Background
Breast cancer is the second most lethal cancer in women [
1]. Early stage breast cancers that are confined to the layer of cells in the breast lobule or duct where they originated have a better prognosis and can be cured [
1]. However, the prognosis for advanced stage cancers that have invaded locally and spread to other parts of the body is poor, with median survival averaging 18–24 months [
1]. Understanding biological mechanisms that could affect the possible progression of breast cancer from the high risk lesions such as atypical ductal or lobular hyperplasia to noninvasive cancers, ductal and lobular carcinoma in situ to invasive cancers could yield new targets for prevention of breast cancer and treatment of more advanced stages and ultimately improve patient survival.
Once considered inert, adipose tissue has emerged as a key player in cancer development and progression [
2]. Adipocyte-derived factors have been shown to both stimulate or inhibit cell growth and cause systemic inflammation [
2]. This knowledge has sparked great interest in cancer researchers worldwide to focus on the link between obesity or dysfunctional white adipose tissue (WAT) and cancer [
2‐
7]. Yet another type of fat, brown adipose tissue (BAT), has recently emerged as an interest in context of cancer and tumor development as well [
4,
5]. BAT is characterized by its multilocular cells, numerous mitochondria, and high vascularity, functions to dissipate energy as heat in response to cold temperatures [
8]. Studies in mice have shown that the activation of BAT is associated with the synthesis and secretion of angiogenic and growth factors, resulting in markedly increased vascular density due to activation of angiogenesis [
9,
10]. Therefore, research investigating the potential role of active BAT in adults should also be accounted for in the context of cancer and tumor development.
Data on connections of BAT with neoplasms of nonadipocytic origin is limited. In humans, BAT was considered only to be of significance in infants as a source of easily accessible energy that would regress and gradually be replaced by WAT with age [
8]. Yet, emerging studies point to a potential association of specific BAT features to certain mutated tumor suppressor genes [
4,
11]. In particular, we observed a significantly increased deposition of BAT in the adult mammary fat pad of a mouse model of
Breast Cancer gene 1 (BRCA1) breast cancer compared to age-matched mammary glands from wildtype mice [
11]. This was quite abnormal considering that high amounts BAT are usually only in the mammary gland from birth until about 8–10 weeks of age (near the completion of puberty) [
12,
13]. Considering that high amounts of BAT are exclusively detected in the mouse early in mammary gland development, particularly during stages of ductal growth and increased estrogen signaling, one can speculate that BAT may play a role in mammary ductal growth. Moreover, the high level of BAT in the mammary gland of these mice was associated with increased angiogenesis [
11]. Indeed it is known that angiogenesis is an essential step for breast cancer progression and dissemination [
14]. Therefore, the unexpected finding of the sustained BAT phenotype in the mammary gland of adult mice predisposed to breast cancer raises an important issue of whether there is a relationship between high levels of BAT and breast cancer. Although such a possibility has not been explored clinically, this is an important next step to determine the value and relevance of our findings for human breast cancer.
18 F-fluorodeoxyglucose (FDG) Positron Emission Tomography/Computerized Tomography (PET/CT) is a widely used modality of imaging glucose metabolism in cancer cells for staging of primary cancer and detection of distant metastasis in patients [
15,
16]. Due to its similar biological properties of hypermetabolism to cancer cells, BAT may also have intense FDG uptake and can be as a “false-positive” for cancer evaluation if detected on PET/CT [
15‐
17]. In the current, study we used FDG PET/CT as a non-invasive approach to determine whether there is a significant difference between FDG uptake in BAT between patients with breast cancer and those scanned for other malignancies. The primary objective for this retrospective pilot study was to explore the patterns of BAT activity with FDG PET/CT in patients with breast cancer with a broader aim to form a basis for further studies that will help to determine whether BAT may be an important determinant for breast cancer risk and progression. We also provide an appreciation of the site-based distribution of BAT observed in the images and the clinical and pathological characteristics of the groups of patients in this study.
Methods
Patients
This retrospective image and chart/medical record review study was approved by the University of Maryland Baltimore Institutional Review Board (IRB). The Institutional review board waived the need to obtain consent from patients. Patients were undergoing their FDG PET/CT scans as part of routine standard of care and no changes to standard of care were made. We reviewed the distribution and intensity (maximum standard uptake value, SUVmax) of BAT on FDG PET/CT scans in a total of 96 breast cancer patients who had PET/CT scans from October 2010 to September 2012 in our institution. If a patient had multiple PET/CT scans during this interval, only the first PET/CT scan was analyzed to avoid over counting BAT rate in the same patient. For comparison, each breast cancer patient was assigned a paired-control of a non breast cancer patient (mainly colon cancer) who had a PET/CT scan on the same day. Both groups were carefully matched in reference to sex (all female), age (± 5 years), and body weight (± 5 kg) to control for some of the known factors that could potentially affect FDG uptake in BAT.
FDG PET/CT imaging
Patients fasted for at least 4 h before PET/CT imaging and had a measured finger stick glucose level less than 220 mg/dl before the administration of FDG. As routine practice, patients with fasting blood glucose level greater than 220 mg/dl were excluded from study as high glucose may interfere with 18 F-FDG tracer uptake based on the imaging guidelines. Scans were acquired approximately 60 min after the injection of about 555 MBq (15 mCi) FDG with the Gemini PET/CT (Philips Medical Systems, Cleveland, Ohio, USA) scanner with a 16-slice Brilliance CT.
Data collection
The distribution of the BAT was analyzed in the breast cancer patients (n = 96) and the non-breast cancer patients (n = 96) with one scan per each patient by 2 nuclear medicine physicians blinded to the clinical history. Training and expertise of the two nuclear medicine physicians reading FDG PET/CT was 7 years and 3 years, respectively, with an interpersonal variation of 0. The interpretation of a positive active BAT site on PET/CT was based on the imaging findings of focal FDG uptake in adipose tissue that is visually more intense than the surrounding muscle activity, which is simple “yes” or “no” with no case showing equivocal findings. No SUVmax threshold value was set to define a positive BAT. The location of the BAT was recorded in the bilateral neck, supraclavicular and paraspinal regions. The SUVmax of brown fat was measured, a positive BAT case was defined as at least one positive BAT site in any of the locations in the neck, supraclavicular or paraspinal regions.
Statistical analysis
The prevalence of positive BAT cases on FDG PET/CT in the breast cancer patients was estimated and compared to the control patients using the Fisher’s exact test for 2×2 tables. The Fisher-Freeman-Halton test with Monte-Carlo simulations was applied for rxc contingency tables. Plausible risk factors were also estimated using the logistic regression approach. The distribution of BAT was compared using the non-parametric approach, the Wilcoxon test. The ANOVA method was applied to assess the differences of SUVmax of BAT in different locations between the 2 study groups. All statistical tests were two-sided and done at the 0.05 level of significance. Analyses were conducted in SAS (SAS Institute Inc., Cary, NC, v.9.3).
Conclusions
We have conducted a retrospective investigation using non-invasive FDG PET/CT imaging to explore the relationship between levels of BAT presence and breast cancer in adult women. Early indications show that there is an increased prevalence of metabolically active BAT seen on FDG PET/CT in breast cancer patients compared to their pair matched control patients with other cancers. This finding is most prevalent in younger premenopausal patients, indicating a possible role of sex hormones. These clinical data provide further support to our experimental studies that BAT is associated with breast cancer, however further studies are required to clarify a potential mechanism. We believe that our investigations to determine whether BAT plays an active or passive role in breast cancer progression will provide future insight on whether breast cancer patients who are positive for FDG uptake in BAT are likely to have more or less aggressive tumors than those patients that do not.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
QC participated in the acquisition of data for the PET/CT scans, and in the interpretation of the data. JH and HL participated in the acquisition of patient information, analysis and interpretation of the data. MS and JJ participated in the acquisition and imaging process of the PET/CT scans. KT and WC participated in the design of the study, provided guidance throughout the study process, participated in the analysis and interpretation of the data and helped draft the manuscript. OG participated in the design of the study and performed the statistical analysis. VD supervised all aspects of the PET/CT data acquisition and data analysis and contributed to the manuscript preparation. LJ conceived of the study, and participated in its design and interpretation of data, the coordination of the Nuclear Medicine, Oncology and Pharmacology Departments and contributed to the manuscript preparation. All authors were involved in revising the manuscript, and have read and approved the final manuscript.