Background
Recent evidences have shown that inflammation has a significant association with malignant disease [
1,
2]. Nowadays, it is generally accepted that inflammatory microenvironment and immune response of the host plays significant roles in cancer proliferation, promotion, angiogenesis, and metastasis [
1,
3]. For breast cancer, it has been found that multiple cytokines and chemokines produced by activated immune cells in the inflammatory microenvironment contribute to not only malignant transformation but also epithelial-to-mesenchymal transition that can lead to distant metastasis of cancer cells [
4,
5]. In clinical settings, multiple serum-derived parameters such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein have been used to estimate the degree of systemic inflammatory response to diseases [
6‐
8]. In patients with breast cancer, the increase of the serum inflammatory markers has been linked to worse prognosis [
7,
8]. Furthermore, the level of NLR in breast cancer patients has a significant association with the risk of distant recurrence after surgical resection [
9,
10].
2-Deoxy-2-[
18F]fluoro-D-glucose ([
18F]FDG) positron emission tomography/computed tomography (PET/CT) has significant prognostic potential for predicting clinical outcomes in patients with breast cancer [
11,
12]. Maximum [
18F]FDG uptake of primary tumor has been the most commonly used predictive parameter of PET/CT; however, recent studies have reported that volumetric PET/CT parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have more significant association with survival than maximum [
18F]FDG uptake in breast cancer [
11‐
13]. In addition to the assessment of primary tumor features, a number of recent studies have demonstrated that the degree of systemic inflammatory response to malignancy can be evaluated with [
18F]FDG PET/CT by measuring [
18F]FDG uptake of bone marrow (BM) [
14,
15]. Because [
18F]FDG uptake of BM mainly reflects glucose metabolism of immune cells, increased [
18F]FDG uptake of BM in patients with malignant diseases is considered to be due to BM activation caused by host inflammatory response [
15,
16]. In various malignant diseases, [
18F]FDG uptake of BM has shown significant correlations with serum inflammatory markers and clinical outcomes [
14,
17‐
20]. However, in patients with breast cancer, only a single study have evaluated the clinical implication of [
18F]FDG uptake of the reticuloendothelial system including BM and the spleen [
21], and the prognostic potential of [
18F]FDG uptake of BM for predicting distant recurrence has not been reported yet.
Thus, the main purpose of this study was to investigate the prognostic significance of [18F]FDG uptake of BM for predicting recurrence-free survival (RFS) and distant RFS in patients with breast cancer after curative surgical resection. We also evaluated whether the risk of distant recurrence could be stratified by combining PET/CT parameters of primary tumor and BM.
Discussion
The present study found that BLR measured on pretreatment [
18F]FDG PET/CT was independently associated with distant RFS as well as RFS in patients with breast cancer. A previous study has reported that only mild [
18F]FDG uptake is observed in the BM of normal healthy subjects, showing mean BM SUV and BLR of 1.31 ± 0.21 and 0.60 ± 0.10, respectively [
23]. On the other hand, physicians have encountered an increase of [
18F]FDG uptake of BM in a significant portion of patients with malignant diseases, even in those without concurrent infectious or hematologic diseases [
23,
24]. Previous studies reported that BM SUV and BLR have significant positive correlations with white blood cell counts, serum C-reactive protein level, NLR, PLR, and transforming growth factor (TGF)-beta [
14,
16‐
19,
24‐
26]. A number of previous studies have demonstrated that PET parameters of BM were significant predictors for survival in various kinds of cancers including small cell lung cancer, non-small cell lung cancer, gastric cancer, cervical cancer, colorectal cancer, lymphoma, malignant pleural mesothelioma, melanoma, and head and neck cancer [
14,
17‐
19,
23‐
25,
27‐
32]. Based on these results, [
18F]FDG uptake of BM has been suggested as an imaging biomarker for evaluating the degree of systemic inflammatory response and predicting cancer progression [
14,
18,
19].
The results of our study showed significant positive correlations of [
18F]FDG uptake of BM with serum inflammatory markers. In addition, BLR was determined to be a significant predictor for RFS, indicating that [
18F]FDG uptake of BM could also serve as PET/CT parameters for estimating inflammatory response of the host in breast cancer. Furthermore, there were significant positive correlations of [
18F]FDG uptake of BM with T stage and maximum SUV of breast cancer, suggesting enhanced systemic inflammatory response in patients with aggressive tumors, consistent with results of previous studies [
17,
18,
25,
33]. Considering that epithelial-mesenchymal transition of breast cancer cells is promoted by neutrophils and macrophages via multiple secretory factors such as S100A8/A9 proteins, tumor necrosis factor-alpha, and TGF-beta [
5,
34,
35], we hypothesized that the risk of distant recurrence could be also associated with the degree of [
18F]FDG uptake of BM. In accordance with our hypothesis, our results demonstrated that patients with distant recurrence had significantly higher BLR than those without recurrence and with locoregional recurrence. Furthermore, BLR remained as a significant predictor for distant RFS even after adjusting the tumor stage, ER status, and TLG. Recently, several studies have attempted to treat breast cancer by modulating immune cells and inflammatory condition in tumor microenvironment [
36,
37]. For future clinical trials that evaluate the effect of such a treatment, patients with high BLR might be good candidates.
In contrast with maximum SUV, MTV and TLG can reflect the extent of metabolically active tumor burden [
38,
39]. They have shown superior prognostic values for predicting clinical outcomes in various malignant diseases [
39,
40]. In previous studies on breast cancer patients, although volumetric parameters of [
18F]FDG PET/CT cannot be used to differentiate hormone receptor status of cancer, TLG was significantly associated with aggressive tumor features and the presence of systemic metastasis [
11‐
13]. In addition, TLG was a significant predictor for disease-free survival and overall survival in breast cancer patients [
11‐
13]. Therefore, it was expected that TLG had significant associations with both RFS and distant RFS in the present study. Moreover, in the multivariate model with maximum SUV, TLG, and BLR for predicting distant recurrence, only TLG and BLR showed statistical significance.
Successful metastatic event of breast cancer cells is known to be governed by not only biological characteristics of cancer cells, but also complex interactions between cancer cells and normal host cells including immune cells based on the “seed and soil theory” [
41,
42]. According to the results of the present study, the risk of distant recurrence of breast cancer could be further stratified by combining TLG of breast cancer and BLR. More than 40% of patients with high values of TLG and BLR experienced distant recurrence, and both BLR and TLG showed good discriminative ability in predicting distant RFS as well as RFS. These results imply that both tumor aggressiveness expressed as TLG (seed) and inflammatory response of the host expressed as BLR (soil) can be quantitatively estimated by a single [
18F]FDG PET/CT scan before treatment of breast cancer and that combination of those PET parameters can be used to predict the risk of distant recurrence. When recurrence is suspected in patients who show high TLG of breast cancer and BLR on pretreatment [
18F]FDG PET/CT, systemic evaluation should be performed for the detection of hidden distant metastasis.
In the literature, only one retrospective study has assessed the prognostic potential of [
18F]FDG uptake of BM in 153 patients with invasive ductal carcinoma of the breast [
21]. In that study, maximum SUV of primary tumor and mean SUV of the liver, spleen, and BM were measured and relationships of the PET/CT parameters with recurrence after curative surgical resection were evaluated. Similar to the results of our study, that study revealed significant associations between BM SUV and maximum SUV of primary tumor and between BM SUV and disease-free survival on univariate analysis. However, on multivariate survival analysis, only mean SUV of the spleen was included because mean SUV of the spleen showed the most significant predictive value among mean SUV of the liver, spleen, and BM. Different from that previous study, we calculated additional PET/CT parameter for BM, the BLR. BLR is a parameter which corrects BM SUV by mean [
18F]FDG uptake of the liver to reduce inter-individual variation in BM SUV [
16]. A number of previous studies have demonstrated that BLR has higher correlation coefficients with serum inflammatory markers than BM SUV and that it is a more preferable parameter than BM SUV on survival analysis [
14,
17,
19,
20,
24]. In the present study, BLR also showed more significant associations with recurrence pattern, NLR, and PLR than BM SUV and was an independent prognostic factor for predicting survival. In future studies, the spleen-to-liver uptake ratio should be measured like BLR and the comparison of prognostic significance between BLR and spleen-to-liver uptake ratio is needed.
There are several limitations that remained to be addressed in the present study. First of all, this study was retrospectively performed with patients enrolled from a single center. Due to small numbers of events with relatively short follow-up durations for evaluating breast cancer recurrence, there might be limitation in interpreting the results of the study. Therefore, further studies with multi-center cohort and long-term follow-up are necessary to validate the results of the study. Second, because distant recurrence was diagnosed mainly by imaging examinations, the exact incidence and recurrence timing might be underestimated. Third, because MTV and TLG values of patients with maximum SUV of primary breast cancer < 2.50 were set to be 0.0 cm
3 and 0.0 g, respectively, metabolic tumor burden in patients with low [
18F]FDG uptake would be underestimated. Fourth, although there was no significant association between [
18F]FDG uptake of BM and hemoglobin level, hematopoiesis of red blood cells might confound [
18F]FDG uptake of BM [
17,
21,
25]. Finally, because of the retrospective nature of the study, we could not assess the relationship of [
18F]FDG uptake of BM with the other well-known prognostic factors for systemic inflammatory response such as the Glasgow prognostic score which has been found to be associated with poor prognosis in patients with malignant diseases including breast cancer [
43,
44]. Therefore, further prospective studies with laboratory as well as histopathologic results are needed to elucidate the connection between BM metabolism on PET/CT and systemic inflammatory response.
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