Tumor size and proliferative marker geminin rather than Ki67 expression levels significantly associated with maximum uptake of 18F-deoxyglucose levels on positron emission tomography for breast cancers

Abstract

It has been well established that maximum standardized uptake value (SUVmax) for 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) is clinically useful for evaluating treatment efficacy as well as predicting prognosis of breast cancer patients. Although SUVmax reflects increased glucose uptake and metabolism possibly induced by activation of growth factor signaling or TP53 dysfunction, tumor characteristics of SUVmax-high breast cancers remain to be elucidated. For the present study, we used immunohistochemical staining to investigate expressions of phospho-ribosomal protein S6 (pS6, downstream molecule of phosphatidyl inositol 3-kinase/Akt/mammalian target of the rapamycin/S6K pathway) and phosphor-p44/42 mitogen-activated protein kinase (pMAPK). Expression levels of TP53 and proliferative marker geminin as well as Ki67 were also examined by means of immunostaining in 163 invasive breast cancers. Cutoff values were set at 10% for pS6, 20% for pMAPK and TP53, and 4% for geminin. The SUVmax levels were significantly higher in the pS6-positive (p = 0.0173), TP53-positive (p = 0.0207) and geminin-high cancers (p<0.0001), but there was no significant association between pMAPK expression levels and SUVmax levels. Multivariable analysis showed that a high geminin level (odds ratio: 6.497, 95% confidence interval: 2.427–19.202, p = 0.0001) and large tumor size (6.438, 2.224–20.946, p = 0.0005) were significantly and independently associated with SUVmax-high. Univariable but not multivariable analysis indicated that Ki67-high significantly correlated with SUVmax-high. Twenty of 23 (87.0%) breast cancers with tumor size >2cm and geminin-high showed SUVmax-high, while only 6 of 49 (12.2%) breast cancers ≤2cm in size and with low geminin levels were SUVmax-high. In conclusion, we could determine that breast cancers with a large tumor and a geminin-high rather than Ki67-high proliferative marker were significantly associated with high levels of SUVmax. These findings may signify that SUVmax reflects tumor characteristics with high proliferative activity but not activation of mTOR/S6K and MAPK pathways or increased glucose metabolism due to dysfunction of TP53.

Relationship between 18F-FDG PET/CT Semi-Quantitative Parameters and International Association for the Study of Lung Cancer, American Thoracic Society/European Respiratory Society Classification in Lung Adenocarcinomas

“…This effect is possibly due to the increased glucose uptake in highly proliferative cancers, resulting in high levels of SUVmax. Consistent with our findings, a high 18 F-FDG avidity (SUVmax) was reported to be significantly associated with a high Ki67 index in breast cancer [ 36 37 38 ], gliomas [ 39 ], and lymphoma [ 40 ]. When analyzing different histological subtypes, we found that better-differentiated lung adenocarcinoma (papillary, acinar, lepidic adenocarcinoma, and variant adenocarcinoma) had a better correlation between Ki67 and PET semi-quantitative parameters than more poorly differentiated ones (micropapillary and solid predominant adenocarcinoma).…”

Associations Between PET Parameters and Expression of Ki-67 in Breast Cancer

“…So, a very wide spectrum of correlation coefficients between SUV max and Ki-67 was reported. Furthermore, most studies investigated small samples ranging from 6 to 75 patients/tumors and only four studies investigated samples over 100 patients [20] , [33] , [34] , [38] . Therefore, the reported data cannot be considered as evident.…”

“…Possibly, glucose metabolism might be stronger associated with other proliferation factors than with Ki-67. In fact, Nishimukai et al showed that SUV max correlated stronger with proliferation marker geminin than with Ki-67 [38] . The authors also suggested that geminin is preferable to Ki-67 evaluating the proliferative activity of breast cancer cells [38] .…”

“…Duplicate articles, review articles, case reports, non-English publications, and articles, which not contain correlation coefficients between PET and Ki-67 were excluded (n= 1568). Therefore, the present analysis comprises 32 studies with 1801 patients ( Table 1 ) [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] . The following data were extracted from the literature: authors, year of publication, number of patients, histopathological parameters, and correlation coefficients.…”

Total metabolic tumor volume and spleen metabolism on baseline [18F]-FDG PET/CT as independent prognostic biomarkers of recurrence in resected breast cancer

“…Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) is currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines for disease staging [5,6] and might also provide significant prognostic information [7,8]. Tumor glucose metabolism assessed by the maximum standardized uptake value (SUVmax) is used as a surrogate of tumor aggressiveness and tumor cell proliferation [9,10]. Several studies have demonstrated the prognostic value of SUVmax of the primary breast tumor and/or regional lymph nodes measured on [18F]-FDG PET/CT in nonmetastatic breast cancer [11][12][13].…”