter transmission times and attenuation correction for all fields of view. For patients with suspected locoregional disease, a limited torso survey from the neck to the bottom of the liver was performed by using three adjacent 15-cm axial field-of-view emission scans (10 minutes) and three adjacent 15-cm field-of-view postinjection transmission scans (15 minutes).
On attenuation-corrected images, the standard uptake value (SUV) for areas of focal FDG accumulation was calculated (15). Images were reconstructed onto a 128 x 128 matrix by using a Hanning filter, which resulted in an effective in-plane resolution (full width at half maximum) of approximately 10–12 mm (13,14). The reconstructed images were displayed in the axial, coronal, and sagittal planes on a workstation, as needed.
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Locoregional Spread of Breast Cancer—Lymphatic Mechanisms
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Much of the current knowledge on locoregional spread of breast cancer is based on anatomic studies of breast lymphatic vessels, which have been ongoing since the 1600s. Since that time, investigators have injected various dyes and radioactive substances into the breast, both after death and in vivo, to study lymphatic drainage to regional nodal groups (16). In more recent years, sentinel node lymphoscintigraphy, performed with perilesion injections of technetium-labeled sulfur colloid, has further validated the lymphatic drainage pathways of early breast cancer (17,18).
Figure 1 shows the major lymphatic pathways to regional nodal groups. As in other parts of the body, the lymph channels of the breast accompany the blood supply. The main drainage pathway is through several intraparenchymal lymphatic trunks that run toward the axilla. Axillary nodes are divided into three levels based on their relation to the pectoralis minor muscle: Level I nodes are lateral to the lateral border of this muscle, level II nodes are deep to this muscle, and level III nodes (also called subclavicular nodes) lie medial to the medial border of this muscle and extend up to the apex of the axilla (Fig 1a). Another important pathway of drainage is to the IM nodes; lymphatic channels arising from the deep aspect of the breast run along or pierce the pectoral fascia and follow the perforating vessels of the intercostal arteries to reach the intercostal spaces. The main drainage to supraclavicular nodes occurs from level III axillary nodes through subclavian lymphatic trunks to sentinel nodes at the jugular-subclavian venous confluence. Lymphatic drainage pathways from the chest wall, neck, IM chain, and mediastinum all converge at the jugular-subclavian venous confluence (Fig 1b).
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Figure 1a. (a) Diagram shows the main lymphatic drainage pattern of the breast. Most of the lymphatic drainage is directed from intraparenchymal lymph channels toward the axilla. Drainage to IM nodes is another important pathway and can occur from any location within the breast. (b) Diagram shows that lymphatic drainage converges at the jugular-subclavian venous confluence from the high axillary, neck, IM, and mediastinal nodes. IJV = internal jugular vein, SV = subclavian vein, SVC = superior vena cava.
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Figure 1b. (a) Diagram shows the main lymphatic drainage pattern of the breast. Most of the lymphatic drainage is directed from intraparenchymal lymph channels toward the axilla. Drainage to IM nodes is another important pathway and can occur from any location within the breast. (b) Diagram shows that lymphatic drainage converges at the jugular-subclavian venous confluence from the high axillary, neck, IM, and mediastinal nodes. IJV = internal jugular vein, SV = subclavian vein, SVC = superior vena cava.
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Regional spread of advanced breast cancer, particularly in patients who have undergone primary surgical treatment and irradiation, occurs through these same routes but may spread in a retrograde direction, since the normal pathways may be obstructed by recurrent disease or scarring from primary treatment. Once disease has spread to the jugular-subclavian venous confluence, it is easy to conceive of many different pathways of dissemination to locoregional nodal sites. Lymphatic spread of tumor is thought to be a marker of primary tumor aggressiveness and may occur independently of hematogenous dissemination (19).
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Locoregional Recurrence
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The breast (Fig 2), the skin of the breast, axillary nodes (Fig 3), the chest wall, and supraclavicular nodes are the most common sites of first locoregional recurrence after primary surgical resection (20,21). Locoregional recurrences are often confined to a single site rather than associated with multiple sites of disease (5,22). The shift toward breast-conserving surgery and local radiation therapy for early breast cancer in recent years has heightened concern over locoregional recurrence (23). The 5-year rate of isolated regional nodal recurrence following conservative surgery and irradiation is 3% (24). Independent risk factors associated with locoregional recurrence in this group of patients include positive margins at surgical resection, tumors with an extensive intraductal component, and patient age under 40 years (4).
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Figure 2a. Recurrence in the breast in a 35-year-old woman who underwent lumpectomy of the right breast and axillary node dissection, which revealed a T1 infiltrating ductal carcinoma in the upper outer quadrant and no positive lymph nodes. She received local radiation therapy only after surgery. Five years after surgery, she presented with a mass in the axillary portion of the right breast; the mass was confirmed to be malignant with fine-needle aspiration. FDG PET was performed to assess the extent of locoregional disease. Coronal (a) and axial (b) FDG PET images show uptake (SUV = 2.0) within the lateral right breast (arrow) and no uptake in locoregional nodes. Right mastectomy revealed a 2-cm-diameter infiltrating ductal carcinoma, which was consistent with recurrent tumor.
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Figure 2b. Recurrence in the breast in a 35-year-old woman who underwent lumpectomy of the right breast and axillary node dissection, which revealed a T1 infiltrating ductal carcinoma in the upper outer quadrant and no positive lymph nodes. She received local radiation therapy only after surgery. Five years after surgery, she presented with a mass in the axillary portion of the right breast; the mass was confirmed to be malignant with fine-needle aspiration. FDG PET was performed to assess the extent of locoregional disease. Coronal (a) and axial (b) FDG PET images show uptake (SUV = 2.0) within the lateral right breast (arrow) and no uptake in locoregional nodes. Right mastectomy revealed a 2-cm-diameter infiltrating ductal carcinoma, which was consistent with recurrent tumor.
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Figure 3a. Axillary node recurrence in a 44-year-old woman in whom a 3-cm-diameter infiltrating ductal carcinoma of the right breast was initially diagnosed. She underwent subtotal mastectomy and axillary node dissection; one of 16 axillary nodes was positive. After surgery, she was treated with adjuvant chemotherapy (Adriamycin [doxorubicin hydrochloride; Pharmacia & Upjohn, Kalamazoo, Mich] and cyclophosphamide) followed by local irradiation. A right axillary recurrence (proved with biopsy) developed 1 years later, and taxane chemotherapy was started. Results of physical examination were inconclusive for the presence of recurrent disease involving the breast, and FDG PET was performed to demonstrate the extent of disease. Coronal (a) and axial (b) FDG PET images obtained at the time of recurrence show a large right axillary mass (SUV = 13.7) (arrow) with a central photopenic defect consistent with necrosis and no uptake in the right breast. Right modified radical mastectomy revealed no cancer within the breast, but two of five axillary nodes were positive with extracapsular extension.
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Figure 3b. Axillary node recurrence in a 44-year-old woman in whom a 3-cm-diameter infiltrating ductal carcinoma of the right breast was initially diagnosed. She underwent subtotal mastectomy and axillary node dissection; one of 16 axillary nodes was positive. After surgery, she was treated with adjuvant chemotherapy (Adriamycin [doxorubicin hydrochloride; Pharmacia & Upjohn, Kalamazoo, Mich] and cyclophosphamide) followed by local irradiation. A right axillary recurrence (proved with biopsy) developed 1 years later, and taxane chemotherapy was started. Results of physical examination were inconclusive for the presence of recurrent disease involving the breast, and FDG PET was performed to demonstrate the extent of disease. Coronal (a) and axial (b) FDG PET images obtained at the time of recurrence show a large right axillary mass (SUV = 13.7) (arrow) with a central photopenic defect consistent with necrosis and no uptake in the right breast. Right modified radical mastectomy revealed no cancer within the breast, but two of five axillary nodes were positive with extracapsular extension.
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Among patients treated with mastectomy, axillary node dissection, and adjuvant chemotherapy, the most common sites of locoregional recurrence are the chest wall (68% of locoregional recurrences) and supraclavicular nodes (41% of locoregional recurrences) (25). Recurrent disease at both of these sites is associated with a poor prognosis in terms of survival after recurrence (26–28). Factors that predict an increased risk of chest wall or supraclavicular node recurrence include four or more positive axillary nodes, tumor diameter of 4 cm or greater, and extranodal extension of 2 mm or greater (25). Chest wall invasion occurs by direct local extension of tumor through the pectoral fascia or extranodal extension from interpectoral nodes (Rotter nodes) into the pectoral muscles (Fig 4). Supraclavicular node recurrence (Fig 5) is technically considered stage IV disease and is generally considered a harbinger of more widely disseminated disease. However, patients with supraclavicular node involvement as the sole site of disseminated disease may benefit from aggressive local radiation therapy.
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Figure 4a. Chest wall recurrence in a 79-year-old woman who underwent right total mastectomy and low-level axillary node dissection, which revealed an estrogen-progesterone receptor-positive infiltrating ductal carcinoma and no positive nodes. She received tamoxifen for 5 years after surgery. She was free of recurrence at clinical examination until 7 years after surgery, when she felt a mass in the upper outer right chest wall. Malignancy was confirmed with fine-needle aspiration of the mass. Coronal (a) and axial (b) FDG PET images show a right chest wall mass (SUV = 7.5) (arrow) and uptake in a high axillary (level III) node (arrowhead). At surgery, the mass was centered between the major and minor pectoral muscles, consistent with an involved Rotter node, and the high axillary node was positive for malignancy.
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Figure 4b. Chest wall recurrence in a 79-year-old woman who underwent right total mastectomy and low-level axillary node dissection, which revealed an estrogen-progesterone receptor-positive infiltrating ductal carcinoma and no positive nodes. She received tamoxifen for 5 years after surgery. She was free of recurrence at clinical examination until 7 years after surgery, when she felt a mass in the upper outer right chest wall. Malignancy was confirmed with fine-needle aspiration of the mass. Coronal (a) and axial (b) FDG PET images show a right chest wall mass (SUV = 7.5) (arrow) and uptake in a high axillary (level III) node (arrowhead). At surgery, the mass was centered between the major and minor pectoral muscles, consistent with an involved Rotter node, and the high axillary node was positive for malignancy.
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Figure 5a. Supraclavicular node involvement in a 40-year-old woman with newly diagnosed invasive lobular carcinoma in the lower outer quadrant of the left breast. (a) Coronal FDG PET image shows a chain of FDG uptake from axillary nodes (arrowheads) to the supraclavicular region (arrow). (b) Axial FDG PET image obtained through the upper chest shows uptake (SUV = 4.1) in a supraclavicular node (arrow). Malignancy was confirmed with fine-needle aspiration of the node, and neoadjuvant chemotherapy was started.
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Figure 5b. Supraclavicular node involvement in a 40-year-old woman with newly diagnosed invasive lobular carcinoma in the lower outer quadrant of the left breast. (a) Coronal FDG PET image shows a chain of FDG uptake from axillary nodes (arrowheads) to the supraclavicular region (arrow). (b) Axial FDG PET image obtained through the upper chest shows uptake (SUV = 4.1) in a supraclavicular node (arrow). Malignancy was confirmed with fine-needle aspiration of the node, and neoadjuvant chemotherapy was started.
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Intrathoracic Recurrence
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IM and Mediastinal Nodes
Lymphatic drainage to the IM nodal chain is an important pathway of spread of disease both at the time of initial diagnosis and after primary treatment of breast cancer (Fig 6). According to early studies of patients who underwent extended radical mastectomy, metastasis to IM nodes occurs in close to one in five women with resectable (stage II or III) breast cancer (29–31). Data from a sentinel node lymphoscintigraphy study of patients with early breast cancer at our institution reveal that the overall prevalence of drainage to the IM nodes is 17% (18). Metastasis to IM nodes can occur from tumor located anywhere in the breast; however, in our study (18), IM drainage was significantly less frequent when tumors were located in the upper outer quadrant of the breast (10%) than when tumors were located in the other three quadrants or the subareolar portion (17%–29%). Metastasis to the IM and axillary nodes usually occurs synchronously; however, it is infrequently (4%–6% of cases) isolated to the IM chain (29,32). The prognosis of patients with IM and axillary node metastases is significantly worse than that of patients with only axillary node disease (33,34), suggesting that the IM nodal chain is a conduit for more widespread dissemination of disease (Fig 7).
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Figure 6a. IM node involvement in a 44-year-old woman who underwent lumpectomy for infiltrating ductal carcinoma in the lower inner quadrant of the left breast. At the time of surgery, sentinel node mapping revealed one positive sentinel node in the axilla. Complete axillary node dissection revealed no additional positive nodes. Despite several cycles of adjuvant chemotherapy, the levels of tumor markers rose. Work-up for recurrent or residual disease included mammography, bone scintigraphy, and CT of the chest, abdomen, and pelvis, but the results were negative for recurrence. Coronal (a) and axial (b) FDG PET images show uptake (SUV = 4.1) in a left IM node (arrow). FDG PET also showed uptake in mediastinal nodes. Fine-needle aspiration of the IM node demonstrated malignancy.
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Figure 6b. IM node involvement in a 44-year-old woman who underwent lumpectomy for infiltrating ductal carcinoma in the lower inner quadrant of the left breast. At the time of surgery, sentinel node mapping revealed one positive sentinel node in the axilla. Complete axillary node dissection revealed no additional positive nodes. Despite several cycles of adjuvant chemotherapy, the levels of tumor markers rose. Work-up for recurrent or residual disease included mammography, bone scintigraphy, and CT of the chest, abdomen, and pelvis, but the results were negative for recurrence. Coronal (a) and axial (b) FDG PET images show uptake (SUV = 4.1) in a left IM node (arrow). FDG PET also showed uptake in mediastinal nodes. Fine-needle aspiration of the IM node demonstrated malignancy.
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Figure 7a. Dissemination of disease through the IM nodal chain in a 35-year-old woman who underwent right mastectomy and axillary node dissection for a multifocal tumor; two of 17 axillary nodes were positive. She received adjuvant chemotherapy only and had no evidence of disease until sternal pain developed 5 years after the mastectomy. Chest CT revealed a right pleural effusion and borderline-sized mediastinal nodes. Bone scanning revealed uptake in the midsternum and the lateral sixth rib; the uptake was thought to most likely represent posttraumatic change. FDG PET was performed to clarify the findings of conventional imaging. (a) Axial FDG PET image of the lower chest shows bilateral substernal uptake in IM nodes (arrows). (b) Coronal FDG PET image of the anterior chest wall shows spread of tumor from IM nodes (arrowheads) to the inferior half of the sternum (arrow). (c) Coronal FDG PET image obtained through the midchest shows uptake in the hila (short arrows) and inferior mediastinum (long arrow). Mediastinoscopy revealed malignancy in several mediastinal nodes.
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Figure 7b. Dissemination of disease through the IM nodal chain in a 35-year-old woman who underwent right mastectomy and axillary node dissection for a multifocal tumor; two of 17 axillary nodes were positive. She received adjuvant chemotherapy only and had no evidence of disease until sternal pain developed 5 years after the mastectomy. Chest CT revealed a right pleural effusion and borderline-sized mediastinal nodes. Bone scanning revealed uptake in the midsternum and the lateral sixth rib; the uptake was thought to most likely represent posttraumatic change. FDG PET was performed to clarify the findings of conventional imaging. (a) Axial FDG PET image of the lower chest shows bilateral substernal uptake in IM nodes (arrows). (b) Coronal FDG PET image of the anterior chest wall shows spread of tumor from IM nodes (arrowheads) to the inferior half of the sternum (arrow). (c) Coronal FDG PET image obtained through the midchest shows uptake in the hila (short arrows) and inferior mediastinum (long arrow). Mediastinoscopy revealed malignancy in several mediastinal nodes.
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Figure 7c. Dissemination of disease through the IM nodal chain in a 35-year-old woman who underwent right mastectomy and axillary node dissection for a multifocal tumor; two of 17 axillary nodes were positive. She received adjuvant chemotherapy only and had no evidence of disease until sternal pain developed 5 years after the mastectomy. Chest CT revealed a right pleural effusion and borderline-sized mediastinal nodes. Bone scanning revealed uptake in the midsternum and the lateral sixth rib; the uptake was thought to most likely represent posttraumatic change. FDG PET was performed to clarify the findings of conventional imaging. (a) Axial FDG PET image of the lower chest shows bilateral substernal uptake in IM nodes (arrows). (b) Coronal FDG PET image of the anterior chest wall shows spread of tumor from IM nodes (arrowheads) to the inferior half of the sternum (arrow). (c) Coronal FDG PET image obtained through the midchest shows uptake in the hila (short arrows) and inferior mediastinum (long arrow). Mediastinoscopy revealed malignancy in several mediastinal nodes.
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The importance of IM node detection and treatment remains controversial (35). Unlike axillary nodes, IM nodes are not routinely biopsied as part of an individual patient’s staging work-up, and their status is generally unknown. There has been reluctance to biopsy IM nodes because (a) early radiation therapy trials (before the era of routine adjuvant chemotherapy) failed to demonstrate a clear survival benefit for IM chain irradiation and (b) there is a relatively high complication risk (pneumothorax and bleeding) associated with IM node sampling. Two recent large, prospective, randomized radiation therapy trials have suggested a benefit from aggressive regional nodal irradiation (including the IM field) following lumpectomy or mastectomy, even in patients with fairly limited spread to the axilla (36,37). These studies have spurred more interest in developing staging methods to identify patients who are at risk for IM node metastasis (35,38). FDG PET may prove to be an ideal method of noninvasively staging this important nodal region and aid in the selection of patients who would potentially benefit most from directed IM node radiation therapy; however, further work needs to be done to confirm the FDG PET findings with histopathologic analysis.
CT has been the main modality used to evaluate mediastinal nodes in oncologic patients (39,40), but this technique, which uses size as the main criterion to assess nodal status, is limited by poor sensitivity. Among patients with non–small cell lung cancer, FDG PET has proved to be significantly more accurate than CT in the evaluation of mediastinal nodes, mainly due to an increase in sensitivity for nodal metastases (41–43). In a preliminary analysis of 73 patients with recurrent or metastatic breast cancer, the prevalence of suspected disease in mediastinal and IM nodes at FDG PET was significantly higher than the prevalence at CT (40% vs 23%) (44). Among 33 patients suspected of having only locoregional disease at physical examination and conventional imaging, including CT, 10 cases (30%) were potentially upstaged by virtue of positive FDG PET findings in the mediastinum or IM chain (Fig 8). This result suggests that, as in staging for non–small cell lung cancer, FDG PET may reveal more mediastinal and IM node disease than CT in breast cancer patients.
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Figure 8a. Increased sensitivity of FDG PET for nodal metastasis in a 45-year-old woman in whom infiltrating ductal carcinoma of the right breast and a positive axillary node were diagnosed with fine-needle aspiration. (a) CT scan obtained during neoadjuvant chemotherapy shows no mediastinal or hilar adenopathy. (b) Corresponding axial FDG PET image shows a focus of activity (SUV = 3.1) in the lower right paratracheal region (long solid arrow) and additional foci corresponding to the primary tumor (short solid arrow) and axillary node metastases (open arrow). (c) Coronal FDG PET image shows an additional focus of activity in the aortopulmonic region of the mediastinum (short arrow), a finding suspicious for metastasis. Long arrow = activity in lower right paratracheal nodes. Mediastinoscopy revealed malignancy in a right paratracheal node. The patient subsequently received mediastinal radiation therapy in addition to chemotherapy.
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Figure 8b. Increased sensitivity of FDG PET for nodal metastasis in a 45-year-old woman in whom infiltrating ductal carcinoma of the right breast and a positive axillary node were diagnosed with fine-needle aspiration. (a) CT scan obtained during neoadjuvant chemotherapy shows no mediastinal or hilar adenopathy. (b) Corresponding axial FDG PET image shows a focus of activity (SUV = 3.1) in the lower right paratracheal region (long solid arrow) and additional foci corresponding to the primary tumor (short solid arrow) and axillary node metastases (open arrow). (c) Coronal FDG PET image shows an additional focus of activity in the aortopulmonic region of the mediastinum (short arrow), a finding suspicious for metastasis. Long arrow = activity in lower right paratracheal nodes. Mediastinoscopy revealed malignancy in a right paratracheal node. The patient subsequently received mediastinal radiation therapy in addition to chemotherapy.
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Figure 8c. Increased sensitivity of FDG PET for nodal metastasis in a 45-year-old woman in whom infiltrating ductal carcinoma of the right breast and a positive axillary node were diagnosed with fine-needle aspiration. (a) CT scan obtained during neoadjuvant chemotherapy shows no mediastinal or hilar adenopathy. (b) Corresponding axial FDG PET image shows a focus of activity (SUV = 3.1) in the lower right paratracheal region (long solid arrow) and additional foci corresponding to the primary tumor (short solid arrow) and axillary node metastases (open arrow). (c) Coronal FDG PET image shows an additional focus of activity in the aortopulmonic region of the mediastinum (short arrow), a finding suspicious for metastasis. Long arrow = activity in lower right paratracheal nodes. Mediastinoscopy revealed malignancy in a right paratracheal node. The patient subsequently received mediastinal radiation therapy in addition to chemotherapy.
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Pleura and Lung Parenchyma
Pleural and lung parenchymal metastases are usually seen with more widely disseminated disease (23) (Fig 9). In a preliminary analysis that compared FDG PET and CT for evaluation of mediastinal and IM nodes (44), patients with mediastinal or IM node disease at FDG PET had a significantly greater likelihood of developing ipsilateral pleural or lung parenchymal metastasis (odds ratio, 5.87; 95% confidence interval, 2.1, 16.5) than did patients without mediastinal or IM node disease at FDG PET. This result suggests that spread to the pleura and lung parenchyma occurs primarily through lymphatic pathways. A characteristic pattern of spread of disease to the pleura, mediastinum, and lung as well as isolated sternal metastases has been described in patients with IM node metastases (45) (Figs 7, 9).
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Figure 9a. Disseminated disease in a 38-year-old woman with a large right breast mass, which was diagnosed as poorly differentiated infiltrating ductal carcinoma with core needle biopsy. She initially declined neoadjuvant chemotherapy or surgery, opting for herbal therapies, and returned for restaging 3 months later. (a) Axial FDG PET image of the lower chest shows focal FDG uptake in a lower thoracic vertebra (long solid arrow), the right pleura (short solid arrow), the parenchyma of both lower lobes (arrowheads), and bilateral IM nodes (open arrows). (b) Coronal FDG PET image of the lower thoracic spine shows diffuse uptake in the thoracic spine (arrowheads). (c) Posterior bone scan obtained 1 day earlier is negative for metastases. This result indicates that the metastases diffusely involve the bone marrow or are lytic lesions without significant blastic response.
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Figure 9b. Disseminated disease in a 38-year-old woman with a large right breast mass, which was diagnosed as poorly differentiated infiltrating ductal carcinoma with core needle biopsy. She initially declined neoadjuvant chemotherapy or surgery, opting for herbal therapies, and returned for restaging 3 months later. (a) Axial FDG PET image of the lower chest shows focal FDG uptake in a lower thoracic vertebra (long solid arrow), the right pleura (short solid arrow), the parenchyma of both lower lobes (arrowheads), and bilateral IM nodes (open arrows). (b) Coronal FDG PET image of the lower thoracic spine shows diffuse uptake in the thoracic spine (arrowheads). (c) Posterior bone scan obtained 1 day earlier is negative for metastases. This result indicates that the metastases diffusely involve the bone marrow or are lytic lesions without significant blastic response.
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Figure 9c. Disseminated disease in a 38-year-old woman with a large right breast mass, which was diagnosed as poorly differentiated infiltrating ductal carcinoma with core needle biopsy. She initially declined neoadjuvant chemotherapy or surgery, opting for herbal therapies, and returned for restaging 3 months later. (a) Axial FDG PET image of the lower chest shows focal FDG uptake in a lower thoracic vertebra (long solid arrow), the right pleura (short solid arrow), the parenchyma of both lower lobes (arrowheads), and bilateral IM nodes (open arrows). (b) Coronal FDG PET image of the lower thoracic spine shows diffuse uptake in the thoracic spine (arrowheads). (c) Posterior bone scan obtained 1 day earlier is negative for metastases. This result indicates that the metastases diffusely involve the bone marrow or are lytic lesions without significant blastic response.
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Extrathoracic Recurrence
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Bone
The skeleton is the most common site of distant metastases in patients treated with mastectomy and adjuvant chemotherapy. FDG PET and bone scintigraphy have been shown to be complemen-tary in the detection of skeletal metastases (46). FDG PET is more sensitive than bone scintigraphy for detection of lytic metastases or lesions predominantly involving the bone marrow, accounting for cases that are positive at FDG PET and negative at bone scanning (Fig 9); bone scintigraphy is more sensitive than FDG PET for detection of osteoblastic metastases, accounting for cases that are positive at bone scanning and negative at FDG PET (46). Serial FDG PET can be used to assess the response of bone metastases to therapy (Fig 10) and may be more helpful than bone scintigraphy, particularly during the period shortly after the start of hormonal or cytotoxic therapy, when the flare phenomenon at bone scintigraphy is most prevalent (47,48).
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Figure 10a. Assessment of therapy response with serial FDG PET in a 28-year-old woman who underwent right lumpectomy and axillary node dissection for a 3-cm-diameter high-grade infiltrating ductal carcinoma; eight of 21 axillary nodes were positive. She also received high-dose adjuvant chemotherapy and breast radiation therapy. Two years after surgery, back pain and elevated levels of tumor markers developed. Bone scanning demonstrated diffuse skeletal metastases, and CT revealed suspiciously enlarged mediastinal lymph nodes. (a) Coronal FDG PET image of the chest shows uptake in subcarinal mediastinal lymph nodes (arrow) and both hila (arrowheads). (b) Coronal whole-body FDG PET image shows diffuse metastases in the spine and pelvis. (c) Coronal whole-body FDG PET image obtained after five cycles of more aggressive chemotherapy shows marked improvement in the mediastinal and skeletal metastases.
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Figure 10b. Assessment of therapy response with serial FDG PET in a 28-year-old woman who underwent right lumpectomy and axillary node dissection for a 3-cm-diameter high-grade infiltrating ductal carcinoma; eight of 21 axillary nodes were positive. She also received high-dose adjuvant chemotherapy and breast radiation therapy. Two years after surgery, back pain and elevated levels of tumor markers developed. Bone scanning demonstrated diffuse skeletal metastases, and CT revealed suspiciously enlarged mediastinal lymph nodes. (a) Coronal FDG PET image of the chest shows uptake in subcarinal mediastinal lymph nodes (arrow) and both hila (arrowheads). (b) Coronal whole-body FDG PET image shows diffuse metastases in the spine and pelvis. (c) Coronal whole-body FDG PET image obtained after five cycles of more aggressive chemotherapy shows marked improvement in the mediastinal and skeletal metastases.
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Figure 10c. Assessment of therapy response with serial FDG PET in a 28-year-old woman who underwent right lumpectomy and axillary node dissection for a 3-cm-diameter high-grade infiltrating ductal carcinoma; eight of 21 axillary nodes were positive. She also received high-dose adjuvant chemotherapy and breast radiation therapy. Two years after surgery, back pain and elevated levels of tumor markers developed. Bone scanning demonstrated diffuse skeletal metastases, and CT revealed suspiciously enlarged mediastinal lymph nodes. (a) Coronal FDG PET image of the chest shows uptake in subcarinal mediastinal lymph nodes (arrow) and both hila (arrowheads). (b) Coronal whole-body FDG PET image shows diffuse metastases in the spine and pelvis. (c) Coronal whole-body FDG PET image obtained after five cycles of more aggressive chemotherapy shows marked improvement in the mediastinal and skeletal metastases.
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Liver
The liver is the main visceral organ where metastases from breast cancer occur. Liver metastases generally occur later than locoregional recurrences and are associated with a much worse prognosis (22) (Fig 11). Patients with estrogen receptor (ER)–negative primary tumors have an increased risk of liver metastases compared with patients with ER-positive tumors (49). The predominant mode of metastasis to the liver is hematogenous; however, lymphatic spread from IM nodes to pericardial nodes and below the diaphragm to nodes in the porta hepatis and finally the hepatic parenchyma (Fig 12) has been described (16). No studies of the accuracy of FDG PET for detection of liver metastases with pathologic or imaging follow-up confirmation in breast cancer patients have been published, to our knowledge. However, investigators have shown that FDG PET has an overall sensitivity of greater than 90% in detection of liver metastases in patients with primary colorectal tumors compared with a sensitivity of 74%–85% for CT (50,51). The sensitivity of FDG PET is limited (25%–43%) for detection of metastatic lesions less than 1 cm in diameter (52,53), but FDG PET (with a positive result) may help characterize lesions of this size, which are generally too small to be characterized with CT.
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Figure 11a. Liver metastasis in a 52-year-old woman in whom infiltrating carcinoma of the left breast was diagnosed; an axillary node was also positive for malignancy at fine-needle aspiration. Despite high-dose chemotherapy, the cancer progressed. Restaging CT 1 year after diagnosis showed a 1.2-cm-diameter lesion in the right hepatic lobe and no suspiciously enlarged mediastinal nodes. FDG PET was performed to better show the extent of disease. (a, b) Coronal (a) and axial (b) FDG PET images of the liver show focal uptake (SUV = 4.8) in the metastasis to the right hepatic lobe (arrow). Arrowheads indicate FDG excretion in the collecting systems of the upper kidneys. (c) Coronal FDG PET image obtained anterior to a shows focal FDG accumulation in the porta hepatis (arrow). (d) Coronal FDG PET image of the midchest shows foci of uptake (SUV = 4.0) in the mediastinum (arrows), findings consistent with metastases. Exploratory laparotomy for potential resection of the liver metastasis was performed, and biopsy of a node in the porta hepatis showed malignancy. Liver resection was not performed.
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Figure 11b. Liver metastasis in a 52-year-old woman in whom infiltrating carcinoma of the left breast was diagnosed; an axillary node was also positive for malignancy at fine-needle aspiration. Despite high-dose chemotherapy, the cancer progressed. Restaging CT 1 year after diagnosis showed a 1.2-cm-diameter lesion in the right hepatic lobe and no suspiciously enlarged mediastinal nodes. FDG PET was performed to better show the extent of disease. (a, b) Coronal (a) and axial (b) FDG PET images of the liver show focal uptake (SUV = 4.8) in the metastasis to the right hepatic lobe (arrow). Arrowheads indicate FDG excretion in the collecting systems of the upper kidneys. (c) Coronal FDG PET image obtained anterior to a shows focal FDG accumulation in the porta hepatis (arrow). (d) Coronal FDG PET image of the midchest shows foci of uptake (SUV = 4.0) in the mediastinum (arrows), findings consistent with metastases. Exploratory laparotomy for potential resection of the liver metastasis was performed, and biopsy of a node in the porta hepatis showed malignancy. Liver resection was not performed.
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Figure 11c. Liver metastasis in a 52-year-old woman in whom infiltrating carcinoma of the left breast was diagnosed; an axillary node was also positive for malignancy at fine-needle aspiration. Despite high-dose chemotherapy, the cancer progressed. Restaging CT 1 year after diagnosis showed a 1.2-cm-diameter lesion in the right hepatic lobe and no suspiciously enlarged mediastinal nodes. FDG PET was performed to better show the extent of disease. (a, b) Coronal (a) and axial (b) FDG PET images of the liver show focal uptake (SUV = 4.8) in the metastasis to the right hepatic lobe (arrow). Arrowheads indicate FDG excretion in the collecting systems of the upper kidneys. (c) Coronal FDG PET image obtained anterior to a shows focal FDG accumulation in the porta hepatis (arrow). (d) Coronal FDG PET image of the midchest shows foci of uptake (SUV = 4.0) in the mediastinum (arrows), findings consistent with metastases. Exploratory laparotomy for potential resection of the liver metastasis was performed, and biopsy of a node in the porta hepatis showed malignancy. Liver resection was not performed.
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Figure 11d. Liver metastasis in a 52-year-old woman in whom infiltrating carcinoma of the left breast was diagnosed; an axillary node was also positive for malignancy at fine-needle aspiration. Despite high-dose chemotherapy, the cancer progressed. Restaging CT 1 year after diagnosis showed a 1.2-cm-diameter lesion in the right hepatic lobe and no suspiciously enlarged mediastinal nodes. FDG PET was performed to better show the extent of disease. (a, b) Coronal (a) and axial (b) FDG PET images of the liver show focal uptake (SUV = 4.8) in the metastasis to the right hepatic lobe (arrow). Arrowheads indicate FDG excretion in the collecting systems of the upper kidneys. (c) Coronal FDG PET image obtained anterior to a shows focal FDG accumulation in the porta hepatis (arrow). (d) Coronal FDG PET image of the midchest shows foci of uptake (SUV = 4.0) in the mediastinum (arrows), findings consistent with metastases. Exploratory laparotomy for potential resection of the liver metastasis was performed, and biopsy of a node in the porta hepatis showed malignancy. Liver resection was not performed.
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Figure 12a. Lymphatic spread of breast cancer to the liver in a 40-year-old woman who underwent lumpectomy and axillary node dissection for infiltrating ductal carcinoma in the upper inner quadrant. The tumor was 3 cm in diameter with positive surgical margins, and three of 12 nodes were positive. She received adjuvant chemotherapy and radiation therapy to the breast and axillary region. One year after surgery, levels of tumor markers were elevated. Restaging bone scans were negative for metastasis, and the only abnormality revealed at CT of the chest and abdomen was a right pleural effusion. (a, b) Coronal FDG PET image obtained through the anterior chest (a) and axial FDG PET image obtained through the upper chest (b) show uptake in a right IM node (long arrow), the subcarinal mediastinum (arrowheads), and a left supraclavicular node (short arrow). (c) Coronal FDG PET image obtained through the midchest and upper abdomen shows foci of uptake in several subcarinal mediastinal nodes (short arrows) and below the diaphragm in the porta hepatis (long arrow). Note the photopenic area in the right hemithorax and the mild linear uptake over the right lung apex (arrowheads), findings consistent with a malignant right pleural effusion. Metastases to the lung and liver subsequently developed.
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Figure 12b. Lymphatic spread of breast cancer to the liver in a 40-year-old woman who underwent lumpectomy and axillary node dissection for infiltrating ductal carcinoma in the upper inner quadrant. The tumor was 3 cm in diameter with positive surgical margins, and three of 12 nodes were positive. She received adjuvant chemotherapy and radiation therapy to the breast and axillary region. One year after surgery, levels of tumor markers were elevated. Restaging bone scans were negative for metastasis, and the only abnormality revealed at CT of the chest and abdomen was a right pleural effusion. (a, b) Coronal FDG PET image obtained through the anterior chest (a) and axial FDG PET image obtained through the upper chest (b) show uptake in a right IM node (long arrow), the subcarinal mediastinum (arrowheads), and a left supraclavicular node (short arrow). (c) Coronal FDG PET image obtained through the midchest and upper abdomen shows foci of uptake in several subcarinal mediastinal nodes (short arrows) and below the diaphragm in the porta hepatis (long arrow). Note the photopenic area in the right hemithorax and the mild linear uptake over the right lung apex (arrowheads), findings consistent with a malignant right pleural effusion. Metastases to the lung and liver subsequently developed.
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Figure 12c. Lymphatic spread of breast cancer to the liver in a 40-year-old woman who underwent lumpectomy and axillary node dissection for infiltrating ductal carcinoma in the upper inner quadrant. The tumor was 3 cm in diameter with positive surgical margins, and three of 12 nodes were positive. She received adjuvant chemotherapy and radiation therapy to the breast and axillary region. One year after surgery, levels of tumor markers were elevated. Restaging bone scans were negative for metastasis, and the only abnormality revealed at CT of the chest and abdomen was a right pleural effusion. (a, b) Coronal FDG PET image obtained through the anterior chest (a) and axial FDG PET image obtained through the upper chest (b) show uptake in a right IM node (long arrow), the subcarinal mediastinum (arrowheads), and a left supraclavicular node (short arrow). (c) Coronal FDG PET image obtained through the midchest and upper abdomen shows foci of uptake in several subcarinal mediastinal nodes (short arrows) and below the diaphragm in the porta hepatis (long arrow). Note the photopenic area in the right hemithorax and the mild linear uptake over the right lung apex (arrowheads), findings consistent with a malignant right pleural effusion. Metastases to the lung and liver subsequently developed.
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Brain
Metastasis to the brain usually occurs near the end of the course of progression of breast cancer. FDG PET has no role in the detection of brain metastases; owing to the high metabolic activity (and therefore the high normal uptake of FDG) in the cortex of the brain, FDG PET is not sensitive for brain metastases. At many centers, including ours, the brain is not routinely included in tumor surveys for breast cancer patients.
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Other PET Tracers
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FDG uptake by the tumor reflects one aspect of its physiology, namely, glucose metabolism. Glucose metabolism is elevated in tumor cells compared with that in normal tissues (54); this fact explains in part why FDG uptake in tumors is increased compared with that in the normal surrounding tissue. The biochemical properties and long half-life of FDG make it a suitable tracer for clinical oncologic imaging, particularly for determining the extent of glycolytically active tumor. Other PET tracers have been developed to probe additional important physiologic characteristics of tumor biology (55,56). [Carbon-11]-thymidine, a precursor in DNA synthesis, has been used to measure in vivo cellular proliferation in tumors (57–59). PET with this tracer shows promise in measurement and prediction of early response to chemotherapeutic agents (58). [F-18]-fluoromisonidazole, a fluorinated version of a compound tested as a radiosensitizer, has been used as a marker for tumor hypoxia (60), a condition that promotes resistance to radiation therapy (61). Imaging with ER-based compounds is particularly relevant to breast cancer because the ER expression in breast tumors is a prognosticator of disease-free and overall survival (ER-negative tumors have a worse prognosis than ER-positive ones) (62) and determines which patients will benefit from hormonal therapy. [F-18]-fluoroestradiol (FES) has shown the most promise among PET tracers developed in this class of compounds (63). Preliminary studies have shown that the quantitative level of FES uptake correlates with the level of ER expression (64) and that the quantitative level of FES uptake in the primary tumor before therapy can predict the response to tamoxifen therapy (65). When these various tracers are used, PET has the ability to provide regional quantitative measurements of in vivo breast tumor physiology, which can aid in selecting individualized treatment plans.
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Abstract
LEARNING OBJECTIVES FOR TEST...
