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  • All authors contributed equally for

    2020-08-18

    1 All authors contributed equally for this work.
    2 Competing Interests: The authors declare that they have no competing interests.
    © 2018 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
    Presumably, metabolic activity showing by PET may be associated with biological patterns of BC. In fact, some studies also indicated that PET parameters can also provide information about tumor microstructure in BC [4,5,7]. For example, Heudel et al. observed significant correlations between SUV and histological grade (P b 0.0001), histological type (P = 0.001), tumor size (P b 0.0435), estrogen receptor status (P b 0.0005), and progesterone receptor status (P = 0.002) [13].
    In clinical practice, associations between PET parameters like SUVmax and expression of proliferation marker Ki-67 are of great importance. Ki-67 is a non-histone, nuclear protein synthesized throughout the whole cell cycle except the G0 phase [14]. According to the literature, BC with high expression of Ki-67 (b25%) are associated with a greater risk of death compared with lower expression rates [14]. Moreover, a higher Ki-67 labeling index is associated with a greater risk of recurrence (64 % increased risk) [14].
    However, the reported data about relationships between PET and Ki-67 are controversial. While some authors identified significant correlations between the parameters, others did not. Therefore, it is unclear, if SUVmax can be used as imaging biomarker reflecting proliferation activity in BC or not.
    The purpose of this meta-analysis was to provide evident data about associations between SUVmax and expression of Ki-67 breast cancer.
    Materials and Methods
    Data Acquisition
    MEDLINE library, EMBASE data 11078-21-0 and SCOPUS data base were screened for associations between PET parameters and proliferation marker Ki-67 in breast cancer up to April 2018. The strategy of data acquisition is shown in Figure 1.
    The following search words were used: “breast cancer OR breast carcinoma AND PET OR positron emission tomography OR SUV OR standardized uptake value AND Ki-67 OR KI 67 OR Ki 67 OR KI67 OR ki67 OR ki-67 OR mitotic index OR proliferation index OR MIB 1 OR MIB-1 OR mitosis index”. Secondary references were also recruited. Overall, 1600 records were identified. 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) [15–46]. The following data were extracted from the literature: authors, year of publication, number of patients, histopathological parameters, and correlation coefficients.
    The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) was used for the research [47].
    Meta-Analysis
    On the first step, the methodological quality of the acquired 32 studies was independently checked by two observers (A.S. and H.J. M.) using the Quality Assessment of Diagnostic Studies (QUADAS) instrument [48]. The results of QUADAS proving are shown in Table 2. The involved studies originated from several work groups world-wide and included different breast carcinomas. Study design was reported for all researches and it was prospective in 50% and retrospective in other 50%.
    Secondly, the acquired correlations between SUVmax and Ki-67 were re-analyzed by Spearman's correlation coefficient. Therefore, the reported Pearson`s correlation coefficients in some studies were 
    Figure 1. Flowchart of the data acquisition.
    converted into Spearman`s correlation coefficients according to the previous description [49].
    Furthermore, the meta-analysis was undertaken by using RevMan 5.3 (Computer program, version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Heterogene-ity was calculated by means of the inconsistency index I2 [50,51]. Finally, DerSimonian and Laird random-effects models with inverse-variance weights were performed without any further correction [52].
    Results
    Discussion
    The possibility to predict biological features and, therefore, tumor behavior based on imaging, in particular on PET findings, is very important. In fact, if PET parameters, for instance, SUVmax, can reflect proliferation activity of lesions, so PET can be used as surrogate biomarker. Theoretically, metabolic activity measuring by PET may predict tumor cellularity and proliferation in malignancies. Therefore, PET parameters like SUVmax may well correlate with expression of Ki-67. However, some reports suggested that this does not apply for all tumors. In fact, it has been shown that different tumor types exhibited varied