Positron-emission tomography (PET) has proven useful in the evaluation of many cancers. However, as with all imaging modalities, PET is best used in the proper clinical scenarios. Although many types of PET radiotracers have been developed to noninvasively interrogate in vivo tumor metabolism, the most widely used US Food and Drug Administration (FDA)–approved PET radiotracer, 2-deoxy-2-(18F)fluoro-D-glucose (FDG), is based on glucose metabolism. FDG is transported into the cell via glucose transporters, but unlike glucose, FDG is not metabolized but is irreversibly phosphorylated by hexokinase and trapped within the cell. Because glucose transport is upregulated in most cancers in a phenomenon termed the Warburg effect, FDG PET exploits greater uptake of FDG within most cancer cells versus normal tissue in order to visualize tumors. Biologic correlates of FDG uptake in breast cancer include mitotic activity index, histologic grade, tumor cell density, as well as other markers of aggressiveness.1-3 For example, FDG uptake is greater with triple-negative breast cancer (TNBC) and HER2 positivity, and lower with luminal A subtypes. While FDG uptake positively correlates with pathologic complete response to neoadjuvant chemotherapy for patients with breast cancer, FDG uptake inversely correlates with prognosis.4,5
Awareness of key principles of FDG PET usage is important for clinicians who order FDG PET for their patients with breast cancer. Most PET scanning today is performed on a combined PET-computed tomography (CT) hybrid instrument, which allows co-registration of metabolic data from the PET scan with anatomic data from the CT scan. Patients should be fasting except for water for at least 4 to 6 hours to optimize the study. Lack of fasting or elevated blood glucose will raise insulin levels and drive FDG into muscle and away from tumor tissue. Recent chemotherapy or marrow stimulation with granulocyte colony-stimulating factors within 2 to 4 weeks before may spuriously lower FDG uptake in tumors. Although FDG uptake has high positive predictive value (PPV) for breast cancer, false-positive uptake has been described with dysplasia, fibroadenomas, silicone leakage, and fat necrosis, among other inflammatory and infectious eti-ologies.6 False-negative results on whole-body FDG PET imaging may be secondary to small lesions (<1 cm), tubular or lobular carcinoma, or carcinoma in situ.
For primary breast lesions, because whole-body FDG PET has lower sensitivity for the detection of small lesions, it is not recommended as a primary staging modality. In a study by Avril et al,7 while PET imaging detected 92% of pT2 lesions, only 68% of pT1 lesions (<2 cm) were detected. In addition, 65% of lobular carcinomas in that series had false-negative results compared with ductal carcinomas (24% false-negative). Yet, because of its high PPV for identification of tumors, whole-body FDG PET may be useful in uncommon problem-solving cases for which magnetic resonance imaging (MRI) is not available. Similarly, if incidental breast focal activity is noted on FDG PET in the evaluation of other cancers, further investigation is warranted.8-10 Although beyond the scope of this review, investigation is ongoing on the clinical utility of such specialized PET techniques as positron-emission mammography (PEM) with dedicated small-field devices in the evaluation of primary breast cancer. There is evidence to suggest that while PEM with FDG has lower sen-sitivity for small breast lesions compared with MRI, specificity is higher than with MRI.11,12 More specialized radiotracers, such as 18F-fluoroestradiol, may also become available for use with PET or PEM for more complete, noninvasive, metabolic interrogation of breast lesions.
Initially there had been speculation that FDG PET could potentially obviate nodal dissection for locoregional axillary nodal staging, but this has not proven to be the case. While FDG PET does have high PPV in the detection of axillary nodes, there is insufficient sensitivity to detect small-volume disease compared with the sentinel node procedure.13,14 Yet, whereas FDG PET is not recommended for initial axillary nodal staging, many studies have demonstrated the superiority of FDG PET compared with conventional imaging such as CT or MRI for mediastinal, inter-nal mammary, and supraclavicular nodal involvement.15,16 In one study by Eubank et al,15 PET scanning demonstrated accuracy of 88% compared with CT staging accuracy of 70%, upstaging 10 of 33 patients. FDG PET scanning, therefore, is especially useful to help guide radiation therapy planning decisions.17-19
The greatest utility for FDG PET imaging is for whole-body staging, including the detection of distant metastasis (Figure 1). In a retrospective study of 225 patients, Niikura et al20 reported 97.4% sensitivity and 91.2% specificity for FDG PET imaging compared with a combination of conventional techniques with 85.9% sensitivity and 67.3% specificity.20 Yet, rapid growth in the use of FDG PET has been reported even in early-stage breast cancer, in which FDG PET is not indicated for asymptomatic patients because of low baseline prevalence for metastatic disease.14,21 According to National Comprehensive Cancer Network (NCCN) guidelines, FDG PET is considered optional for locally advanced (clinical stage 3a), recurrent, or stage 4 disease, but is not indicated for clinical stages 1, 2, or operable stage 3.22 Most third-party payers reference these guidelines. However, there is compelling evidence that even at clinical stage 2b, whole-body staging of patients with FDG PET has excellent utility. In a prospective study of 254 patients with breast cancer, Groheux et al23 reported stage modification due to N3 disease and/or distant metastases detection in 16.1% of patients with clinical stage 2b disease.23 In another retrospective study of 134 asymptomatic women younger than 40 years, distant metastases were discovered in 17% of patients initially staged with 2b disease.24
Finally, in a prospective study by Cochet et al25 of 142 patients with T2 or larger breast lesions in which standard conventional staging was followed by FDG PET, not only did FDG PET scanning have greater prognostic significance compared with conven-tional imaging, but the addition of FDG PET resulted in 21% upstaging and 16% downstaging. In patients with inflammatory breast cancer, there is broad consensus as to the added value of FDG PET for complete staging.26-28 Yet, with less FDG avid breast tumor histology, such as lobular carcinoma, recent evidence suggests that FDG PET imaging may not contribute much to systemic staging compared with conventional imaging.29 The long-term impact of treatment changes based on PET scanning, however, remains unknown.
There has been some controversy as to the role of FDG PET versus routine bone scanning for the detection of skeletal metastasis. In a study of 89 patients who underwent both FDG PET and bone scans, whereas FDG PET had inferior performance compared with bone scanning for purely osteoblastic lesions, FDG PET outperformed bone scanning for osteolytic, mixed, and CT-silent lesions.30 The addition of CT to PET, as in most modern PET-CT scanners, also reveals osteoblastic lesions that may not be metabolically active on FDG PET alone. Thus, most imaging specialists support the use of FDG PET over bone scan for initial staging, and then recommend bone scan or 18F-NaF PET-CT if there is still clinical suspicion after a negative or equivocal FDG PET scan (Figure 2). Finally, lesions on bone scan may appear worse, when in fact the lesions are healing (flare phenomenon). Although metabolic flare has been reported with FDG PET scanning in response to hormonal therapy, it is considered rare with other systemic therapy. Thus, in general, FDG PET more accurately reflects metabolic response to therapy.30-33
FDG PET has also proven useful for monitoring response to chemotherapy in the neoadjuvant and metastatic settings. Wahl et al34 first reported that response on FDG PET imaging performed mid-therapy could discriminate between responders and nonresponders. The current overall consensus is that: (1) early-or mid-therapy FDG PET during neoadjuvant therapy is the best predictor of ultimate response; (2) poor response on FDG PET is highly predictive of therapy failure; and (3) the absence of FDG uptake is not sensitive for histologic complete response since minimal residual disease might not be detected. In addition, initial uptake and optimal response criteria on FDG PET imaging depend on histologic subtype, and type and even sequence of neoadjuvant chemotherapy.35-41
Although more work in well-controlled trials to define precise indices for response criteria is required, lack of response on FDG PET imaging has utility in predicting poor clinical response to therapy, and provides prognostic information that may result in modification of chemotherapy or encourage closer post-therapy surveillance.42 Finally, in patients with metastatic disease in which early identification of nonresponders may avert futile chemotherapy, FDG PET scanning is a highly accurate technique to assess response at the end of therapy and to monitor overall biologic behavior, especially in lesions that are difficult to follow with anatomic imaging, such as bone metastasis.
FDG PET is highly valuable in the setting of recurrence (Figure 3). With conventional imaging, it can be difficult to differentiate recurrent cancer from postsurgical and radiation sequelae. However, FDG PET performs well in this regard, with excellent diagnostic performance in the detection and staging of recurrent breast cancer. FDG PET scanning has proven accurate on or off hormonal therapy, and may alter management in up to 51% of patients. Although FDG PET is not recommended for routine surveillance of asymptomatic patients after a complete response to therapy, whole-body restaging with FDG PET imaging has proven value over conventional imaging for patients with rising tumor markers or otherwise clinical suspicion of recurrence.43-46
Affiliation: David M. Schuster, MD, is from the Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA.
Disclosure: Dr Schuster has no relevant financial conflicts of interest to disclose.
Address correspondence to: David M. Schuster, MD, Director, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University Hospital, Room E152, 1364 Clifton Rd, Atlanta, GA 30322. Phone: 404-712-4859; fax: 404-712-4860; email: firstname.lastname@example.org.
- Bos R, van Der Hoeven JJ, van Der Wall E, et al. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol. 2002;20(2):379-387.
- Osborne JR, Port E, Gonen M, et al. 18F-FDG PET of locally invasive breast cancer and association of estrogen receptor status with standardized uptake value: microarray and immunohisto-chemical analysis. J Nucl Med. 2010;51(4):543-550.
- Miyake KK, Nakamoto Y, Kanao S, et al. Journal Club: diagnostic value of (18)F-FDG PET/CT and MRI in predicting the clinicopathologic subtypes of invasive breast cancer. Am J Roent-genol. 2014;203(2):272-279.
- Jin S, Kim SB, Ahn JH, et al. 18 F-fluorodeoxyglucose uptake predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: a retrospective cohort study. J Surg Oncol. 2013;107(2):180-187.
- Kadoya T, Aogi K, Kiyoto S, et al. Role of maximum standardized uptake value in fluorodeoxyglucose positron emission- tomography/computed tomography predicts malignancy grade and prognosis of operable breast cancer: a multiinstitute study. Breast Cancer Res Treat. 2013;141(2):269-275.
- Benveniste AP, Yang W, Benveniste MF, et al. Benign breast lesions detected by positron emission tomography-computed to- mography. Eur J Radiol. 2014;83(6):919-929.
- Avril N, Rose CA, Schelling M, et al. Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations. J Clin Oncol. 2000;18(20):3495-3502.
- Kang BJ, Lee JH, Yoo Ie R, et al. Clinical significance of incidental finding of focal activity in the breast at 18F-FDG PET/ CT. Am J Roentgenol. 2011;197(2):341-347.
- Kim MY, Cho N, Chang JM, et al. Mammography and ultrasonography evaluation of unexpected focal 18F-FDG uptakes in breast on PET/CT. Acta Radiol. 2012;53(3):249-254.
- Dunne RM, O’Mahony D, Wilson G, et al. The role of the breast radiologist in evaluation of breast incidentalomas detected on 18-fludeoxyglucose positron emission tomography/CT. Br J Radiol. 2013;86(1026):20130034.
- Berg WA, Madsen KS, Schilling K, et al. Breast cancer: comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast. Radiology. 2011;258(1):59-72.
- Schilling K, Narayanan D, Kalinyak JE, et al. Positron emission mammography in breast cancer presurgical planning: comparisons with magnetic resonance imaging. Eur J Nucl Med Mol Imaging. 2011;38(1):23-36.
- Veronesi U, De Cicco C, Galimberti VE, et al. A comparative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary metastases. Ann Oncol. 2007;18(3):473-478.
- Pritchard KI, Julian JA, Holloway CM, et al. Prospective study of 2-[(1)(8)F]fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario Clinical Oncology Group study. J Clin Oncol. 2012;30(12):1274-1279.
- Eubank WB, Mankoff DA, Takasugi J, et al. 18fluorode-oxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer. J Clin Oncol. 2001;19(15):3516-3523.
- Seo MJ, Lee JJ, Kim HO, et al. Detection of internal mam-mary lymph node metastasis with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with stage III breast cancer. Eur J Nucl Med Mol Imaging. 2014;41(3):438-445.
- Koolen BB, Valdes Olmos RA, Elkhuizen PH, et al. Locoregional lymph node involvement on 18F-FDG PET/CT in breast cancer patients scheduled for neoadjuvant chemotherapy. Breast Cancer Res Treat. 2012;135(1):231-240.
- Choi JE. The metastatic rate of internal mammary lymph nodes when metastasis of internal mammary lymph node is suspected on PET/CT. J Breast Cancer. 2013;16(2):202-207.
- Chen SA, Schuster DM, Mister D, et al. Radiation field design and patterns of locoregional recurrence following definitive radiotherapy for breast cancer. Int J Radiat Oncol Biol Phys. 2013;85(2):309-314.
- Niikura N, Costelloe CM, Madewell JE, et al. FDG-PET/CT compared with conventional imaging in the detection of distant metastases of primary breast cancer. Oncologist. 2011;16(8):1111-1119.
- Crivello ML, Ruth K, Sigurdson ER, et al. Advanced imaging modalities in early stage breast cancer: preoperative use in the United States Medicare population. Ann Surg Oncol. 2013;20(1):102-110.
- Gradishar WJ, Anderson BO, Blair SL, et al. Breast cancer version 3.2014. J Natl Compr Canc Netw. 2014;12(4):542-590.
- Groheux D, Hindie E, Delord M, et al. Prognostic impact of (18)FDG-PET-CT findings in clinical stage III and IIB breast cancer. J Natl Cancer Inst. 2012;104(24):1879-1887.
- Riedl CC, Slobod E, Jochelson M, et al. Retrospective analysis of 18F-FDG PET/CT for staging asymptomatic breast cancer patients younger than 40 years. J Nucl Med. 2014;55(10):1578-1583.
- Cochet A, Dygai-Cochet I, Riedinger JM, et al. (1)(8)F-FDG PET/CT provides powerful prognostic stratification in the primary staging of large breast cancer when compared with conventional explorations. Eur J Nucl Med Mol Imaging. 2014;41(3):428-437.
- Carkaci S, Macapinlac HA, Cristofanilli M, et al. Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: preliminary data. J Nucl Med. 2009;50(2):231-238.
- Alberini JL, Lerebours F, Wartski M, et al. 18F-fluorode-oxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging in the staging and prognosis of inflammatory breast cancer. Cancer. 2009;115(21):5038-5047.
- Yeh ED, Jacene HA, Bellon JR, et al. What radiologists need to know about diagnosis and treatment of inflammatory breast cancer: a multidisciplinary approach. Radiographics. 2013;33(7):2003-2017.
- Parsons M, Dashevsky B, Jochelson M, et al. Value of staging FDG- PET/CT in newly diagnosed invasive lobular breast cancer Presented at: the American Roentgen Ray Society Annual Meeting; April 19-24, 2015; Toronto, Canada. Abstract 2423.
- Nakai T, Okuyama C, Kubota T, et al. Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer. Eur J Nucl Med Mol Imaging. 2005;32(11):1253-1258.
- Morris PG, Lynch C, Feeney JN, et al. Integrated positron emission tomography/computed tomography may render bone scintigraphy unnecessary to investigate suspected metastatic breast cancer. J Clin Oncol. 2010;28(19):3154-3159.
- Hahn S, Heusner T, Kummel S, et al. Comparison of FDG-PET/CT and bone scintigraphy for detection of bone metastases in breast cancer. Acta Radiol. 2011;52(9):1009-1014.
- Balasubramanian Harisankar CN, Preethi R, John J. Metabolic flare phenomenon on 18 fluoride-fluorodeoxy glucose positron emission tomography-computed tomography scans in a patient with bilateral breast cancer treated with second-line chemotherapy and bevacizumab. Indian J Nuclear Med. 2015;30(2):145-147.
- Wahl RL, Zasadny K, Helvie M, et al. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol. 1993;11(11):2101-2111.
- Schneider-Kolsky ME, Hart S, Fox J, et al. The role of chemo-therapeutic drugs in the evaluation of breast tumour response to chemotherapy using serial FDG-PET. Breast Cancer Res. 2010;12(3):R37.
- Humbert O, Berriolo-Riedinger A, Riedinger JM, et al. Changes in 18F-FDG tumor metabolism after a first course of neoadjuvant chemotherapy in breast cancer: influence of tumor subtypes. Ann Oncol. 2012;23(10):2572-2577.
- Zucchini G, Quercia S, Zamagni C, et al. Potential utility of early metabolic response by 18F-2-fluoro-2-deoxy-D-glucose-posi-tron emission tomography/computed tomography in a selected group of breast cancer patients receiving preoperative chemotherapy. Eur J Cancer. 2013;49(7):1539-1545.
- Garcia Vicente AM, Cruz Mora MA, Leon Martin AA, et al. Glycolytic activity with 18F-FDG PET/CT predicts final neo-adjuvant chemotherapy response in breast cancer. Tumour Biol. 2014;35(11):11613-11620.
- Groheux D, Hindie E, Giacchetti S, et al. Early assessment with 18F-fluorodeoxyglucose positron emission tomography/ computed tomography can help predict the outcome of neoadjuvant chemotherapy in triple negative breast cancer. Eur J Cancer. 2014;50(11):1864-1871.
- Hirakata T, Yanagita Y, Fujisawa T, et al. Early predictive value of non-response to docetaxel in neoadjuvant chemotherapy in breast cancer using 18F-FDG-PET. Anticancer Res. 2014;34(1):221-226.
- Martoni AA, Zamagni C, Quercia S, et al. Early (18)F-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. Cancer. 2010;116(4):805-813.
- Groheux D, Espie M, Giacchetti S, Hindie E. Performance of FDG PET/CT in the clinical management of breast cancer. Radiology. 2013;266(2):388-405.
- Khatcheressian JL, Hurley P, Bantug E, et al. Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(7):961-965.
- Grassetto G, Fornasiero A, Otello D, et al. 18F-FDG-PET/ CT in patients with breast cancer and rising Ca 15-3 with neg-ative conventional imaging: a multicentre study. Eur J Radiol. 2011;80(3):828-833.
- Evangelista L, Baretta Z, Vinante L, et al. Tumour markers and FDG PET/CT for prediction of disease relapse in patients with breast cancer. Eur J Nucl Med Mol Imaging. 2011;38(2):293-301.
- Champion L, Brain E, Giraudet AL, et al. Breast cancer re-currence diagnosis suspected on tumor marker rising: value of whole-body 18FDG-PET/CT imaging and impact on patient management. Cancer. 2011;117(8):1621-1629.