Metabolically active BAT has been recognized in adult humans after the advent of PET/CT [11, 14, 15]. Different studies have confirmed that adipose tissue does not only store energy but also secretes adipokines, inflammatory cytokines, growth factors, and free fatty acids, which can contribute to tumor growth and cancer progression [16,17,18]. Moreover, BAT has a similar biological property of hypermetabolism to cancer cells, this allowed in vivo quantification of BAT metabolism, which provided a major advancement in the field of BAT biology [19]. On 18F-FDG PET/CT imaging, BAT is most often detected in the cervical, supraclavicular, mediastinal, and paravertebral regions, and less frequently in the sub-phrenic areas [12]. In accordance, we found among patients with positive BAT, 15/16 (93.75%) patients had active BAT in the cervical, supraclavicular, mediastinal, and thoracic paravertebral regions, and only one (6.25%) patient had active perinephric BAT (sub-phrenic) as well.
Consistent with previous studies [10, 12], the current study showed that BAT activation is significantly associated with younger age, lower BMI, and lower outdoor temperature (P=0.001, 0.001, and 0.035), respectively. On the other hand, other studies found no significant difference between the BMI of patients with metabolically active BAT and that of patients without BAT [5, 8, 20]. Also, in a study done by Fujii et al. [4], discussing the association between BAT and BC, they reported no statistically significant association between the intensity of supraclavicular BAT activity and age or BMI of the patients (P=0.910 and 0.146), respectively.
The incidence of hypermetabolic BAT identified by 18F-FDG PET/CT has been reported in 1.7–9.3% of patients [21]. However, a relatively higher prevalence of activated BAT was found in patients with lymphoma (17%) and BC (15.2–80%) [3, 6, 10, 12, 22]. Our study demonstrated a lower prevalence (10.2%) of active BAT in the included BC patients, this difference could be explained by patients mismatching for age and weight (active versus non-active BAT groups). While in the other studies, analysis of BAT activity was based on age and body weight-matched groups of patients [3, 4, 12].
Given the retrospective nature of our study, we could not obtain the information about the menopausal status for each patient, to overcome this challenge, we stratified the data by age (<50 and ≥ 50 years old) to roughly classify the patients into premenopausal and postmenopausal groups, respectively.
Considering the positive BAT group, we found that active BAT is significantly prevalent in patients <50 years (14/16, 87.5%) versus (2/16, 12.5%) in patients ≥ 50 years, (P=0.001). In addition, the multivariate analysis revealed that BMI and age of the patients were the only factors significantly associated with BAT activity (P= 0.025 and 0.043, respectively). Furthermore, we found a more frequent expression of PR and ER in patients with active BAT, in consistent with other studies which documented higher prevalence of hypermetabolic BAT in non-menopausal patients and suggested that BAT metabolism is sex hormone-dependent and female sex hormones promote 18F-FDG uptake in BAT [6, 23, 24].
Our patients with active BAT showed insignificantly higher prevalence of lymph node metastasis and a lower prevalence of distant metastasis compared to patients without BAT activation. Also, TMA and SUVmax of BAT were insignificantly higher in patients with nodal metastasis. However, we demonstrated a significant positive association between SUVmax of BAT and absence of distant metastasis (P=0.021), this comes in contrast to Pace et al .[12], who documented that patients with active BAT had a significantly less frequent nodal and distant metastasis than in patients without active BAT (P < 0.05). Yet, in agreement with our findings, they stated the absence of significant difference in TMA and SUVmax of BAT between patients with and without nodal metastasis.
Moreover, we revealed that active BAT is more frequent in luminal B subtype, HER2−, and grade II, with higher activity of BAT in grade I. Both SUVmax and TMA tended to be higher in less aggressive molecular subtypes (luminal A and B), respectively. Although TMA of BAT was significantly higher among HER2+ patients (P=0.019), in the setting of HER2-targeted therapy, HER2+ BC is no longer associated with poor prognosis [25].
In the present study, we found a negative association between both metabolic activity (SUVmax), size of the primary tumor, and the prevalence of BAT activity, both of them tend to be lower in activated BAT group. Also, there was an insignificant correlation between the intensity of metabolic status of the primary tumor and that of BAT. In contrast, other studies found a positive association [4, 9, 10].
Our study had some limitations, the first one being a retrospective analysis, a small number of BAT-positive patients; other factors known to be associated with BAT activation including psychological factors and catecholamine levels and medical history of patients were not evaluated. A large prospective multicenter study is needed to verify the relationship between BAT activation and the long-term outcome of BC patients.