Performance of FDG PET/CT in the clinical management of breast cancer.

In this analysis, the role of metabolic imaging with fluorine 18 fluorodeoxyglucose (FDG) in breast cancer is reviewed. The analysis was limited to recent works by using state-of-the-art positron emission tomography (PET)/computed tomography (CT) technology. The strengths and limitations of FDG PET/CT are examined in various clinical settings, and the following questions are answered: Is FDG PET/CT useful to differentiate malignant from benign breast lesions? Can FDG PET/CT replace sentinel node biopsy for axillary staging? What is the role of FDG PET/CT in initial staging of inflammatory or locally advanced breast cancer? What is the role of FDG PET/CT in initial staging of clinical stage IIA and IIB and primary operable stage IIIA breast cancer? How does FDG PET/CT compare with conventional techniques in the restaging of cancer in patients who are suspected of having disease recurrence? What is the role of FDG PET/CT in the assessment of early response to neoadjuvant therapy and of response to therapy for metastatic disease? Some recommendations for clinical practice are given.

Related papers:

title: SUV varies with time after injection in (18)F-FDG PET of breast cancer: characterization and method to adjust for time differences.
abstract: The purpose of this study was to measure how (18)F-FDG PET standardized uptake values (SUVs) change over time in breast cancer and to examine the feasibility of a method to adjust for modest variations in the time of uptake measurement experienced in clinical practice.



(18)F-FDG PET was performed as 60-min dynamic imaging with an additional image acquired at approximately 75 min after injection. For 20 newly diagnosed, untreated, locally advanced breast cancer patients, both the maximum SUV and the average SUV within the lesion were calculated with and without correction for blood glucose concentration. A linear regression analysis of the portion of the time-activity curves starting at 27 min after injection was used to estimate the rate of SUV change per minute during the interval from 27 to 75 min. The rate of SUV change with time was compared with the instantaneous SUV obtained at different times from 27 to 75 min.



In untreated breast cancer, (18)F-FDG SUV values changed approximately linearly after 27 min at a rate ranging from -0.02 to 0.15 per minute. In addition, the rate of SUV change was linearly correlated with the instantaneous SUV measured at different times after injection (r(2) ranged from 0.82 to 0.94; P < 0.001). Using this information, an empirical linear model of SUV variation with time from injection to uptake measurement was formulated. The comparison method was then applied prospectively to a second set of 20 locally advanced breast cancer lesions not included in the initial analysis. The average percent error using the method to adjust for time differences was 8% and 5% for maximum SUVs and average SUVs ranging from 2 to 12.



In untreated breast cancer, the SUV at any time point approximately predicts the rate of change of SUV over time. A comparison method based on this finding appears feasible and may improve the usefulness of the SUV by providing a means of comparing SUV acquired at different times after injection.

title: Time Course of Tumor SUV in 18F-FDG PET of Breast Cancer: Presentation of a Simple Model Using a Single Reference Point for Time Corrections of Tumor SUVs
abstract: Tumor standardized uptake values (SUVs) vary with the interval between 18F-FDG injection and image acquisition. This paper presents a simple method using a single reference point to make appropriate time corrections for tumor SUVs.  The reference point method was algebraically deduced from observations made by Beaulieu et al., who found that tumor SUVs behaved linearly over time (∼30 to 75 min after 18F-FDG injection). Eighteen patients with breast cancer were dynamically examined with PET/CT (∼60 and 80 min after 18F-FDG injection). Maximum SUV was calculated by applying 2 different iterative reconstruction methods (high-definition reconstruction and attenuation-weighted ordered-subsets expectation maximization). Reference points for time corrections were given, and errors for corrections obtained with the reference point method were calculated.  Variations in the reconstruction algorithm strongly influenced the coordinates of the reference point. Time corrections using the reference point method were more accurate at higher tumor SUVs (>8 at high-definition reconstruction and >6 at attenuation-weighted ordered-subsets expectation maximization) than at lower ones.  A common origin of tumor SUVs over time exists in breast cancer. In combination with the linear behavior of tumor SUVs between approximately 30 and 80 min, such a reference point allows for straightforward time corrections of tumor SUVs. Parameters for image reconstruction must be considered because they influence the coordinates of the reference point.

title: Dual-Modality Imaging: Combining Anatomy and Function*
abstract: The extensive development of image fusion techniques over the past 20 y has shown that the fusion of images from complementary modalities offers a more complete and accurate assessment of disease than do images from a single modality. Although software techniques have been successful in fusing images of the brain from different modalities, they have achieved rather limited success for other parts of the body. The recent introduction of technology that can acquire both anatomic and functional images in a single scan has addressed many of the limitations of software fusion. The combination of CT and PET was introduced commercially in 2001, followed by CT and SPECT in 2004. Clinical adoption of PET/CT has been surprisingly rapid, and despite continuing debate, the new technology has advanced the use of clinical molecular imaging, particularly for oncology.

title: PET/CT: form and function.
abstract: Functional imaging with positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of malignant disease, image-guided therapy planning, and treatment monitoring. PET with the labeled glucose analogue fluorine 18 fluorodeoxyglucose (FDG) is a relatively recent addition to the medical technology for imaging of cancer, and FDG PET complements the more conventional anatomic imaging modalities of computed tomography (CT) and magnetic resonance imaging. CT is complementary in the sense that it provides accurate localization of organs and lesions, while PET maps both normal and abnormal tissue function. When combined, the two modalities can help both identify and localize functional abnormalities. Attempts to align CT and PET data sets with fusion software are generally successful in the brain; other areas of the body is more challenging, owing to the increased number of degrees of freedom between the two data sets. These challenges have recently been addressed by the introduction of the combined PET/CT scanner, a hardware-oriented approach to image fusion. With such a device, accurately registered anatomic and functional images can be acquired for each patient in a single scanning session. Currently, over 800 combined PET/CT scanners are installed in medical institutions worldwide, many of them for the diagnosis and staging of malignant disease and increasingly for monitoring of the response to therapy. This review will describe some of the most recent technologic developments in PET/CT instrumentation and the clinical indications for which combined PET/CT has been shown to be more useful than PET and CT performed separately.

title: The evolving role of PET/CT in breast cancer
abstract: Departments of Nuclear Medicine, Medical Oncology, Breast Diseases Unit, Saint-Louis Hospital, EAD Imagerie Moléculaire Diagnostique et Ciblage Thérapeutique, IUH, University of Paris VII, Paris, France, Department of Nuclear Medicine, Santa Maria della Misericordia, Rovigo Hospital, Rovigo, Italy and Department of Nuclear Medicine, Imperial College Healthcare, Hammersmith Hospital, London, UK Correspondence to Domenico Rubello, MD, Department of Nuclear Medicine, PET/CT Centre, Medical Physics, Radiology, Santa Maria della Misericordia Hospital, Rovigo, Italy Tel: + 39 320 7985599; fax: + 39 42 5394434;

title: The Effects of Estrogen, Progesterone, and C-erbB-2 Receptor States on 18F-FDG Uptake of Primary Breast Cancer Lesions
abstract: The purpose of this prospective study was to investigate whether correlations exist between 18F-FDG uptake of primary breast cancer lesions and predictive and prognostic factors such as estrogen receptor (ER), progesterone receptor (PR), and C-erbB-2 receptor (C-erbB-2R) states.  Before undergoing partial or total mastectomy, 213 patients with newly diagnosed breast cancer underwent 18F-FDG PET (5.2 MBq/kg of body weight). The maximum standardized uptake value (SUV) of the primary lesion was measured in each patient. Standard immunohistochemistry was performed on a surgical specimen of the cancer lesion to characterize the receptor state of the tumor cells. Pearson χ2 tests were performed on the cross-tables of different receptor states to test any association that may exist among ER, PR, and C-erbB-2R. Maximum SUV measurements for different receptor states were compared using factorial ANOVA in a completely random design.  After exclusion of certain lesions, 118 lesions were analyzed for this study. The mean maximum SUVs of ER-positive and ER-negative lesions were 3.03 ± 0.26 and 5.64 ± 0.75, whereas those of PR were 3.24 ± 0.29 and 4.89 ± 0.67, respectively, and those of C-erbB-2R were 4.64 ± 0.70 and 3.70 ± 0.35, respectively. χ2 tests for ER and PR showed that if one is positive then the other tends to be positive as well (χ2 = 71.054, P < 0.01). For ER and C-erbB-2R states, if ER is positive, C-erbB-2R will more likely be negative (χ2 = 13.026, P < 0.01). No relationship was detected between PR and C-erbB-2R states (χ2 = 3.695, P > 0.05). ANOVAs showed that PR state alone (F = 0.095, P > 0.05) and C-erbB-2R state alone (F = 0.097, P > 0.05) had no effect on 18F-FDG uptake but ER state alone had an effect (F = 9.126, P < 0.01). ER and PR being together had no additional effect on 18F-FDG uptake. Our study also demonstrated that interactions exist between ER and C-erbB-2R state and between PR and C-erbB-2R state.  SUV measurements may provide valuable information about the state of ER, PR, and C-erbB-2R and the associated glucose metabolism as measured by 18F-FDG uptake of the primary breast cancer lesions. Such an association may be of importance to treatment planning and outcome in these patients.

title: Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography.
abstract: Variable uptake of the glucose analog (18)fluorodeoxyglucose (FDG) has been noticed in positron emission tomography (PET) studies of breast cancer patients, with low uptake occurring especially in lobular cancer. At present, no satisfactory biologic explanation exists for this phenomenon. This study compared (18)FDG uptake in vivo with biomarkers expected to be involved in the underlying biologic mechanisms.



Preoperative (18)FDG-PET scans were performed in 55 patients. (18)FDG activity was assessed visually by three observers using a four-point score. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut-1); Hexokinase (HK) I, II, and III; macrophages; hypoxia-inducible factor-1-alfa (HIF-1alpha); vascular endothelial growth factor (VEGF(165)); and microvessels. Mitotic activity index (MAI), amount of necrosis, number of lymphocytes, and tumor cells/volume were assessed.



There were positive correlations between (18)FDG uptake and Glut-1 expression (P <.001), MAI (P =.001), amount of necrosis (P =.010), number of tumor cells/volume (P =.009), expression of HK I (P =.019), number of lymphocytes (P =.032), and microvessel density (r =.373; P =.005). ), HK II, HK III, and macrophages showed no univariate correlation with (18)FDG. In logistic regression, however, HIF-1alpha and HK II added value to MAI and Glut-1.



(18)FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of (18)FDG into the cell, HK for entering (18)FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1alpha for upregulating Glut-1. Together, these features explain why breast cancers vary in (18)FDG uptake and elucidate the low uptake in lobular breast cancer.

title: Overexpression of glut‐1 glucose transporter in human breast cancer an immunohistochemical study
abstract: Breast cancers have higher than normal glucose metabolism, but the mechanism of glucose entry into these tumors is not well understood.

title: Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations.
abstract: To evaluate the diagnostic value of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) for the diagnosis of primary breast cancer.



Preoperatively, 144 patients with masses suggestive of breast cancer underwent PET imaging of the breast. To identify breast cancer by increased metabolic activity, parametric FDG-PET images were analyzed for increased tracer uptake applying conventional image reading (CIR) and sensitive image reading (SIR). One hundred eighty-five breast tumors were evaluated by histology, revealing 132 breast carcinomas and 53 benign masses.



Breast carcinomas were identified with an overall sensitivity of 64.4% (CIR) and 80.3% (SIR). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, from 94.3% (CIR) to 75.5% (SIR). At stage pT1, only 30 (68.2%) of 44 breast carcinomas were detected, compared with 57 (91.9%) of 62 at stage pT2. A higher percentage of invasive lobular carcinomas were false-negative (65.2%) compared with invasive ductal carcinomas (23.7%). Nevertheless, positive PET scans provided a high positive-predictive value (96.6%) for breast cancer.



Partial volume effects and varying metabolic activity (dependent on tumor type) seem to represent the most significant limitations for the routine diagnostic application of PET. The number of invasive procedures is therefore unlikely to be significantly reduced by PET imaging in patients presenting with abnormal mammography. However, the high positive-predictive value, resulting from the increased metabolic activity of malignant tissue, may be used with carefully selected subsets of patients as well as to determine the extent of disease or to assess therapy response.

title: Clinicopathologic factors associated with false negative FDG–PET in primary breast cancer
abstract: The present study was aimed to determine the clinicopathologic factors that predict false negative (FN) PET results in these patients. total of 116 breast lesions in 111 patients (pre-menopausal 45; perimenopausal 15; post-menopausal 51) with known or suspicious of breast cancer who underwent FDG–PET scans for staging, were included in this study. The median age was 52±11 years (range 32–79 years). All PET studies results were correlated with follow-up surgical pathology results. A cut off value of 2.5 was considered for positive or negative PET results. Univariate and multivariate analyses were performed to identify factors associated with FN results.ResultsOf 116 breast lesions, 85 were malignant and 31 were benign on histopathology. Of the 85 malignant lesions, 41 were true positive (TP) and 44 were FN. Among the 31 benign lesions, 30 were true negative and one was false positive. There was significant difference in the tumor size (p=0.003) and tumor grade (p=0.001) in patients with TP and FN PET results. Multivariate logistic regression demonstrated that tumor size (≤10 mm) and low tumor grade were independently associated with FN results. No significant relationship of FN PET results was found with age, menopausal status, tumor type, c-erbB-2, estrogen and progesterone receptors, sentinel lymph node or distant metastasis, parenchymal density and multifocality of primary breast tumor.ConclusionIn present study, tumor size and tumor grade are independent factors that predict FDG–PET results. Smaller tumors (≤10 mm) and low-grade tumors are strong predictor of FN FDG–PET results.

title: [PET/CT in breast cancer: an update].
abstract: The authors discuss the various roles of 18F-FDG PET/CT in the management of breast cancer. Roles of new tracers such as F-18 fluoro-L-thymidine (a marker of cell proliferation), 18-fluoro-17-B-estradiol (marker of estrogen receptor) and sodium fluoride (marker of bone matrix) are also mentioned. There is little justification for the use of FDG-PET/CT in patient with clinically T1 (< or = 2 cm) N0 tumours. Notably, it cannot be used as a substitute to SLNB "sentinel lymph node biopsy" for axillary staging due to limited sensitivity for the detection of small metastases. The case is different in higher risk patients, and especially so in patients with locally advanced disease. FDG-PET/CT in these patients might depict lymph node involvement in the level III of Berg or in supraclavicular or internal mammary basins. It might also uncover occult distant metastases, notably, early osteomedullary infiltration. Thus, for these tumors, initial PET/CT can enable better intramodality treatment planning or a change in treatment. PET/CT as a whole-body examination is also very efficient in case of suspicion of recurrence. On the other hand, many studies show that this functional imaging could be used to assess early response to neoadjuvant chemotherapy or to chemotherapy of metastatic disease. 18FDG-PET/CT could thus become an unavoidable modality to answer various clinical situations.

title: 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) imaging in the staging and prognosis of inflammatory breast cancer
abstract: To prospectively assess fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) staging and prognosis value in patients with suspected inflammatory breast cancer (IBC).

title: Association between [18F]fluorodeoxyglucose uptake and prognostic parameters in breast cancer
abstract: This study analysed the correlation between [18F]fluorodeoxyglucose (FDG) uptake assessed by positron emission tomography (PET) in breast tumours, and histopathological and inmunohistochemical prognostic factors.

title: Association between [18F]fluorodeoxyglucose uptake and postoperative histopathology, hormone receptor status, thymidine labelling index and p53 in primary breast cancer: a preliminary observation
abstract: To investigate the possible role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in the prognostic evaluation of primary breast cancer, we studied 86 patients with T1–3 (TNM classification) breast tumours before surgery and compared the tumour FDG uptake, calculated as a standardized uptake value (SUV), with postoperative histopathological findings, steroid hormone receptor status of the tumour, thymidine labelling index (LI) and tissular expression of p53. SUV was significantly higher in infiltrating ductal carcinomas (n = 68; median SUV = 5.6) than in lobular ones (n = 18; median SUV = 3.8), and in grade 3 carcinomas (n = 26; median SUV = 6.2) than in grade 1–2 ones (n = 60; median SUV = 4.9). Moreover, SUV was significantly higher in carcinomas with high levels of p53 (n = 12; median SUV = 9.5) than in those with low levels (n = 48; median SUV = 4.25). By contrast, there was no significant correlation between SUV and the steroid hormone receptor status or LI of tumours. Our data demonstrate that FDG uptake, expressed as SUV, is associated with certain prognostic factors in breast cancer, such as histopathological grading and p53 expression, which can be assessed only by means of postoperative in vitro examinations. Hence, the information provided by FDG-PET is to some extent related to relevant information on tumour biology. The clinical value of these data will have to be confirmed by analysis of the independence of SUV from other prognostic factors by means of a multivariate analysis performed on a larger series of patients with adequate follow-up. If SUV is confirmed as an independent variable, FDG-PET could assume an important role in the determination of appropriate therapeutic strategies for primary breast cancer.

title: Standardized Uptake Values for Breast Carcinomas Assessed by Fluorodeoxyglucose-Positron Emission Tomography Correlate with Prognostic Factors
abstract: Several studies have revealed the diagnostic value of fluorodeoxyglucose-positron emission tomography for breast carcinomas. However, breast carcinomas display considerable variation in 18F-labeled 2-fluoro-2-deoxy-D-glucose uptake, and few papers have reported the clinical utility of the standardized uptake values (SUV). The purpose of this study is to investigate the relationship between SUV assessed by positron emission tomography (PET) and the clinicopathological characteristics of breast carcinoma. We reviewed 52 breast carcinomas of 45 patients presented at our department between January 2004 and July 2005. We compared the histopathological findings of the breast carcinomas with the preoperative SUV. Of the 52 breast carcinomas, 49 (94%) were detected by preoperative PET. A positive correlation was found between the SUV and tumor size (P < 0.01), histological grade (P < 0.01), the expression of the estrogen receptor (P < 0.001), progesterone receptor (P < 0.01), and p53 (P < 0.01). The number of metastatic axillary lymph nodes (r = 0.73; P < 0.0001) and the MIB-1 labeling rates (r = 0.5; P < 0.01) correlated with the SUV of the breast carcinomas. No relationship existed between the SUV and the following: histological tumor types (P = 0.07), human epidermal growth factor receptor-2 status (P = 0.10), and the presence of metastatic lymph nodes (P = 0.10). The SUV of the breast carcinomas correlate with several histopathological and immunohistochemical prognostic factors. We can obtain information on the degree of malignancy of the carcinoma and prognostic factors by preoperative PET examination.

title: FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters
abstract: The aim of this study was to evaluate the possible correlation between preoperative FDG-PET results in human breast cancer and the prognostic markers Ki-67, c-erb B2, p53, oestrogen/progesterone receptor status, axillary lymph node status, tumour size and tumour grading. Seventy-five female patients with breast cancer were included in this prospective study. Patient selection was independent of tumour size and the suspected clinical stage of disease. A high-resolution full-ring scanner (Siemens ECAT HR+) was used for PET imaging. The FDG uptake of breast tumours was calculated as the tumour to background ratio (TBR). In resected cancer tissue specimens, the proliferative fraction was evaluated by Ki-67 immunostaining. Additionally, immunostaining of the prognostic markers c-erb B2, p53, and progesterone and oestrogen receptors was performed. Haematoxylin and eosin-stained sections were used for tumour grading. Correlations between FDG uptake and prognostic markers were assumed to be significant at P<0.05 using the Mann-Whitney U test. In ductal breast cancer, mean TBR was 17.3 (median 7.7, range 1.6–122.7), while in lobular cancer it was 6.5 (median 3.7, range 1.4–22.7). Mean proliferative fraction (% Ki-67 positive tumour cells) was 15%±13.8% (median 10%, range 0%–60%). Twenty-three carcinomas showed <5% Ki-67 positive tumour cells. Statistical analysis indicated a positive correlation between FDG uptake and proliferative index in ductal breast cancer (P<0.0001, r=0.63). By contrast, there was no correlation between FDG uptake and c-erb B2 (P=0.79), p53 (P=0.92), tumour grading (P=0.09), oestrogen receptor status (P=0.41), progesterone receptor status (P=0.34), axillary lymph node status (P=0.90) and tumour size (P=0.3). It is concluded that FDG uptake is significantly higher in ductal breast cancer than in lobular cancer (P<0.05). FDG uptake correlates with proliferative activity assessed by Ki-67 immunostaining (P<0.05). A significant correlation with the other prognostic markers, however, could not be demonstrated.

title: Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer
abstract: PurposeThe aim of this study was to determine the impact of the main clinicopathological and biological prognostic factors of breast cancer on 18F-fluorodeoxyglucose (FDG) uptake. Only women with tumours larger than 20 mm (T2–T4) were included in order to minimize bias of partial volume effect.MethodsIn this prospective study, 132 consecutive women received FDG PET/CT imaging before starting neoadjuvant chemotherapy. Maximum standardized uptake values (SUVmax) were compared to tumour characteristics as assessed on core biopsy.ResultsThere was no influence of T and N stage on SUV. Invasive ductal carcinoma showed higher SUV than lobular carcinoma. However, the highest uptake was found for metaplastic tumours, representing 5% of patients in this series. Several biological features usually considered as bad prognostic factors were associated with an increase in FDG uptake: the median of SUVmax was 9.7 for grade 3 tumours vs 4.8 for the lower grades (p < 0.0001); negativity for oestrogen receptors (ER) was associated with higher SUV (ER+ SUV = 5.5; ER− SUV = 7.6; p = 0.003); triple-negative tumours (oestrogen and progesterone receptor negative, no overexpression of c-erbB-2) had an SUV of 9.2 vs 5.8 for all others (p = 0005); p53 mutated tumours also had significantly higher SUV (7.8 vs 5.0; p < 0.0001). Overexpression of c-erbB-2 had no effect on the SUV value.ConclusionKnowledge of the factors influencing uptake is important when interpreting FDG PET/CT scans. Also, findings that FDG uptake is highest in those patients with poor prognostic features (high grade, hormone receptor negativity, triple negativity, metaplastic tumours) is helpful to determine who are the best candidates for baseline staging.

title: Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis.
abstract: Breast cancer is characterized by elevated glucose consumption resulting in increased uptake of 18F-FDG. However, tracer uptake varies considerably among tumors imaged with PET. This study compared histologic and immunohistochemical tissue analysis of breast carcinomas with preoperative FDG uptake assessed by PET to identify tumor characteristics that define the degree of tracer accumulation.



FDG uptake in breast tumors was quantified by calculating standardized uptake values (SUVs) corrected for partial-volume effect and normalized to blood glucose level at the time of tracer injection. The histologic sections of 50 invasive and 6 noninvasive breast carcinomas were analyzed for histologic type, microscopic tumor growth pattern, percentage of tumor cells, presence of inflammatory cells, density of blood vessels, histopathologic grading, tumor cell proliferation (mitotic rate and antibody binding of MIB-1), expression of estrogen and progesterone receptors, and expression of the glucose transporter protein Glut-1.



A positive correlation was found between FDG uptake and histologic tumor type (ductal vs. lobular; P = 0.003), microscopic tumor growth pattern (nodular vs. diffuse; P = 0.007), and tumor cell proliferation (MIB-1; P = 0.009). Tumors with diffuse growth patterns had significantly lower SUVs compared with clearly defined tumors. A weak relationship was found between FDG uptake and the percentage of tumor cells (P = 0.06). Lower densities of blood vessels corresponded to higher FDG uptakes (P = 0.08). However, even significant correlations showed poor correlation coefficients. No relationship was found between FDG uptake and the following: tumor size; axillary lymph node status; percentage of necrotic, fibrotic, and cystic compounds; presence of inflammatory cells; steroid receptor status; and expression of Glut-1.



Histologic and immunohistochemical tissue analysis was unable to sufficiently explain the variation of FDG uptake in breast cancer. The degree of metabolic changes after malignant transformation is most likely explained by a complex interaction between cellular energy demand and tumoral microenvironment. Therefore, FDG PET imaging may not be used to estimate tumor biologic behavior of breast cancer such as differentiation, histopathologic grading, cell proliferation, or axillary lymph node status.

title: Utility of 18F-fluoro-deoxyglucose emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in combination with ultrasonography for axillary staging in primary breast cancer
abstract: BackgroundAccurate evaluation of axillary lymph node (ALN) involvement is mandatory before treatment of primary breast cancer. The aim of this study is to compare preoperative diagnostic accuracy between positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) and axillary ultrasonography (AUS) for detecting ALN metastasis in patients having operable breast cancer, and to assess the clinical management of axillary 18F-FDG PET/CT for therapeutic indication of sentinel node biopsy (SNB) and preoperative systemic chemotherapy (PSC).MethodsOne hundred eighty-three patients with primary operable breast cancer were recruited. All patients underwent 18F-FDG PET/CT and AUS followed by SNB and/or ALN dissection (ALND). Using 18F-FDG PET/CT, we studied both a visual assessment of 18F-FDG uptake and standardized uptake value (SUV) for axillary staging.ResultsIn a visual assessment of 18F-FDG PET/CT, the diagnostic accuracy of ALN metastasis was 83% with 58% in sensitivity and 95% in specificity, and when cut-off point of SUV was set at 1.8, sensitivity, specificity, and accuracy were 36, 100, and 79%, respectively. On the other hand, the diagnostic accuracy of AUS was 85% with 54% in sensitivity and 99% in specificity. By the combination of 18F-FDG PET/CT and AUS to the axilla, the sensitivity, specificity, and accuracy were 64, 94, and 85%, respectively. If either 18F-FDG PET uptake or AUS was positive in allixa, the probability of axillary metastasis was high; 50% (6 of 12) in 18F-FDG PET uptake only, 80% (4 of 5) in AUS positive only, and 100% (28 of 28) in dual positive. By the combination of AUS and 18F-FDG PET/CT, candidates of SNB were more appropriately selected. The axillary 18F-FDG uptake was correlated with the maximum size and nuclear grade of metastatic foci (p = 0.006 and p = 0.03).ConclusionThe diagnostic accuracy of 18F-FDG PET/CT was shown to be nearly equal to ultrasound, and considering their limited sensitivities, the high radiation exposure by 18F-FDG PET/CT and also costs of the examination, it is likely that AUS will be more cost-effective in detecting massive axillary tumor burden. However, when we cannot judge the axillary staging using AUS alone, metabolic approach of 18F-FDG PET/CT for axillary staging would enable us a much more confident diagnosis.

title: Biological characterisation of breast cancer by means of PET
abstract: Breast cancer is associated with increased glucose consumption and can therefore be visualised with the glucose analogue [18F]2-deoxy-2-fluoro-d-glucose (FDG) and positron emission tomography (PET). FDG uptake in the primary tumour can vary substantially, and specific tumour characteristics have been demonstrated to determine the degree of glucose metabolism. Factors with a major influence on FDG uptake in breast cancer comprise expression of glucose transporter Glut-1 and hexokinase I, number of viable tumour cells per volume, histological subtype, tumour grading, microvessel density and proliferative activity. Recently, an association between high FDG uptake and a worse prognosis was suggested. Several studies have been performed correlating FDG uptake with a variety of prognostic and molecular biomarkers as well as parameters predicting tumour response to therapy. However, a correlation with important clinical prognostic markers such as axillary lymph node status and size of the primary tumour, expression of oestrogen and progesterone receptors, proto-oncogene c-erbB-2 or VEGF could not be demonstrated. The lack of correlation with important markers of prognosis does not suggest that FDG uptake might be used as a prognostic criterion in breast cancer. Innovative radiotracers for specific imaging of tumoural perfusion ([15O]H2O), hormone receptor expression ([18F]FES), protein synthesis ([11C]methionine), proliferation rate ([18F]FLT) or bone mineralisation ([18F]fluoride) may provide additional information compared with that provided by FDG PET.

title: 18F-FDG PET of Locally Invasive Breast Cancer and Association of Estrogen Receptor Status with Standardized Uptake Value: Microarray and Immunohistochemical Analysis
abstract: PET imaging is useful for evaluating locally advanced primary breast cancer. Expression of specific molecular markers in these cancers, such as estrogen receptor (ER), progesterone receptor (PR), and HER2 status, has direct prognostic and therapeutic implications in patient management. This study aimed to determine whether a relationship exists between tumor glucose use and important molecular markers in invasive breast cancer. For our purposes, tumor glucose use is quantified by the PET-derived parameter maximum standardized uptake value (SUV).  Breast tumors from 36 patients were excised and examined histologically after PET. ER, PR, and HER2 status were determined for all lesions histopathologically. In addition, genomewide expression for a subset of 20 tumors was analyzed using the human genome U133A oligonucleotide microarray.  A significant association was found between estrogen ER status and lesion SUV. ER-negative tumors (n = 17; median SUV, 8.5) demonstrated a significantly higher maximum SUV than did ER-positive tumors (n = 19; median SUV, 4.0) (P < 0.001). No significant association existed between SUV and PR status, HER2/neu status, lymph node involvement, or tumor size. Unsupervised hierarchic clustering of the 20 genetically profiled cancers segregated tumor samples into 2 primary groups of 10 patients each, largely corresponding to ER status.  In locally invasive primary breast cancer, ER-negative tumors display higher 18F-FDG uptake than ER-positive tumors. Microarray analysis confirms these data and identifies genes associated with increased glucose use as measured by PET. These genes significantly overlap those of a previously validated ER-status molecular phenotype. These preliminary data support a growing body of evidence that ER-positive and ER-negative breast cancers have distinct disease-specific patterns. Further validation prospectively and with larger numbers will be required to establish a robust molecular signature for metabolic uptake and patterns of aggressive behavior in advanced breast cancer.

title: FDG PET/CT and diffusion-weighted imaging for breast cancer: prognostic value of maximum standardized uptake values and apparent diffusion coefficient values of the primary lesion
abstract: PurposeTo correlate both primary lesion 18F-fluorodeoxyglucose (FDG) maximum standardized uptake value (SUVmax) and diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) with clinicopathological prognostic factors and compare the prognostic value of these indexes in breast cancer.MethodsThe study population consisted of 44 patients with 44 breast cancers visible on both preoperative FDG PET/CT and DWI images. The breast cancers included 9 ductal carcinoma in situ (DCIS) and 35 invasive ductal carcinomas (IDC). The relationships between both SUVmax and ADC and clinicopathological prognostic factors were evaluated by univariate and multivariate regression analysis and the degree of correlation was determined by Spearman’s rank test. The patients were divided into a better prognosis group (n = 24) and a worse prognosis group (n = 20) based upon invasiveness (DCIS or IDC) and upon their prognostic group (good, moderate or poor) determined from the modified Nottingham prognostic index. Their prognostic values were examined by receiver operating characteristic analysis.ResultsBoth SUVmax and ADC were significantly associated (p<0.05) with histological grade (independently), nodal status and vascular invasion. Significant associations were also noted between SUVmax and tumour size (independently), oestrogen receptor status and human epidermal growth factor receptor-2 status, and between ADC and invasiveness. SUVmax and ADC were negatively correlated (ρ=−0.486, p = 0.001) and positively and negatively associated with increasing of histological grade, respectively. The threshold values for predicting a worse prognosis were ≥4.2 for SUVmax (with a sensitivity, specificity and accuracy of 80%, 75% and 77%, respectively) and ≤0.98 for ADC (with a sensitivity, specificity and accuracy of 90%, 67% and 77%, respectively).ConclusionSUVmax and ADC correlated with several of pathological prognostic factors and both indexes may have the same potential for predicting the prognosis of breast cancer.

title: Clinicopathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer.
abstract: Using integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT), the clinical significance of 18F-FDG uptake was evaluated in patients with primary breast cancer.



Clinicopathological correlation with the level of maximum standardized uptake values (SUV) 60 min obtained from preoperative 18F-FDG PET/CT were examined in 152 patients with primary breast cancer. The prognostic impact of the level of SUV was explored using simulated prognosis derived from computed program Adjuvant! in 136 (89%) patients with invasive ductal carcinoma (IDC).



High SUV level was significantly correlated with tumor invasive size (< or = 2 cm) (P < 0.0001), higher score of nuclear grade (P < 0.0001), nuclear atypia (P < 0.0001) and mitosis counts (P < 0.0001), negative hormone receptor status (P = 0.001), high score of c-erbB-2 expression (P = 0.006), lymph node metastasis (P = 0.002), and IDC in comparison with invasive lobular carcinoma (P = 0.004). Multivariate analyses showed tumor invasive size, nuclear grade and estrogen receptor negativity were significantly correlated with SUV in primary breast cancer (P < 0.0001,< 0.0001, and < 0.012, respectively), and nuclear grade was significantly correlated with SUV in tumors of invasive size 2 cm or less (P < 0.0001). Tumors with high SUV (cutoff value 4.0) showed higher relapse and mortality rate compared to those with low SUV (P < 0.0001).



High uptake of 18F-FDG would be predictive of poor prognosis in patients with primary breast cancer, and aggressive features of cancer cells in patients with early breast cancer. 18F-FDG PET/CT could be a useful tool to pre-therapeutically predict biological characteristics and baseline risk of breast cancer.

title: Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis.
abstract: Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer.



Eleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach.



Across 26 studies evaluating PET or PET/CT (n = 2591 patients), mean sensitivity was 63% (95% CI: 52-74%; range 20-100%) and mean specificity 94% (95% CI: 91-96%; range 75-100%). Across 7 studies of PET/CT (n = 862), mean sensitivity was 56% (95% CI: 44-67%) and mean specificity 96% (90-99%). Across 19 studies of PET-only (n = 1729), mean sensitivity was 66% (50-79%) and mean specificity 93% (89-96%). Mean sensitivity was 11% (5-22%) for micrometastases (≤2 mm; five studies; n = 63), and 57% (47-66%) for macrometastases (>2 mm; four studies; n = 111).



PET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla.

title: Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation.
abstract: Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning.



To evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer.



A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK.



One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second.



Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients.



No included studies directly compared PET and MRI.



Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques.



This study was funded by the Health Technology Assessment programme of the National Institute of Health Research.

title: A comparative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary
abstract: metastases.  In all, 236 patients with breast cancer and clinically negative axilla were enrolled in the study. 18-FDG-PET was carried out before surgery, using a positron emission tomography (PET)/computed tomography scanner. In all patients, SNB was carried out after identification through lymphoscintigraphy. Patients underwent axillary lymph nodes dissection (ALND) in cases of positive FDG-PET or positive SNB. The results of PET scan were compared with histopathology of SNB and ALND.  In all, 103 out of the 236 patients (44%) had metastases in axillary nodes. Sensitivity of FDG-PET scan for detection of axillary lymph node metastases in this series was low (37%); however, specificity and positive predictive values were acceptable (96% and 88%, respectively).  The high specificity of PET imaging indicates that patients who have a PET-positive axilla should have an ALND rather than an SNB for axillary staging. In contrast, FDG-PET showed poor sensitivity in the detection of axillary metastases, confirming the need for SNB in cases where PET is negative in the axilla.

title: Diagnostic value of full-dose FDG PET/CT for axillary lymph node staging in breast cancer patients
abstract: PurposeThe aims of this study were (1) to evaluate FDG PET/CT and CT for the detection of axillary lymph node metastases in breast cancer (BC) patients and (2) to evaluate FDG PET/CT as a pre-test for the triage to sentinel lymph node biopsy (SLNB) versus axillary lymph node dissection (ALND).MethodsThe sensitivity, specificity, positive and negative predictive value (PPV, NPV), and accuracy of FDG PET/CT and CT for axillary lymph node metastases were determined in 61 patients (gold standard: histopathology). According to the equation “NPV = specificity ∙ (1-prevalence) / [specificity ∙ (1-prevalence) + (1-sensitivity) ∙ prevalence]” FDG PET/CT was evaluated as a triage tool for SLNB versus ALND.ResultsThe sensitivity, specificity, PPV, NPV and accuracy of FDG PET/CT was 58, 92, 82, 77 and 79% and of CT 46, 89, 72, 71 and 72%, respectively. Patients with an up to ~60% risk for axillary lymph node metastases appear to be candidates for SLNB provided that the axilla is unremarkable on FDG PET/CT.ConclusionFDG PET/CT cannot replace invasive approaches for axillary staging but may extend the indication for SLNB.

title: The Sentinel Node Procedure in Breast Cancer: Nuclear Medicine as the Starting Point
abstract: Axillary node status is a major prognostic factor in early breast cancer. Staging with sentinel node biopsy (SNB) leads to a substantial reduction in surgical morbidity. Recent multiinstitutional studies revealed SNB false-negative rates ranging from 5.5% to 16.7%, higher than the target (<5%) set by the 2005 guidelines of the American Society of Clinical Oncology. These alarming data point to the necessity of optimization. Dual mapping with radiotracer and blue dye, combining 2 different injection sites, and routinely using lymphoscintigraphy may improve accuracy. Factors associated with decreased sensitivity, such as prior excisional biopsy or neoadjuvant chemotherapy, should be recognized. The use of SNB in situations with a high prevalence of node positivity (large tumor, multifocality) is controversial. The risk of missed disease after negative SNB ranges from 1% to 4% in patients with T1 tumor and up to 15% in patients with T3. With peritumoral injection, internal mammary drainage is seen in about 20% of cases. Patients combining internal mammary drainage with a positive axillary sentinel node have close to a 50% probability of internal mammary involvement. Lymphoscintigraphy might thus be helpful in selecting patients for whom internal mammary radiation has a high benefit-to-risk ratio.

title: Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: a report of the staging breast cancer with PET Study Group.
abstract: To determine the accuracy of positron emission tomography with fluorine-18-labeled 2-fluoro-2-deoxy-d-glucose (FDG-PET) in detecting axillary nodal metastases in women with primary breast cancer.



In this prospective multicenter study, 360 women with newly diagnosed invasive breast cancer underwent FDG-PET. Images were blindly interpreted by three experienced readers for abnormally increased axillary FDG uptake. Imaging results from 308 assessable axillae were compared with axillary node pathology.



For detecting axillary nodal metastasis, the mean estimated area under the receiver operator curve for the three readers was 0.74 (range, 0.70 to 0.76). If at least one probably or definitely abnormal axillary focus was considered positive, the mean (and range) sensitivity, specificity, and positive and negative predictive values for PET were 61% (54% to 67%), 80% (79% to 81%), 62% (60% to 64%), and 79% (76% to 81%), respectively. False-negative axillae on PET had significantly smaller and fewer tumor-positive lymph nodes (2.7) than true-positive axillae (5.1; P <.005). Semiquantitative analysis of axillary FDG uptake showed that a nodal standardized uptake value (lean body mass) more than 1.8 had a positive predictive value of 90%, but a sensitivity of only 32%. Finding two or more intense foci of tracer uptake in the axilla was highly predictive of axillary metastasis (78% to 83% positive predictive value), albeit insensitive (27%).



FDG-PET has moderate accuracy for detecting axillary metastasis but often fails to detect axillae with small and few nodal metastases. Although highly predictive for nodal tumor involvement when multiple intense foci of tracer uptake are identified, FDG-PET is not routinely recommended for axillary staging of patients with newly diagnosed breast cancer.

title: Breast Cancer Staging in a Single Session: Whole-Body PET/CT Mammography
abstract: Our objective was to compare the diagnostic accuracy of an all-in-one protocol of whole-body 18F-FDG PET/CT and integrated 18F-FDG PET/CT mammography with the diagnostic accuracy of a multimodality algorithm for initial breast cancer staging.  Forty women (mean age, 58.3 y; range, 30.8–78.4 y; SD, 12 y) with suspected breast cancer were included. For the primary tumor, we compared 18F-FDG PET/CT mammography versus MRI mammography; for axillary lymph node status, 18F-FDG PET/CT versus clinical investigation and ultrasound; and for distant metastases, 18F-FDG PET/CT versus a multimodality staging algorithm. Histopathology and clinical follow-up served as the standard of reference. The Fisher exact test evaluated the significance of differences (P < 0.05). Alterations in patient management caused by 18F-FDG PET/CT were documented.  No significant differences were found in the detection rate of breast cancer lesions (18F-FDG PET/CT, 95%; MRI, 100%; P = 1). 18F-FDG PET/CT correctly classified lesion focality significantly more often than did MRI (18F-FDG PET/CT, 79%; MRI, 73%; P < 0.001). MRI correctly defined the T stage significantly more often than did 18F-FDG PET/CT (MRI, 77%; 18F-FDG PET/CT, 54%; P = 0.001). 18F-FDG PET/CT detected axillary lymph node metastases in 80% of cases; clinical investigation/ultrasound, in 70%. This difference was not statistically significant (P = 0.067). Distant metastases were detected with 18F-FDG PET/CT in 100% of cases, and the multimodality algorithm identified distant metastases in 70%. This difference was not statistically significant (P = 1). Three patients had extraaxillary lymph node metastases that were detected only by PET/CT (cervical, retroperitoneal, mediastinal/internal mammary group). 18F-FDG PET/CT changed patient management in 12.5% of cases.  Our data suggest that a whole-body 18F-FDG PET/CT mammography protocol may be used for staging breast cancer in a single session. This initial assessment of the 18F-FDG PET/CT protocol indicates similar accuracy to MRI for the detection of breast cancer lesions. Although MRI seems to be more accurate when assessing the T stage of the tumor, 18F-FDG PET/CT seems able to more accurately define lesion focality. Although 18F-FDG PET/CT mammography was able to detect axillary lymph node metastases with a high sensitivity, this method cannot soon be expected to replace the combination of clinical examination, ultrasound, and sentinel lymph node biopsy for axillary assessment.

title: Unexpected foci of 18F-FDG uptake in the breast detected by PET/CT: incidence and clinical significance
abstract: PurposeThe aim of this study was to evaluate the frequency and clinical significance of unexpected focal 18F-fluorodeoxyglucose (FDG) uptake localized by PET/CT within the breast. files of 4,038 consecutive female cancer patients referred for FDG PET/CT over a period of 74 months were retrospectively reviewed. Patients with breast cancer were excluded from the study. The incidence of focal sites of increased FDG uptake localized by PET/CT to the breast was determined. The intensity of uptake was measured using the lean body mass maximum standard uptake value (LBM SUVmax), and the presence and patterns of morphologic changes on CT were assessed. The etiology and clinical significance of findings were confirmed histologically or with imaging and clinical follow-up.ResultsUnexpected FDG foci in the breast were identified in 33 of 4,038 patients (0.82%). Follow-up data were available for 30 patients. Malignancy was diagnosed in 17 patients (histology 12, clinical 5) and excluded in 13 patients (histology 9, clinical 4). There was a borderline statistically significant difference in FDG uptake (LBM SUVmax) between malignant (3.13 ± 2.25) and benign (1.85 ± 1.18) lesions (p = 0.05). Focal lesions were seen on CT in 23 patients (malignant 11, benign 12), and CT was negative in 7 patients (malignant 6, benign 1).ConclusionAlthough rare, incidental focal abnormal FDG uptake in the breast may represent malignant lesions in up to 57% of patients. Breast incidentalomas on PET/CT warrant further assessment including tissue sampling to define the etiology of these unexpected FDG-avid foci.

title: AJCC Cancer Staging Manual
abstract: General Information on Cancer Staging and End-Results  Purposes and Principles of Cancer Staging.- Cancer Survival Analysis.- Head and Neck.- Lip and Oral Cavity.- Pharynx.- Larynx.- Nasal Cavity and Paranasal Sinuses.- Major Salivary Glands.- Thyroid.- Mucosal Melanoma of the Head and Neck.-  Small Intestine.- Colon and Rectum.- Anus.- Gastrointestinal Stromal Tumor.- Neuroendocrine Tumors.- Liver.- Intrahepatic Bile Ducts.- Gallbladder.- Perihilar Bile Ducts.- Distal Bile Duct.- Ampulla of Vater.- Exocrine and Endocrine Pancreas.- Thorax.- Lung.- Pleural Mesothelioma.- Musculoskeletal Sites.- Bone.- Soft Tissue Sarcoma.- Skin.- Cutaneous Squamous Cell Carcinoma and Other Cutaneous Carcinomas.- Merkel Cell  Melanoma of the Skin.- Breast.- Breast.- Gynecologic Sites.- Vulva.- Vagina.- Cervix Uteri.- Corpus Uteri.- Ovary and Primary Peritoneal Carcinoma.- Fallopian Tube.- Gestational Trophoblastic Tumors.- Genitourinary Sites.- Penis.- Prostate.- Testis.- Kidney.- Renal Pelvis and Ureter.- Urinary Bladder.- Urethra.- Adrenal.- Ophthalmic Sites.- Carcinoma of the Eyelid.- Carcinoma of the Conjunctiva.- Malignant Melanoma of the Conjunctiva.- Malignant Melanoma of the Uvea.- Retinoblastoma.- Carcinoma of the Lacrimal Gland.- Sarcoma of the Orbit.- Ocular Adnexal Lymphoma.- Central Nervous System.- Brain and Spinal Cord.- Lymphoid Neoplasms.- Lymphoid Neoplasms.

title: Retrospective Study of 18F-FDG PET/CT in the Diagnosis of Inflammatory Breast Cancer: Preliminary Data
abstract: Our objective was to retrospectively evaluate 18F-FDG PET/CT in the initial staging of inflammatory breast cancer (IBC).  The institutional review board waived informed consent and approved this study, which was compliant with the Health Insurance Portability and Accountability Act. The cases of 41 women with a mean age of 50 y (range, 25–71 y) and newly diagnosed IBC who underwent 18F-FDG PET/CT at diagnosis were retrospectively reviewed. All PET/CT images were analyzed visually and semiquantitatively by 2 physicians. The maximum standardized uptake value in the primary breast, regional nodes (axillary, subpectoral, supraclavicular, internal mammary), and extranodal regions was documented. The accuracy of PET/CT image interpretation was assessed by histopathologic analysis, if available; concurrent or subsequent imaging findings (contrast-enhanced CT, contrast-enhanced MRI, sonography, or PET/CT follow-up); or clinical follow-up.  All patients presented with unilateral IBC. PET/CT showed hypermetabolic uptake in the skin in all patients, in the affected breast in 40 (98%), in the ipsilateral axillary nodes in 37 (90%), and in the ipsilateral subpectoral nodes in 18 (44%). Twenty patients (49%) were found to have distant metastases at staging, 7 (17%) of whom were not known to have metastases before undergoing PET/CT. Disease sites included bone, liver, contralateral axilla, lung, chest wall, pelvis, and the subpectoral, supraclavicular, internal mammary, mediastinal, and abdominal nodes.  PET/CT should be considered in the initial staging of IBC, as the technique provided valuable information on locoregional and distant disease in this preliminary retrospective study.

title: Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings
abstract: PurposeTo describe the role of Positron Emission Tomography/Computed Tomography (PET/CT), Magnetic Resonance Imaging (MRI), sonography, and mammography in patients with inflammatory breast cancer (IBC).Materials and methodsPatients who had been newly diagnosed with IBC and who had undergone mammography, sonography, MRI, PET/CT, or a combination of these were included in this study. The visibility of breast parenchymal lesion (BPLs), skin abnormalities, regional (axillary, supraclavicular, or internal mammary) nodal disease, and distant metastatic disease was documented with the imaging techniques.ResultsEighty patients (median age, 51 years, [range, 25–78 years]) were included in this study: 75 (94%) had undergone mammography, 76 (95%) sonography, 33 (41%) MRI, and 24 (30%) PET/CT. A primary BPL was found in 60 patients (80%) on mammography (mass or calcifications), 72 (95%) on sonography (mass or architectural distortion), 23 (96%) on PET/CT (hypermetabolic BPL), and 33 (100%) on MRI (enhancing BPL). Regional axillary nodal disease was found in 74 patients (93%) by histologic or cytologic examination, in 71 patients (93%) on sonography, in 21 (88%) on PET/CT, in 29 (88%) on MRI, and in 34 (45%) on mammography. Distant metastases in the bone, liver, and contralateral lymph nodes were diagnosed in nine patients (38%) on PET/CT.ConclusionMRI was the most accurate imaging technique in detecting a primary BPL in IBC patients. Sonography can be useful in diagnosing regional nodal disease. PET/CT provides additional information on distant metastasis, and it should be considered in the initial staging of IBC.

title: Effect of (18)F-FDG PET/CT imaging in patients with clinical Stage II and III breast cancer.
abstract: To investigate the potential effect of using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in the initial assessment of patients with clinical Stage II or III breast cancer.



During 14 consecutive months, 39 patients (40 tumors) who presented with Stage II or III breast cancer on the basis of a routine extension assessment were prospectively included in this study. PET/CT was performed in addition to the initial assessment.



In 3 cases, PET/CT showed extra-axillary lymph node involvement that had not been demonstrated with conventional techniques. Two of these patients had hypermetabolic lymph nodes in the subpectoral and infraclavicular regions, and the third had a hypermetabolic internal mammary node. PET/CT showed distant uptake in 4 women. Of these 4 women, 1 had pleural involvement and 3 had bone metastasis. Overall, of the 39 women, the PET/CT results modified the initial stage in 7 (18%). The modified staging altered the treatment plan for 5 patients (13%). It led to radiotherapy in 4 patients (bone metastasis, pleural lesion, subpectoral lymph nodes, and internal mammary nodes) and excision of, and radiotherapy to, the infraclavicular lymph nodes in 1 patient.



PET/CT can provide information on extra-axillary lymph node involvement and can uncover occult distant metastases in a significant percentage of patients. Therefore, initial PET/CT could enable better treatment planning for patients with Stage II and III breast cancer.

title: Additional Value of PET–CT in Staging of Clinical Stage IIB and III Breast Cancer
abstract: To evaluate retrospectively the accuracy of integrated PET/CT, against PET, CT, or conventional staging in breast cancer. Seventy consecutive biopsy proven clinical stage IIB and III breast cancer patients were included. Descriptive statistics of integrated PET/CT for the primary tumor, nodal status and metastasis detection were compared to PET, CT with contrast, and conventional staging (biochemistry, chest X‐ray, liver ultrasound, and bone scintigraphy). Sensitivity of PET/CT for primary tumor and nodal status was 97.1% and 62.5%, respectively. Specificity and negative predictive value for nodal status were 100% and 66.6%, respectively. The values for conventional staging for nodal involvement were 100% and 85.7% with a sensitivity of 87.5%. PET/CT showed metastatic disease in seven women despite normal conventional staging. PET/CT is able to visualize most clinical stage IIB and III primary breast cancers. PET/CT is superior to conventional staging for detecting internal mammary chain nodes and metastatic disease, but not for axillary staging. Future studies will have to test whether therapy adjustment based on PET/CT has the potential to improve survival.

title: Preoperative staging of large primary breast cancer with [18F]fluorodeoxyglucose positron emission tomography/computed tomography compared with conventional imaging procedures.
abstract: To evaluate the utility of positron emission tomography (PET) and [(18)F]fluorodeoxyglucose in the initial staging of large primary breast tumors.



This prospective study was approved by the ethics committee, and all patients gave their informed consent before enrollment. Sixty consecutive patients with large (> 3 cm) primary breast cancer diagnosed by clinical examination and breast magnetic resonance imaging (MRI) were entered onto the study. The mean age was 57 +/- 13 years. Chest computed tomography (CT), liver ultrasonography, bone scan, and PET/CT were performed in all patients. All findings were histologically confirmed, and/or at least 1 year of follow-up was required. Correlation between parameters was calculated using Pearson's correlation coefficient. P < .05 was considered statistically significant.



Primary tumor was identified by both PET/CT and MRI in all patients. Multifocal and/or multicentric tumors were found in 19 patients by MRI. Axillary lymph node metastases were found in 20 of 52 patients. Extra-axillary metastatic lymph nodes were also found in three patients. One patient showed an infiltrated lymph node in the contralateral axilla. The sensitivity and specificity for PET/CT to detect axillary lymph nodes metastases were 70% and 100%, respectively. PET/CT diagnosed all extra-axillary lymph nodes. The overall sensitivity and specificity of PET/CT in detecting distant metastases were 100% and 98%, respectively; whereas the sensitivity and specificity of conventional imaging were 60% and 83%, respectively. PET led to a change in the initial staging in 42% of patients.



PET/CT underestimates locoregional lymph node staging in large primary breast cancer patients. PET/CT is a valuable tool to discard unsuspected extra-axillary lymph nodes and distant metastases.

title: Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer
abstract: PurposeThe purpose of this study was to investigate the pitfalls of using 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the evaluation of osteoblastic bone metastases in patients with breast cancer by comparing it with 99mTc-hydroxymethylene diphosphonate bone scintigraphy.MethodsAmong the 89 breast cancer patients (mean age 59±15 years) who had undergone both FDG-PET and bone scintigraphy within 1 month between September 2003 and December 2004, 55 with bone metastases were studied. The bone metastases were visually classified by multi-slice CT into four types according to their degree of osteosclerosis and osteolysis—osteoblastic, osteolytic, mixed and invisible—and compared in terms of tracer uptake on FDG-PET or bone scintigraphy and SUVmean on FDG-PET. Differences in the rate of detection on bone scintigraphy and FDG-PET were analysed for significance by the McNemar test.ResultsThe sensitivity, specificity and accuracy of bone scintigraphy were 78.2%, 82.4% and 79.8% respectively, and those of FDG-PET were 80.0%, 88.2% and 83.1%, respectively, revealing no significant differences. According to the CT image type, the visualisation rate of bone scintigraphy/FDG-PET was 100%/55.6% for the blastic type, 70.0%/100.0% for the lytic type, 84.2%/94.7% for the mixed type and 25.0%/87.5% for the invisible type. The visualisation rates of bone scintigraphy for the blastic type and FDG-PET for the invisible type were significantly higher. The SUVmean of the blastic, lytic, mixed and invisible types were 1.72±0.28, 4.14±2.20, 2.97±1.98 and 2.25±0.80, respectively, showing that the SUVmean tended to be higher for the lytic type than for the blastic type.ConclusionFDG-PET showed a low visualisation rate in respect of osteoblastic bone metastases. Although FDG-PET is useful for detection of bone metastases from breast cancer, it is apparent that it suffers from some limitations in depicting metastases of the osteoblastic type.

title: Detection of Bone Metastases in Breast Cancer by Positron Emission Tomography.
abstract: Positron emission tomography (PET) is able to demonstrate changes in the metabolism of malignant tumors and metastases before they become visible on anatomical imaging. The skeleton is the most common site of distant metastases of breast cancer. There is convincing evidence that FDG-PET is more sensitive in detecting osteolytic metastases than bone scintigraphy, whereas bone scintigraphy is more sensitive in detecting osteoblastic metastases. Because both types of metastases can occur in breast cancer, bone scintigraphy and FDG-PET should be considered as complementary and can currently be regarded as standard of care for staging in breast cancer patients, whereas the decision to use F-18 fluoride PET should be made individually for each patient, depending on the expected change of therapy management.

title: Integrated positron emission tomography/computed tomography may render bone scintigraphy unnecessary to investigate suspected metastatic breast cancer.
abstract: Although the accurate detection of osseous metastases in the evaluation of patients with suspected metastatic breast cancer (MBC) has significant prognostic and therapeutic implications, the ideal diagnostic approach is uncertain. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BSc) in women with suspected MBC.



Women with suspected MBC evaluated with PET/CT and BSc (within 30 days) between January 1, 2003 and June 30, 2008, were identified through institutional databases. Electronic medical records were reviewed, and radiology reports were classified as positive/negative/equivocal for osseous metastases. A nuclear medicine radiologist (blinded to correlative and clinical end points) reviewed all equivocal PET/CT and BSc images and reclassified some reports. Final PET/CT and BSc classifications were compared. Baseline patient/tumor characteristics and bone pathology were recorded and compared to the final imaging results.



We identified 163 women who had a median age of 52 years (range, 30 to 90 years); 32% had locally advanced breast cancer, 42% had been diagnosed with breast cancer less than 12 weeks before identification. Twenty studies were originally deemed equivocal (five with PET/CT, and 15 with BSc), and 13 (65%) of these studies were reclassified after radiology review. Overall, PET/CT and BSc were highly concordant for reporting osseous metastases with 132 paired studies (81%); 32 (20%) were positive, and 100 (61%) were negative. Thirty-one occurrences (19%) were discordant. Twelve of these (39%) had pathology confirming osseous metastases: nine (of 18) were PET/CT positive and BSc negative; one (of three) was PET/CT positive and BSc equivocal; and two (of two) were PET/CT equivocal and BSc negative.



This study supports the use of PET/CT in detecting osseous metastases for suspected MBC. Whether PET/CT may supplant BSc in this setting is unknown.

title: Diagnostic value of diffusion-weighted magnetic resonance imaging (DWI) compared to FDG PET/CT for whole-body breast cancer staging
abstract: PurposeThe aim of the study was to prospectively compare the diagnostic value of whole-body diffusion-weighted imaging (DWI) and FDG PET/CT for breast cancer (BC) staging.MethodsTwenty BC patients underwent whole-body FDG PET/CT and 1.5-T DWI. Lesions with qualitatively elevated signal intensity on DW images (b = 800 s/mm2) were rated as suspicious for tumour and mapped to individual lesions and different compartments (overall 552 lesions). The apparent diffusion coefficient (ADC) value was determined for quantitative evaluation. Histopathology, MRI findings, bone scan findings, concordant findings between FDG PET/CT and DWI, CT follow-up scans and plausibility served as the standards of reference defining malignancy.ResultsAccording to the standards of reference, breasts harboured malignancy in 11, regional lymph nodes in 4, M1 lymph nodes in 3, bone in 7, lung in 2, liver in 3 and other tissues in 3 patients. On a compartment basis, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for the detection of malignancies were 94, 99, 98, 97 and 98% for FDG PET/CT and 91, 72, 76, 50 and 96% for DWI, respectively. Of the lesions seen on DWI only, 348 (82%) turned out to be false-positive compared to 23 (11%) on FDG PET/CT. The average lesion ADC was 820 ± 300 with true-positive lesions having 929 ± 252 vs 713 ± 305 in false-positive lesions (p < 0.0001).ConclusionBased on these initial data DWI seems to be a sensitive but unspecific modality for the detection of locoregional or metastatic BC disease. There was no possibility to quantitatively distinguish lesions using ADC. DWI alone may not be recommended as a whole-body staging alternative to FDG PET(/CT). Further studies are necessary addressing the question of whether full-body MRI including DWI may become an alternative to FDG PET/CT for whole-body breast cancer staging.

title: Integrated contrast-enhanced diagnostic whole-body PET/CT as a first-line restaging modality in patients with suspected metastatic recurrence of breast cancer.
abstract: )
Only few information exist about the diagnostic accuracy of PET/CT for restaging patients with metastatic recurrence of breast carcinoma. Therefore, our study hypothesis was to perform diagnostic contrast enhanced CT (ce-CT) and FDG-PET in a one-step investigation, to prove sensitivity of each modality and to determine whether diagnostic PET/CT adds information over PET or contrast enhanced CT alone for restaging of patients with suspected recurrence of breast cancer.



Fifty-two patients with suspected recurrence of breast cancer were included in our study. All of them were free of metastasis after the first line therapy. Indications for restaging were: Elevated tumor markers n=32, clinical deterioration n=16 and/or suspicious findings on other imaging studies n=48. Integrated PET/CT was performed using contrast-enhanced diagnostic CT for attenuation correction.



PET was correct in 44/52 patients (85%), ce-CT in 38/52 patients (73%) and PET/CT in 50/52 patients (96%). Sensitivity and specificity of lesion detection of PET, CT and PET/CT were 84%, 66% and 93%, and 100%, 92%, and 100%, respectively.



PET/CT can improve staging and alter therapeutic options in patients suspected to have breast cancer recurrence and distant metastatic disease, primarily by demonstrating local or distant nodal involvement occult at other imaging studies. The added value of FDG-PET/CT over other diagnostic modalities is mainly expressed by the fact that a noninvasive whole-body evaluation is possible in a single examination.

title: The role of FDG‐PET/CT in suspected recurrence of breast cancer
abstract: Early diagnosis of recurrent breast cancer is crucial to selection of the most appropriate therapy. The current study evaluated the role of FDG‐PET/CT in the assessment of suspected recurrent breast cancer in patients who presented with elevated serum tumor markers.

title: The role of FDG PET/CT in patients with locoregional breast cancer recurrence: a comparison to conventional imaging techniques.
abstract: The aim of this study was to evaluate the impact of (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) on clinical management in patients with locoregional breast cancer recurrence amenable for locoregional treatment and to compare the PET/CT results with the conventional imaging data.



From January 2006 to August 2008, all patients with locoregional breast cancer recurrence underwent whole-body PET/CT. PET/CT findings were compared with results of the conventional imaging techniques and final pathology. The impact of PET/CT results on clinical management was evaluated based on clinical decisions obtained from patient files.



56 patients were included. In 32 patients (57%) PET/CT revealed additional tumour localisations. Distant metastases were detected in 11 patients on conventional imaging and in 23 patients on PET/CT images (p < 0.01). In 25 patients (45%), PET/CT detected additional lesions not visible on conventional imaging. PET/CT had an impact on clinical management in 27 patients (48%) by detecting more extensive locoregional disease or distant metastases. In 20 patients (36%) extensive surgery was prevented and treatment was changed to palliative treatment. The sensitivity, specificity, accuracy, positive and negative predictive values of FDG PET/CT were respectively 97%, 92%, 95%, 94% and 96%.



PET/CT, in addition to conventional imaging techniques, plays an important role in staging patients with locoregional breast cancer recurrence since its result changed the clinical management in almost half of the patients. PET/CT could potentially replace conventional staging imaging in patients with a locoregional breast cancer recurrence.

title: 18F-FDG-PET/CT in patients with breast cancer and rising Ca 15-3 with negative conventional imaging: a multicentre study.
abstract: Breast cancer is the second cause of death in women in Europe and North America. The mortality of this disease can be reduced with effective therapy and regular follow up to detect early recurrence. Tumor markers are sensitive in detecting recurrent or residual disease but imaging is required to customize the therapeutic option. Rising tumor markers and negative conventional imaging (US, X-mammography, CT and MR) poses a management problem. Our aim is to assess the role of 18F-FDG-PET/CT in the management of post-therapy patients with rising markers but negative conventional imaging.



In the period from January 2008 to September 2009, 89 female patients with breast cancer who developed post-therapy rising markers (serum Ca 15-3 levels=64.8±16.3 U/mL) but negative clinical examination and conventional imaging were investigated with 18F-FDG-PET/CT.



Tumor deposits were detected in 40/89 patients in chest wall, internal mammary nodes, lungs, liver and skeleton. The mean SUVmax value calculated in these lesions was 6.6±1.7 (range 3.1-12.8). In 23/40 patients solitary small lesion were amenable to radical therapy. In 7 out of these 23 patients a complete disease remission lasting more than 1 year was observed.



18F-FDG-PET/CT may have a potential role in asymptomatic patients with rising markers and negative conventional imaging. Our findings agree with other studies in promoting regular investigations such as tumor markers and 18F-FDG-PET/CT rather than awaiting the developments of physical symptoms as suggested by current guidelines since the timely detection of early recurrence may have a major impact on therapy and survival.

title: The Yield of 18F-FDG PET/CT in Patients with Clinical Stage IIA, IIB, or IIIA Breast Cancer: A Prospective Study
abstract: The purpose of this study was to prospectively evaluate the role of 18F-FDG PET/CT in patients with stage IIA, IIB, or IIIA breast cancer.  During 56 mo, 131 consecutive patients with large (>2 cm) breast cancer and clinical stage IIA, IIB, or IIIA (based on clinical examination, mammography, breast MRI, and ultrasonography) underwent 18F-FDG PET/CT. The nuclear physician was unaware of the results of any other procedure (bone scan, chest radiography, liver ultrasound, or thoracoabdominal CT scan).  Of the 131 examined patients, 36 had clinical stage IIA (34 T2N0 and 2 T1N1), 48 stage IIB (20 T3N0 and 28 T2N1), and 47 stage IIIA (29 T3N1, 9 T2N2, and 9 T3N2). 18F-FDG PET/CT modified staging for 5.6% of stage IIA patients, for 14.6% of stage IIB patients, and for 27.6% of stage IIIA patients. However, within stage IIIA, the yield was specifically high among the 18 patients with N2 disease (56% stage modification). When considering stage IIB and primary operable IIIA (T3N1) together, the yield of 18F-FDG PET/CT was 13% (10/77); extraaxillary regional lymph nodes were detected in 5 and distant metastases in 7 patients. In this series, 18F-FDG PET/CT outperformed bone scanning, with only 1 misclassification versus 8 for bone scanning (P = 0.036).  18F-FDG PET/CT provided useful information in 13% of patients with clinical T3N0, T2N1, or T3N1 disease. The yield was more modest in patients with stage IIA. The high yield in the case of N2 disease demonstrates that stage IIIA comprises 2 quite distinct groups of patients.

title: F-18-Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography in the Follow-up of Breast Cancer With Elevated Levels of Tumor Markers
abstract: The value of combined positron emission tomography (PET)/computed tomography (CT) in the follow-up of patients with breast cancer with elevated tumor markers but without proven metastases or local recurrence was assessed.  Thirty-four women underwent PET/CT. The PET and CT images were first analyzed separately; fused findings were then interpreted, blinded to the results of the other modalities. The results of CT, PET, and PET/CT were compared with each other and correlated to the final diagnosis.  The PET/CT identified 149 malignant foci in 24 patients (71%). The CT detected 96 of these foci in 18 patients, whereas PET identified 124 foci in 17 patients. Differences between CT and PET were not significant. Differences between PET/CT and CT (P < 0.01) and PET/CT and PET (P < 0.01) were significant. The person-based sensitivity of PET/CT, PET, and CT was 96%, 88% and 96%, respectively. Specificity of PET/CT, PET, and CT was 89%, 78%, and 78%, respectively.  The PET/CT is a valuable modality for the follow-up of patients with breast cancer and elevated levels of tumor markers.

title: FDG-PET and other imaging modalities for the evaluation of breast cancer recurrence and metastases: a meta-analysis
abstract: Background and purposeBreast carcinoma is the most common cancer in female patients with a propensity for recurrence and metastases. The accuracy of ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), scintimammography (SMM) and positron emission tomography (PET) in diagnosing the recurrent and/or breast cancer has never been systematically assessed, and present systematic review was aimed at this issue.MethodsMEDLINE and EMBASE were searched for articles dealt with detection of recurrent and/or metastatic breast cancer by US, CT, MRI, SMM or PET whether interpreted with or without the use of CT. Histopathologic analysis and/or close clinical and imaging follow-up for at least 6 months were used as golden reference. We extracted data to calculate sensitivity, specificity, summary receiver operating characteristic curves and area under the curve and to test for heterogeneity.ResultIn 42 included studies, US and MRI had highest pooled specificity (0.962 and 0.929, respectively); MRI and PET had highest pooled sensitivity (0.9500 and 0.9530, respectively). The AUC of US, CT, MRI, SMM and PET was 0.9251, 0.8596, 0.9718, 0.9386 and 0.9604, respectively. Results of pairwise comparison between each modality demonstrated that AUC of MRI and PET was higher than that of US or CT, p < 0.05. No statistical significance was found between MRI and PET. There was heterogeneity among studies and evidence of publication bias.ConclusionIn conclusion, MRI seemed to be a more useful supplement to current surveillance techniques to assess patients with suspected recurrent and/or metastatic breast cancer. If MRI shows an indeterminate or benign lesion or MRI was not applicable, FDG-PET could be performed in addition.

title: A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence.
abstract: Breast cancer (BC) accounts for one-third of all cases of cancer in women in the UK. Current strategies for the detection of BC recurrence include computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy. Positron emission tomography (PET) and, more recently, positron emission tomography/computed tomography (PET/CT) are technologies that have been shown to have increasing relevance in the detection and management of BC recurrence.



To review the accuracy of PET and PET/CT for the diagnosis of BC recurrence by assessing their value compared with current practice and compared with each other.



MEDLINE and EMBASE were searched from inception to May 2009.



Studies were included if investigations used PET or PET/CT to diagnose BC recurrence in patients with a history of BC and if the reference standard used to define the true disease status was histological diagnosis and/or long-term clinical follow-up. Studies were excluded if a non-standard PET or PET/CT technology was used, investigations were conducted for screening or staging of primary breast cancer, there was an inadequate or undefined reference standard, or raw data for calculation of diagnostic accuracy were not available.



Quality assessment and data extraction were performed independently by two reviewers. Direct and indirect comparisons were made between PET and PET/CT and between these technologies and methods of conventional imaging, and meta-analyses were carried out. Analysis was conducted separately on patient- and lesion-based data. Subgroup analysis was conducted to investigate variation in the accuracy of PET in certain populations or contexts and sensitivity analysis was conducted to examine the reliability of the primary outcome measures.



Of the 28 studies included in the review, 25 presented patient-based data and 7 presented lesion-based data for PET and 5 presented patient-based data and 1 presented patient- and lesion-based data for PET/CT; 16 studies conducted direct comparisons with 12 comparing the accuracy of PET or PET/CT with conventional diagnostic tests and 4 with MRI. For patient-based data (direct comparison) PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] and significantly higher specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 67% to 92%, relative specificity 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with conventional imaging tests (CITs)--test performance did not appear to vary according to the type of CIT tested. For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, p = 0.015), but the increase in specificity was not significant (89%, 95% CI 69% to 97% vs 77%, 95% CI 50% to 92%, relative specificity 1.15, 95% CI 0.95 to 1.41, p = 0.157). For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with PET (96%, 95% CI 90% to 98% vs 85%, 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 to 1.18, p = 0.006), but the increase in specificity was not significant (89%, 95% CI 74% to 96% vs 82%, 95% CI 64% to 92%, relative specificity 1.08, 95% CI 0.94 to 1.20, p = 0.267). For patient-based data there were no significant differences in the sensitivity or specificity of PET when compared with MRI, and, in the one lesion based study, there was no significant differences in the sensitivity or specificity of PET/CT when compared with MRI.



Studies reviewed were generally small and retrospective and this may have limited the generalisability of findings. Subgroup analysis was conducted on the whole set of studies investigating PET and was not restricted to comparative studies. Conventional imaging studies that were not compared with PET or PET/CT were excluded from the review.



Available evidence suggests that for the detection of BC recurrence PET, in addition to conventional imaging techniques, may generally offer improved diagnostic accuracy compared with current standard practice. However, uncertainty remains around its use as a replacement for, rather than an add-on to, existing imaging technologies. In addition, PET/CT appeared to show clear advantage over CT and PET alone for the diagnosis of BC recurrence.


FUTURE WORK
Future research should include: prospective studies with patient populations clearly defined with regard to their clinical presentation; a study of diagnostic accuracy of PET/CT compared with conventional imaging techniques; a study of PET/CT compared with whole-body MRI; studies investigating the possibility of using PET/CT as a replacement for rather than an addition to CITs; and using modelling of the impact of PET/CT on patient outcomes to inform the possibility of conducting large-scale intervention trials.

title: Performance of 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography and Integrated PET/CT in Restaged Breast Cancer Patients
abstract: PurposeThis study was conducted to compare the clinical stage derived from 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) positron emission tomography (PET) to that of integrated PET/computed tomography (CT) in restaged breast cancer patients.ProceduresFifty-eight female patients (age range 29–80 years, mean age ±SD, 53.3 ± 11.7 years) underwent PET/CT restaging for breast cancer. Two experienced nuclear medicine physicians interpreted PET images. A radiologist was added for reading PET/CT studies. A patient-based analysis was performed. Histopathological findings, correlative imaging studies, changes in number, size, and hypermetabolic activity of suspicious lesions and/or patient outcome served as standard of reference for determining the diagnostic accuracy of both modalities.ResultsPET staged 79.3% (46/58) of the patients correctly, overstaged seven (12.1%), and understaged five patients (8.6%). Integrated PET/CT staged 89.7% (52/58) of the patients correctly, overstaged four (6.9%), and understaged two patients (3.4%). The staging accuracy of PET/CT was not significantly better than that of PET alone (p = 0.059). Lesions exhibiting mild hypermetabolic activity, benign inflammatory lesions, and physiological variants largely explained incorrect PET findings.ConclusionIntegrated PET/CT only marginally improves the restaging accuracy over PET alone (p = 0.059) in breast cancer patients.

title: FDG-PET/CT in restaging of patients with recurrent breast cancer: possible impact on staging and therapy.
abstract: We aimed to compare the value of combined positron emission tomography (PET)/CT, PET+CT (viewed side by side), CT alone and PET alone concerning the rTNM stage and influence on therapy in patients with recurrent breast cancer. 44 patients with suspicion of recurrent breast cancer underwent whole-body [18F]-2-fluoro-2-deoxy-d-glucose (FDG)-PET/CT. Images of combined PET/CT, PET+CT, PET alone and CT alone were evaluated by four blinded reader teams. Diagnostic accuracies and influence on therapy were compared. Histology and a mean clinical follow up of 456 days served as the standard of reference. Differences between the staging procedures were tested for statistical significance by McNemar's test. Overall TNM tumour stage was correctly determined in 40/44 patients with PET/CT, in 38/44 with PET+CT, in 36/44 with PET alone and in 36/44 patients with CT alone. No statistically significant difference was detected between all tested imaging modalities. PET/CT changed the therapy in two patients compared with PET+CT, in four patients compared with PET alone and in five patients compared with CT alone. Combined PET/CT appeared to be more accurate in assessing the rTNM and showed a moderate impact on therapy over PET and CT. Minor improvements were noted when compared with PET+CT. Experienced readers might therefore be able to provide accurate staging results for further therapy from separately acquired studies.

title: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.
abstract: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies.



Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response.



There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model.



Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

title: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.
abstract: National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS.



Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T.



Results from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not.



B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response.

title: Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27.
abstract: This study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and overall survival (OS).



Women with operable breast cancer (N = 2,411) were randomly assigned to receive preoperative AC followed by surgery, AC followed by T and surgery, or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2,404 patients with follow-up was 77.9 months.



Addition of T to AC did not significantly impact DFS or OS. There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events (P = .0034). Preoperative T, but not postoperative T, significantly improved DFS in patients who had a clinical partial response after AC (hazard ratio [HR] = 0.71; 95% CI, 0.55 to 0.91; P = .007). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001). Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001).



The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.

title: Early monitoring of response to neoadjuvant chemotherapy in breast cancer with 18F-FDG PET/CT: defining a clinical aim
abstract: In Europe, in 2008, it was estimated that 421,000 new cases of breast cancer were diagnosed; 129,000 women died from breast cancer in the same year . Neoadjuvant chemotherapy (NAC), initially used only for locally advanced breast cancer, is now commonly used in patients with operable but large breast cancer. This strategy allows patients to undergo breast-conserving surgery (BCS) and gives information on the efficacy of chemotherapy [2]. Long-term outcomes are significantly correlated with pathological tumour response rates . In the present paper we here focus on what could be the role of an early evaluation with F-FDG PET/CT of the response to NAC in patients with operable breast cancer.

title: Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy.
abstract: To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy.



Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens.



Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012).



[(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.

title: Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography.
abstract: This study aimed to assess prospectively the efficacy of sequential [18F]fluorodeoxyglucose positron emission tomography (FDG PET) to evaluate early response to neoadjuvant chemotherapy in stage II and III breast cancer patients.



Images were acquired with a PET/computed tomography scanner in 64 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third, and sixth course of chemotherapy. Ultrasound and mammography were used to assess tumor size. Decrease in the standardized uptake value (SUV) with PET was compared with the pathologic response.



Surgery was performed after six courses of chemotherapy and pathologic analysis revealed gross residual disease in 28 patients and minimal residual disease in 36 patients. Although SUV data did not vary much in nonresponders (based on pathology findings), they decreased markedly to background levels in 94% (34 of 36) of responders. When using 60% of SUV at baseline as the cutoff value, the sensitivity, specificity, and negative predictive value of FDG PET were 61%, 96%, and 68% after one course of chemotherapy, 89%, 95%, and 85% after two courses, and 88%, 73%, and 83% after three courses, respectively. The same parameters with ultrasound (US) and mammography were 64%, 43%, and 55%, and 31%, 56%, and 45%, respectively. Assessment of tumor response with US or mammography was never significant whatever the cutoff.



Pathologic response to neoadjuvant chemotherapy in stage II and III breast cancer can be predicted accurately by FDG PET after two courses of chemotherapy.

title: [18F]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy
abstract: PurposeTo evaluate, in breast cancer patients treated by neoadjuvant chemotherapy, the predictive value of reduction in FDG uptake with regard to complete pathological response (pCR).MethodsForty-seven women with non-metastatic, non-inflammatory, large or locally advanced breast cancer were included. Tumour uptake of FDG was evaluated before and after the first course of neoadjuvant chemotherapy. Four indices were used: maximal and average SUV without or with correction by body surface area and glycaemia (SUVmax, SUVavg, SUVmax-BSA-G and SUVavg-BSA-G, respectively). The predictive value of reduction in FDG uptake with respect to pCR was studied by logistic regression analysis. Relationships between baseline [18F]FDG uptake and prognostic parameters were assessed.ResultsThe relative decrease in FDG uptake (ΔSUV) after the first course of neoadjuvant chemotherapy was significantly greater in the pCR group than in the non-pCR group (p < 0.000066). The four FDG uptake indices were all strongly correlated with each other. A decrease in SUVmax-BSA-G of 85.4% ± 21.9% was found in pCR patients, versus 22.6% ± 36.6% in non-pCR patients. ΔSUVmax-BSA-G <−60% predicted the pCR with an accuracy of 87% and ΔSUVs were found to be only factors predictive of the pCR at multivariate analysis. An elevated baseline SUV was associated with high mitotic activity (p < 0.0016), tumour grading (p < 0.004), high nuclear pleomorphism score (p < 0.03) and negative hormonal receptor status (p < 0.005).ConclusionIn breast cancer patients, after only one course of neoadjuvant chemotherapy the reduction in FDG uptake is an early and powerful predictor of pCR.

title: Monitoring primary breast cancer throughout chemotherapy using FDG-PET
abstract: We have compared 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) images of large or locally advanced breast cancers (LABC) acquired during Anthracycline-based chemotherapy. The purpose was to determine whether there is an optimal method for defining tumour volume and an optimal imaging time for predicting pathologic chemotherapy response.  PET data were acquired before the first and second cycles, at the midpoint and at the endpoint of neoadjuvant chemotherapy. FDG uptake was quantified using the mean and maximum standardized uptake values (SUV) and the coefficient of variation within a region of interest. Receiver-operator characteristic (ROC) analysis was used to determine the discrimination between tumours demonstrating a high pathological response (i.e. those with greater than 90% reduction in viable tumour cells) and low pathological response.  Only tumours with an initial tumour to background ratio (TBR) of greater than five showed a difference between response categories. In terms of response discrimination, there was no statistically significant advantage of any of the methods used for image quantification or any of the time points. The best discrimination was measured for mean SUV at the midpoint of therapy, which identified 77% of low responding tumours whilst correctly identifying 100% of high responding tumours and had an ROC area of 0.93.  FDG-PET is efficacious for predicting the pathologic response of most primary breast tumours throughout the duration of a neoadjuvant chemotherapy regimen. However, this technique is ineffective for tumours with low image contrast on pre-therapy PET scans.

title: 18F-FDG PET/CT for early prediction of response to neoadjuvant chemotherapy in breast cancer
abstract: PurposeThe aim of this study was to prospectively evaluate 18F-FDG PET/CT in predicting response to neoadjuvant chemotherapy in large primary breast cancer.MethodsFifty consecutive patients underwent PET/CT at baseline and after the second cycle. Baseline MRI was performed to establish tumour size. All findings were confirmed by histopathological analysis. Changes in maximum standardized uptake value (SUVmax) between baseline study and after two cycles of neoadjuvant chemotherapy (epirubicin + cyclophosphamide + taxanes) were compared using response evaluation criteria in solid tumours (RECIST) criteria and the Miller and Payne (M&P) scale.ResultsThe mean tumour size was 4.3 ± 1.4 cm. Forty patients were considered responders and ten as non-responders. SUVmax changes in patients with good prognosis (M&P grades 4–5) were higher than in patients with bad prognosis (M&P grades 1–3) (p = 0.025). SUVmax changes between responders and non-responders following RECIST criteria were also statistically significant (p = 0.0028). A cut-off ΔSUV value of 40% differentiates both groups, with a sensitivity of 77% and a specificity of 80%.Conclusion18F-FDG PET/CT can predict response to neoadjuvant chemotherapy at an early stage.

title: The role of 18F-FDG PET/CT in evaluation of early response to neoadjuvant chemotherapy in patients with locally advanced breast cancer
abstract: We evaluated the role of 18F-FDG PET/CT for the assessment of response after two cycles of neo-adjuvant chemotherapy (NACT) for breast cancer. Twenty-three women with locally advanced breast cancer were included in this study. Early response to NACT was evaluated after two cycles using clinical examination, CT, and 18F-FDG PET/CT. Final histopathology following surgery after six cycles of NACT served as reference. Baseline PET/CT demonstrated a total of 26 lesions in 23 patients. The size of the primary tumor ranged from 1.90 cm to 11.60 cm, and the maximum value of the standardized uptake value of FDG (SUVmax) ranged from 3.6 to 38.6 (mean, 11.7). Post-chemotherapy PET/CT examinations were done after two cycles of NACT. The size of the primary tumor on follow-up PET/CT examinations ranged from 0.0 cm to 7.6 cm, and SUVmax ranged from 0.0 to 12.0 (mean, 3.96). On clinical, CT, and PET/CT examinations, 50% reduction in the parameters was taken as the cutoff value to differentiate between responders and non-responders. Post-NACT PET/CT demonstrated that 16 patients were responders and 7 non-responders. Among 16 responders on PET/CT scan, 14 were true positive and 2 were false positive when compared with histopathology. Among seven non-responder patients, six were true negative, and one was false negative. The sensitivity, specificity, and accuracy of PET/CT in detecting responders were 93%, 75%, and 87%, respectively. In conclusion, 18F-FDG PET/CT can differentiate responders from non-responders with high accuracy after two cycles of NACT in patients with LABC.

title: Early 18F‐2‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography may identify a subset of patients with estrogen receptor‐positive breast cancer who will not respond optimally to preoperative chemotherapy
abstract: A pathologic complete response (pCR) and minimal residual disease (pMRD) after preoperative chemotherapy (PCT) for early stage or locally advanced breast cancer (BC) correlates with a good prognosis.

title: FDG-PET and beyond: molecular breast cancer imaging.
abstract: Positron emission tomography (PET) scanning has gained widespread acceptance for the diagnosis, staging, and management of a variety of malignancies, including breast cancer. This has heralded an exciting new era of molecular imaging research of which using FDG as the primary PET tracer is only the beginning. The fundamental strength of PET over conventional imaging is the ability to convey functional information that even the most exquisitely detailed anatomic image cannot provide. As the standard PET radiotracer in current clinical use, FDG is a glucose analog that is taken up by cells in proportion to their rate of glucose metabolism. The increased glycolytic rate and glucose avidity of malignant cells in comparison to normal tissue is the basis of the ability of FDG-PET imaging to accurately differentiate cancer from benign tissue irregardless of morphology. The level or intensity of FDG uptake on PET is semiquantified and reported as the standardized uptake value (SUV). A multitude of new PET tracers are under development, many of which are aimed at targeting cellular processes that are more specific than glucose metabolism. In relation to breast cancer, these tracers include thymidine analogs such as [F-18]fluoro-L-thymidine (FLT) that target DNA replication as a measure of cell proliferation, annexin V derivatives that evaluate apoptosis, estrogen receptor (ER) tracers such as 16 -[F-18]fluoroestradiol-17 (FES), and engineered antibody fragments that directly target HER-2/neu receptors. In addition to new tracers, scanner technology is also rapidly evolving. Chief among these is the advent of the dual modality PET/CT scanner, which at the very least increases patient convenience by permitting PET and computed tomography (CT) imaging in a single appointment. But perhaps more importantly, initial studies indicate that the sum of the two modalities is better than either used separately and also may be an extremely useful tool in preradiation therapy planning. Other new scanning devices are also being developed, including small gantry PET scanners designed specifically for breast imaging, and handheld PET probes for direct intraoperative localization of tracer-avid tumor foci.

title: Positron emission tomographic assessment of ”metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy
abstract: We have investigated whether increased tumor uptake of fluorine-18 fluorodeoxyglucose (FDG) detected with positron emission tomography (PET) early after initiating tamoxifen therapy (”metabolic flare”) predicts a hormonally responsive breast cancer. Eleven postmenopausal women with biopsy-proved estrogen receptor-positive (ER+) metastatic breast cancer were studied by PET with FDG and 16α[18F]fluoro-17β-estradiol (FES) before and 7–10 days after initiation of tamoxifen therapy. FDG and FES uptake was evaluated semiquantitatively in 21 lesions. The PET results were correlated with follow-up evaluation, continued until the patient became unresponsive to hormone therapy (3–24 months). There were seven responders and four nonresponders based on clinical follow-up. None of the responders had a clinical flare reaction, but all demonstrated metabolic flare, with a mean ± standard deviation increase in tumor standardized uptake value (SUV) for FDG of 1.4±0.7. No evidence for flare was noted in the nonresponders (change in SUV for FDG –0.1±0.4; P = 0.008 vs. responders). The degree of ER blockade by tamoxifen was greater in responders (mean decrease in SUV 2.7±1.7) than in nonresponders (mean decrease 0.8±0.5) (P = 0.04). The lesions of responders had higher baseline SUVs for FES than did those of three of four nonresponders (≥2.2 vs ≤1.7). The findings of a metabolic flare by FDG-PET and the degree of ER blockade by FES-PET early after institution of tamoxifen treatment appear to predict responsiveness to antiestrogen therapy in patients with ER+ metastatic breast cancer.

title: PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer
abstract: To determine if response to endocrine therapy of breast cancer can be predicted by either a metabolic “flare reaction” detected by positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the estrogen analog 16α-[18F]fluoroestradiol-17β (FES).  Fifty-one post-menopausal women with advanced estrogen-receptor positive breast cancer were studied. Patients underwent FES-PET and FDG-PET at baseline and repeat FDG-PET after 30 mg estradiol. Tracer uptakes was measured as the standardized uptake value (SUV). Patients were subsequently treated with either an aromatase inhibitor or fulvestrant. A prospectively defined cut-off SUV ≥ 2 for FES was considered positive for ER expression. A cutoff of ≥12% increase in SUV for FDG, determined by ROC analysis, represented metabolic flare. PET results were correlated with responsiveness to endocrine therapy.  Seventeen patients responded and 34 patients did not respond to endocrine therapy. Four responders and one non-responder had a clinical flare reaction, while only the responders demonstrated metabolic flare. After estradiol challenge, a significantly higher mean (±SD) percent change in SUV for FDG was noted in responders (20.9 ± 24.2) compared with non-responders (−4.3 ± 11.0, P < 0.0001). On FES-PET, a higher tumor SUV was noted in responders (3.5 ± 2.5) compared with non-responders (2.1 ± 1.8, P = 0.0049). There was significantly longer overall survival in patients with metabolic flare than in those without flare regardless of type of endocrine therapy (P = 0.0062).  Baseline tumor FES uptake and metabolic flare after an estradiol challenge are both predictive of responsiveness to endocrine therapy in ER+ breast cancer.

title: Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.
abstract: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [(18)F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[(18)F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer.



Forty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy.



In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003).



The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.

title: Preoperative evaluation of prognosis in breast cancer patients by [18F]2-Deoxy-2-fluoro-D-glucose-positron emission tomography
abstract: D-glucose (FDG)-positron emission tomography (PET) was applied to breast cancer patients for the purpose of preoperative evaluation of patient prognosis with more accuracy than conventional TNM staging. FDG-PET was performed preoperatively in 81 patients with breast cancer, and the maximum standardized uptake value (SUVmax) of tumors as well as the focal accumulation of FDG in the axillary region (PET-N status) were investigated in their association with patient prognosis. The SUVmax high group (n=40) showed a significantly (P=0.011) poorer prognosis than the SUVmax low group (n=41) (5-year disease-free survival (DFS) rates; 75.0% vs 95.1%). FDG-PET was more accurate in the diagnosis of axillary lymph node status than physical examination, i.e., diagnostic accuracy was 80% and 70% for FDG-PET and physical examination, respectively. The combination of high SUVmax and positive PET-N (+) was shown to be a highly significant risk factor being independent of the clinical T and N factors, i.e., patients with high SUVmax and positive PET-N (+) showed a significantly (P<0.001) poorer prognosis than the other patients (5-year DFS rates; 44.4% vs 96.8%).Conclusions These results suggest that FDG-PET is useful in the preoperative evaluation of prognosis in breast cancer patients with more accuracy than conventional TNM staging. It is expected that the indication of neoadjuvant chemotherapy can be decided more precisely by the preoperative evaluation of patient prognosis with FDG-PET due to a possible elimination of overtreatment for those who have good prognosis and, thus, need not to be treated with chemotherapy.

title: Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2‐deoxy‐2‐fluoro[18F]‐D‐glucose
abstract: Positron emission tomography (PET) with 2‐deoxy‐2‐fluoro[18F]‐D‐glucose (FDG) can provide quantitative information about tumor glucose metabolism. The prognostic value of this technique was evaluated for breast carcinoma patients.

title: Comparison of FDG PET and MRI for evaluating the tumor extent of breast cancer and the impact of FDG PET on the systemic staging and prognosis of patients who are candidates for breast-conserving therapy
abstract: BackgroundFDG PET has not yet found a role in the clinical evaluation of the tumor extent of breast cancer. FDG PET has been reported to be useful for evaluating the prognoses of breast cancer patients with more accuracy than conventional imaging modalities. The purpose of this study was to compare the accuracy of FDG PET and MRI for the preoperative assessment of the tumor extent of breast cancer, for evaluating the impact of FDG PET on systemic staging, and also for predicting the prognosis of patients who are candidates for breast-conserving therapy.MethodsThe study was a prospective series of 23 breasts with breast cancer that underwent both FDG PET and MRI before surgery. Systemic staging with FDG PET was also performed. The correlation between the results of these examinations and histological findings was thus examined. The maximum standardized uptake value (SUVmax) of the tumors was investigated in association with the patient prognoses.ResultsWhen evaluating the local tumor extent, the accuracy of FDG PET (43.5%) was significantly lower than that of MRI (91%) (P < 0.001). The sensitivity, specificity, and accuracy of FDG PET regarding the nodal status were 60, 94, and 87%, respectively. No patients demonstrated any distant metastasis, whereas FDG PET gave a false positive in one patient. The mean follow-up period was 61 months. The SUVmax value of the worse prognosis patient group was significantly higher than that of the good prognosis patient group (P = 0.032).ConclusionsFDG PET is not a breast imaging modality for evaluating the local tumor extent, but it is useful for predicting the prognoses of patients who are candidates for breast-conserving therapy.

title: Sequential Positron Emission Tomography Using [18F]Fluorodeoxyglucose for Monitoring Response to Chemotherapy in Metastatic Breast Cancer
abstract: To evaluate the clinical value of positron emission tomography (PET) for monitoring chemotherapy in metastatic breast cancer.  Twenty patients with hormonorefractory or hormonoreceptor-negative multimetastatic breast cancer were prospectively included. PET studies were done at baseline, at day 21 after the first cycle and at day 21 after the third cycle of chemotherapy. Metabolic response was defined based on visual and various modes of standardized uptake value (SUV) analysis of sequential PET studies.  After one cycle, PET indicated a partial response in 12 patients, stable disease in 7 patients, and progressive disease in 1 patient, according to the visual analysis. After three cycles, PET showed a complete response in 5 patients, partial response in 11 patients, stable disease in 3 patients, and progressive disease in 1 patient. Seventy-five percent of the patients showing a metabolic response on visual analysis effectively responded to the treatment. The average SUV decreased on both the second and the third PET study, but only changes measured after three cycles of chemotherapy predicted the clinical response to chemotherapy and the overall survival. All methods for calculating the SUV (normalized for body weight, body surface area, or lean body mass) provided similar results.  Semiquantitative analysis of [18F]fluorodeoxyglucose-PET studies done after three cycles of chemotherapy is useful for monitoring the response to chemotherapy in metastatic breast cancer.

title: Serial 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) to monitor treatment of bone-dominant metastatic breast cancer predicts time to progression (TTP)
abstract: BackgroundThe response of bone-dominant (BD) breast cancer to therapy is difficult to assess by conventional imaging. Our preliminary studies have shown that quantitative serial 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) correlates with therapeutic response of BD breast cancer, but the relationship to long-term outcome measures is unknown. Our goal was to evaluate the prognostic power of serial FDG PET in BD breast cancer patients undergoing treatment.MethodsWe reviewed medical records of 405 consecutive breast cancer patients referred for FDG PET. Of these, 28 demonstrated metastatic BD breast cancer, were undergoing treatment, had at least 2 serial PET scans, and had abnormal FDG uptake on the first scan. Standardized uptake value (SUV) for the most conspicuous bone lesion at the initial scan, absolute change in SUV over an interval of 1–17 months, and percent change in SUV were considered as predictors of time-to-progression (TTP) and time to skeletal-related event (t-SRE).ResultsUsing proportional hazards regression, smaller percentage decreases in SUV (or increases in SUV) were associated with a shorter TTP (P < 0.006). A patient with no change in SUV was twice as likely to progress compared to a patient with a 42% median decrease in SUV. A higher SUV on the initial FDG PET predicted a shorter t-SRE (hazard ratio = 1.30, P < 0.02).ConclusionsChanges in serial FDG PET may predict TTP in BD metastatic breast cancer patients. However, larger prospective trials are needed to validate changes in FDG PET as a surrogate endpoint for treatment response.

title: Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET.
abstract: Chemotherapy is currently the treatment of choice for patients with high-risk metastatic breast cancer. Clinical response is determined after several cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures including CT, MRI, plain film radiography, or ultrasound. The aim of this study was to evaluate the use of sequential 18F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for metastatic breast cancer.



Eleven patients with 26 metastatic lesions underwent 31 (18)F-FDG PET examinations (240-400 MBq of 18F-FDG; 10-min 2-dimensional emission and transmission scans). Clinical response, as assessed by conventional imaging after completion of chemotherapy, served as the reference. 18F-FDG PET images after the first and second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients' blood glucose levels. In addition, whole-body 18F-FDG PET images were viewed for overall changes in the 18F-FDG uptake pattern of metastatic lesions within individual patients and compared with conventional imaging results after the third and sixth cycles of chemotherapy.



After completion of chemotherapy, 17 metastatic lesions responded, as assessed by conventional imaging procedures. In those lesions, SUV decreased to 72% +/- 21% after the first cycle and 54% +/- 16% after the second cycle, when compared with the baseline PET scan. In contrast, 18F-FDG uptake in lesions not responding to chemotherapy (n = 9) declined only to 94% +/- 19% after the first cycle and 79% +/- 9% after the second cycle. The differences between responding and nonresponding lesions were statistically significant after the first (P = 0.02) and second (P = 0.003) cycles. Visual analysis of 18F-FDG PET images correctly predicted the response in all patients as early as after the first cycle of chemotherapy. As assessed by 18F-FDG PET, the overall survival in nonresponders (n = 5) was 8.8 mo, compared with 19.2 mo in responders (n = 6).



In patients with metastatic breast cancer, sequential 18F-FDG PET allowed prediction of response to treatment after the first cycle of chemotherapy. The use of 18F-FDG PET as a surrogate endpoint for monitoring therapy response offers improved patient care by individualizing treatment and avoiding ineffective chemotherapy.

title: Bone metastases in patients with metastatic breast cancer: morphologic and metabolic monitoring of response to systemic therapy with integrated PET/CT.
abstract: To retrospectively compare morphologic and metabolic changes in bone metastases in response to systemic therapy in patients with metastatic breast cancer (MBC) with integrated positron emission tomography (PET)/computed tomography (CT).



The institutional review board waived the requirement for informed consent and approved this HIPAA-compliant study. A retrospective analysis was performed with 102 women (mean age, 55 years) with MBC who received systemic treatment. All patients underwent integrated PET/CT before and after treatment. Two reviewers analyzed the images in consensus. Morphologic changes, including morphologic patterns, and lesion attenuation were evaluated. Standardized uptake value (SUV) and total lesion glycolysis (TLG) were analyzed to evaluate metabolic changes. Uni- and multivariate analyses were performed to identify factors that enabled response duration (RD) to be predicted.



At baseline, the morphologic patterns of the target lesions were lytic (n = 33), sclerotic (n = 22), mixed (n = 42), and unclassified (n = 5). Progression of sclerotic change after treatment was identified in 49 patients (48%). After treatment, the mean attenuation of the lesion increased, whereas the mean SUV and TLG decreased. Increases in attenuation correlated significantly with decreases in SUV (r = -0.510, P < .001) and TLG (r = -0.491, P < . 001). Univariate analysis revealed that the increase in attenuation and the decrease in SUV were potential predictors of RD. Multivariate analysis revealed that an increase in the change in SUV was a significant predictor of RD (relative risk, 2.4; P = .003).



A decrease in SUV after treatment was an independent predictor of RD in patients with MBC who had bone metastases.

title: Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.
abstract: [18F]-fluorodeoxyglucose ([18F]-FDG) uptake is enhanced in most malignant tumours which in turn can be measured using positron emission tomography (PET). A number of small clinical trials have indicated that quantification of the change in tumour [18F]-FDG uptake may provide an early, sensitive, pharmacodynamic marker of the tumoricidal effect of anticancer drugs. This may allow for the introduction of subclinical response for anticancer drug evaluation in early clinical trials and improvements in patient management. For comparison of results from smaller clinical trials and larger-scale multicentre trials a consensus is desirable for: (i) common measurement criteria; and (ii) reporting of alterations in [18F]-FDG uptake with treatment. This paper summarises the current status of the technique and recommendations on the measurement of [18F]-FDG uptake for tumour response monitoring from a consensus meeting of the European Organization for Research and Treatment of Cancer (EORTC) PET study group held in Brussels in February 1998 and confirmed at a subsequent meeting in March 1999.

title: From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors
abstract: The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with 18F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0.  PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment.  Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to 18F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test–retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm3 in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for “response,” and deferring to RECIST 1.1 in cases that do not have 18F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed.  Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas 18F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.

title: Triple-Negative Breast Cancer: Early Assessment with 18F-FDG PET/CT During Neoadjuvant Chemotherapy Identifies Patients Who Are Unlikely to Achieve a Pathologic Complete Response and Are at a High Risk of Early Relapse
abstract: Triple-negative breast cancer, an aggressive subtype, represents 15% of invasive breast tumors. This prospective study investigated whether early changes in 18F-FDG tumor uptake during neoadjuvant chemotherapy (NAC) can predict outcomes.  Twenty (M0) patients underwent 18F-FDG PET/CT at baseline and after the second cycle. NAC was continued irrespective of PET results.  At surgery, 6 patients had a pathologic complete response, whereas 14 had residual tumor. Four patients showed early relapse (in the 2 y after surgery). There were 11 metabolic responders and 9 nonresponders using a 42% decrease in maximum standardized uptake value as a cutoff. In nonresponding patients, the risk of residual tumor at surgery was 100% (vs. 45% in responders; P = 0.014), and the risk of early relapse was 44% (vs. 0%; P = 0.024).  A less than 42% decrease in 18F-FDG uptake at 2 cycles means residual tumor at the end of NAC and a high risk of early relapse.

title: Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: relevance of breast cancer subtype.
abstract: To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC).



MRI examinations were performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index [BRI], representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations.



Residual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve [AUC], 0.84; P < .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearson's r = 0.465; P < .001). In subset analysis, this was only significant for triple-negative tumors (P < .001) and HER2-positive tumors (P < .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P < .001). No associations were found for ER-positive/HER2-negative tumors.



MRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.

title: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
abstract: Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

title: [New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)].
abstract: This paper is an overview of the new response evaluation criteria in solid tumours: revised RECIST guideline (version 1. 1), with a focus on updated contents.

title: Powerful prognostic stratification by [18F]fluorodeoxyglucose positron emission tomography in patients with metastatic breast cancer treated with high-dose chemotherapy.
abstract: This study examines the use of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of the therapeutic response for patients treated with high-dose chemotherapy (HDC) with autologous stem cell transplantation for metastatic breast cancer (MBC) focusing on prognostic stratification.



Forty-seven patients with MBC were treated with a maximum of three cycles of HDC. Therapeutic response was assessed with conventional imaging (CImg; including a computed tomography in all cases and ultrasound, mammography, and bone scanning as clinically indicated) and by FDG-PET study performed after the last cycle of HDC. Parameters analyzed for predicting survival were FDG-PET and CImg results, pattern of disease, prior treatment, and HDC regimen.



Complete responses were observed in 16 patients (37%) with CImg and 34 patients (72%) with FDG-PET. The FDG-PET result was the most powerful and independent predictor of survival; patients with a negative post-treatment FDG-PET had a longer median survival than patients with a positive FDG-PET (24 months v 10 months; P < .001). By multivariate analysis the relative risk (RR) of death was higher in patients with FDG-PET-positive disease (RR, 5.3), prior anthracycline treatment (RR, 3.3), or with visceral metastasis (RR, 2.4).



A single FDG-PET study performed after completion of HDC for MBC can powerfully stratify for survival. This may have implications for how we should assess outcome after conventional-dose therapy for MBC and warrants additional study.