Introduction

Breast cancer, which is the most common type of cancer in women, is seen at a rate of 11.6% when all cancers are considered (1). The Ki-67 antigen, a protein encoded by the MKI67 gene, is a factor used for the subgrouping of breast cancer as luminal A and luminal B (2). As in many cancers, it has prognostic significance in breast cancer, and high Ki-67 expression levels are associated with poor prognosis (3). Keam et al. (4) reported that triple-negative breast cancer patients with high Ki-67 expression levels had pathological complete response to neo-adjuvant therapy. However, these patients have earlier recurrence potential, and overall survival is shorter than in patients with low Ki-67 expression levels.

Using state-of-the-art imaging methods in breast cancer for early detection and appropriate treatment strategies play a key role in improving survival rates. Magnetic resonance imaging of the breast has an important role in the detection of breast cancer, whereas ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is a valuable imaging method that is frequently used in routine assessment of disease, treatment response, staging, and restaging. Maximum standardized uptake value (SUV_max), which is a numerical value indicating the uptake of FDG by the malignant tissue during  PET/CT imaging, has a prognostic, predictive value in breast cancers as in many tumors (5).

The purpose of our study was to evaluate the relationship between SUV_max and Ki-67 expression levels in primary breast cancer.

Methods

In this retrospective study, we included 51 female patients with the mean age of 64.7±9.7 years (range: 43-83 years) diagnosed with breast cancer and operated between January 6, 2017 and July 1, 2019 in Cumhuriyet University Training and Research Hospital Surgical Oncology Clinic. ¹⁸F-FDG PET/CT was performed in all patients. The data of the patients were obtained from patient files, electronic file systems, data archive system of the pathology department, and data archive system of the nuclear medicine department. SUV_max value in the primary breast tumor and metastatic axillary lymph nodes, if any, were noted from the original PET/CT reports. The histologic type of breast cancer, percentages of Ki-67-positive cells (Ki-67 index), and estrogen receptor (ER), and progesterone receptor (PR) status were noted from pathology reports of biopsies taken from the patients individually. The patients were divided into three groups according to their Ki-67 expression levels; <15%; 15-29% and >30%.

PET/CT Imaging Acquisition Analysis

Positron emission tomography was performed using a combined PET/CT scanner (Discovery600 PET/CT GE Medical Systems, USA). Each patient fasted for at least 6 h before imaging. After ensuring that blood glucose was <180 mg/dL, approximately 0.14 mCi/kg ¹⁸F-FDG were administered i.v. 1 h before image acquisition. Attenuation correction of PET images with the CT data was performed. CT scan was performed firstly. Right after CT acquisition, a standard PET imaging protocol was taken from the cranium to the mid-thigh with an acquisition time of 3 min/bed in 3-dimensional mode. All PET studies were acquired in 3-D mode. CT images were acquired with 70 mA, 120 kV, axial slice thickness of 2.5 mm. CT and PET images were matched and fused into transaxial, coronal, and sagittal images. The data were transferred via the Digital Imaging and Communications in Medicine protocol to a processing Workstation (AW Volume Share5 GE Medical Systems S.C.S, France). Later, visual and semi-quantitative analyses were performed, respectively.

Statistical Analysis

Statistical analysis was performed using the SPSS software, version 24.0. A p value less than 0.05 was considered statistically significant. Correlation analysis was performed to determine the relationship between Ki-67 expression levels and SUV_max. Following the grouping according to Ki-67 expression levels, the chi-square test was used to analyze estrogen and PRs and triple-negative/positive patients.

Results

Of the 51 patients included in the study, 42 (82.4%) had invasive ductal carcinoma, two (3.9%) micropapillary carcinoma, two (3.9%) apocrine carcinoma, two (3.9%) mucinous carcinoma, one (2%) cribriform, one (2%) invasive papillary carcinoma and one (2%) ductal carcinoma in situ. Median SUV_max in primary breast malignancies was 4 (range: 1-23). The analysis of Ki-67 expression levels and SUV_max of the primary tumor revealed a moderate and significant correlation between SUV_max and Ki-67 expression levels (correlation coefficient: 0.68; p<0.05). It was found that in patients with axillary involvement detected by PET, axillary SUV_max levels increased with the increase of Ki-67 expression levels (Table 1; Figure 1), but it was not statistically significant. ER and PR positivity/negativity was tested in 49 patients. A statistically significant relationship was found between SUV_max of the primary tumor in the breast and ER and PR positivity (p=0.007 and p=0.005, respectively) (Table 2). Besides, there was a statistically significant relationship between Ki-67 expression levels and ER and PR positivity (p=0.002 and p=0.015, respectively). Ki-67 expression levels were <15% in triple-negative patients, whereas Ki-67 expression levels were higher in triple-positive patients (p=0.086) (Table 3). The mean SUV_max in triple-positive patients was also high, but it was not statistically significant (p=0.072).

Discussion

Breast cancer is the most common cancer in women in Turkey (6). Disease-free survival rates are high in patients diagnosed at an early stage (7). ¹⁸F-FDG PET/CT is a common imaging modality used in the evaluation of many types of cancer, including breast cancer. In their study, Kitajima et al. (8) reported that high SUV_max (≥6.20) and high Ki-67 expression levels were associated with recurrence, and high SUV_max values were associated with death. In their meta-analysis, Surov et al. (9) found a moderate correlation between SUV_max and Ki-67 expression in breast cancer and suggested that SUV_max cannot be used as a surrogate marker for tumor proliferation. On the other hand, in their study including 140 breast cancer cases, of which 136 were women, Ekmekcioglu et al. (10) reported a high degree of correlation between SUV_max of the primary tumor and tumor/background SUV_max rates and high Ki-67 expression levels. In the same study, SUV_max was found to be significantly associated with histological type and grade, pleomorphism, number of mitoses, lymphatic invasion, necrosis, oestrogen negativity, high Ki-67 level, axillary lymph node involvement and triple negativity, and it was reported that ¹⁸F-FDG uptake might be a prognostic indicator of tumor’s biological behavior. Similarly, Abubakar et al. (11) found that high SUV_max values were associated with high Ki-67 as well as high grade, triple-negative status, and axillary lymph node involvement. In our study, we showed that high Ki-67 expression levels were associated with high SUV_max values in the primary tumor (p=0.001). The mean SUV_max was 9.46 in patients with a Ki-67 index of >30%. These results were in accordance with studies by Ekmekcioglu et al. (10) and Abubakar et al. (11). It is known that Ki-67 levels are higher in triple-negative tumors and associated with more invasive and poorer prognosis (12). According to the data of our study, unlike the literature, patients with triple-positive tumors were found to have higher Ki-67 levels, but these data were not statistically significant. However, SUV_max levels were significantly higher in ER and PR negative patients than in positive ones (Table 2). Recent publications indicated that PET/CT was vital in axillary lymph node staging. According to some studies, although the sensitivity of PET/CT for the detection of axillary lymph nodes in patients with breast cancer is quite high, its sensitivity is low (13,14). Orsaria et al. (15) found that sensitivity, specificity, positive, and negative predictive values of ¹⁸F-FDG PET/CT were high for axillary lymph node staging. In the same study, it was found that high SUV in both lymph nodes and primary tumor was significantly correlated with high Ki-67 expression levels. Although Chung et al. (16) found no correlation between SUV_max of axillary lymph node and Ki-67 expression levels, they reported that axillary lymph node examination should be performed in patients with a SUV greater than 2.3; by adopting a SUV threshold of 2.3, the sensitivity, specificity and positive predictive value of FDG-PET was 60%, 100% and 100%, respectively. In our study, we could not find a relationship between Ki-67 expression levels and SUV_max levels in the axillary lymph nodes.

Conclusion

According to our study, the correlation between SUV_max and Ki-67 expression levels was found to be moderate and significant. However, further studies with more homogeneous groups and larger sample size are needed.

Authorship Contributions

Concept: M.E.B., Z.H. Design: M.E.B., Z.H. Data Collection or Processing: M.E.B., Z.H. Analysis or Interpretation: M.E.B., Z.H. Literature Search: M.E.B., Z.H. Writing: M.E.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.