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Metabolic Imaging Parameters of 18F FDG PET/CT in Differentiating the Ki-67 Index in Carcinoma Breast
Address for correspondence: Dr. Deepanksha Datta, Department of Nuclear Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India. E-mail: dattadeepanksha@gmail.com
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Received: ,
Accepted: ,
This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Background:
The proliferation index (Ki-67 index) is a known independent prognostic marker in carcinoma breast, and its expression is directly proportional to higher recurrence and worse prognosis. However, there is no standard cutoff of the Ki-67 index to determine its low or high expression. In this study, we aim to find the association of various metabolic parameters on 18F FDG positron emission tomography/computed tomography (PET/CT) with Ki-67 index in carcinoma breast patients and further evaluate its correlation with low and high Ki-67 index groups.
Materials and Methods:
This is a retrospective study conducted in a tertiary hospital in North India between February 2021 and 2024. All histopathologically proven female cases of carcinoma breast with reported Ki-67 index and baseline 18F FDG PET/CT before any treatment or surgery were included. The metabolic parameters, namely, standardized uptake value (SUVmax), the metabolic ratio of the primary tumor to the liver (SUR), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were recorded for each case. The correlation between the metabolic parameters and the Ki-67 index was analyzed, and subgroup analysis was done.
Results:
Sixty-five female patients met the inclusion criteria, and the majority of them presented with intraductal carcinoma. The median value (interquartile range [IQR]) of the Ki-67 index was 40% (IQR: 50%). The primary breast tumor showed median (IQR) of SUVmax, SUR, TLG, and MTV of 10.3 g/mL (7.2), 3.7 (2.9), 102.9 g.cub/mL (184.7), and 16.2 cm3 (25.4), respectively. A significant correlation was noted between all the metabolic parameters studied and the Ki-67 index. In subgroup analysis, a significant difference was noted in all the metabolic parameters between the subgroups of the Ki-67 index ≤25% versus >25%.
Conclusion:
Metabolic parameters on 18F FDG PET/CT show a promising role in the determination of the status of proliferation marker Ki-67 index in carcinoma breast.
Keywords
Carcinoma breast
18F FDG positron emission tomography/computed tomography
Ki-67 index
metabolic tumor volume
radiogenomics
SUVmax
total lesion glycolysis
Introduction
Radiogenomics is an interdisciplinary field that integrates imaging and genomics.[1] In the age of personalized medicine where the focus is on molecular characterization of cancer in individual patients, combining radiomics and genomic or genetic mutation data holds significant potential. Radiogenomics holds promise for diagnosing and treating breast malignancy by identifying and characterizing multiple genomic signatures on computed tomography (CT) and magnetic resonance imaging, which in turn has an impact on early diagnosis, treatment response, and prognosis.[2]
Role of 18F 2-fluro 2-deoxy D-glucose (FDG) positron emission tomography/CT (PET/CT) in breast malignancy is well-established ranging from staging,[3] especially of early breast and occult breast malignancy,[4] response assessment,[5] recurrence evaluation,[6] and prognosis.[7] Radiogenomic features of PET have been widely explored in breast malignancy, especially investigating the relation between the SUVmax and various receptor status and molecular subtypes.[89] In this study, we aim to evaluate the relation between the SUVmax as well as other metabolic parameters on 18F FDG PET/CT with the Ki-67 index in carcinoma breast patients.
Materials and Methods
Study settings
This study was conducted in the department of nuclear medicine at a tertiary healthcare institute in North India and was approved by the institutional ethical committee (AIIMS/IEC/2024/4910) which waived off the patient consent due to its retrospective nature.
18F FDG positron emission tomography/computed tomography acquisition
18F FDG PET/CT imaging was carried out in accordance with the standard clinical PET protocol as per the European association of the nuclear medicine (EANM) guidelines.[10] The patients were intravenously injected with 18F FDG 3.7 MBq/kg body weight to a maximum dose of 370 MBq after a 4–6 h fasting period. All patients were imaged with an integrated PET-CT system (Discovery GE MIDR710). After 45–60 min of uptake period at rest, in a dimly lit quiet room, the images were acquired at 1 min per bed position. In the patients with serum creatinine under normal limits, and with no other contraindications to iodinated contrast, the PET scan was acquired together with the contrast-enhanced CT scan, a delay of 70 s was between the intravenous iodinated contrast injection and acquisition of the CT scan.
Fluorescence in situ hybridization was done in all the primary tumor biopsy samples to identify the receptors’ status and the Ki-67 index. The four imaging parameters, namely SUVmax of the primary tumor site, SUR (metabolic ratio of the primary tumor with that of the liver), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor site were recorded.
Statistical analysis
Data were entered in a Microsoft Excel spreadsheet (Microsoft Technologies, USA). Continuous data were expressed as median (inter-quartile range [IQR]) while discrete data were expressed as proportions. The Statistical Package for Social Sciences (SPSS) software (version 25, IBM, New York, USA) was used for all the statistical analysis. The correlation between the four imaging parameters and the Ki-67 index was assessed using Pearson’s coefficient. An attempt was made to compare the metabolic parameters in subgroups of the Ki-67 index using 25% as cutoff, as it has been previously reported to be of prognostic value.[11] The independent–t-test was used to demonstrate any difference in the metabolic parameters between Ki-67 ≤25% versus >25%. A two-tailed P < 0.05 was considered statistically significant.
Results
Sixty-five female patients were included in this study, of which the majority had intraductal carcinoma breast. The median value (IQR) of the Ki-67 index was 40% (IQR: 50%). The primary breast tumor showed median (IQR) of SUVmax, SUV ratio, TLG, and MTV as 11,010.3 g/mL (7.2), 3.7 (2.9), 102.9 g.cub/mL (184.7), and 16.2 cm3 (25.4), respectively.
A weak positive correlation (P < 0.05; r = 0.36) was noted between all four metabolic parameters and the Ki-67 index [Figure 1] on Pearson coefficient test. Furthermore, there was a significant difference noted in all the metabolic parameters between the groups showing Ki-67 ≤25% and Ki-67 >25% with P values for SUVmax, SUR, TLG, and MTV as 0.05, 0.04, 0.03, and 0.03, respectively [Figure 2].
Figure 3 shows representative cases of the carcinoma breast with low and high Ki-67 indices.
Discussion
The literature focusing on radiogenomics in oncology, especially breast cancer has surged in recent times. The insights from such analyses are anticipated to enhance the characterization of primary breast cancer, enabling more precise identification of patients who would benefit from the specific therapeutic interventions.[12] Multiple previous studies have documented significant variations in the SUVmax on 18F FDG PET/CT in the primary breast tumor across various molecular subtypes, of which significantly higher SUVmax is seen in apocrine, estrogen negative, progesterone negative, and Her2neu receptor negative groups as compared to their counterparts.[913]
Ki-67 index is a proliferation marker represented as the percentage of cells in the cell cycle and serves as an independent prognostic marker in breast malignancy.[14] Antigen Ki-67, also known as MKI67, is a protein encoded by the MKI67 gene[15] and was initially identified in 1983 in Hodgkin lymphoma cell nuclei.[11] It remains active during the G1, S, G2, and M phases of the cell cycle, making it a reliable marker of cell proliferation and oncogenesis. Ki-67 is present in cell nuclei during interphase and relocates to chromosome surfaces in mitosis, absent during the G0 phase, and decreases during anaphase and telophase.[1617] Despite being a reliable prognostic biomarker, challenges in the standardization of its evaluation hinder its consistent use in clinical practice. Inconsistencies in detection arise due to variations in specimen type, fixation methods, surgical procedures, and preanalytical, analytical, and interpretation phases.[1819] Thus, there is a need for the noninvasive assessment of this proliferation marker which can also aid in the prognostification of the disease.
PET parameters such as SUVmax, TLG, and MTV are expected to correlate with the cellularity and proliferation in malignancies, which is evident from the published literature that shows a consistent correlation between the SUVmax and Ki-67 index in breast malignancy.[5678] The findings of our study are similar to the published literature, and we found a significant but moderate correlation between the four metabolic parameters and Ki-67 indexes, which is also reported by Deng et al. with pooled correlation coefficient, r = 0.44.[20] In the meta-analysis conducted by Surov et al., a similar weaker association with the Ki-67 index was found with FDG SUVmax (r = 0.40 in 1624 patients) as compared with FLT SUVmax (r = 0.50 in 181 patients).[21] However, none of these studies evaluated a threshold or cutoff value of low or high Ki-67 index with SUVmax. Current guidelines lack consistency in defining clinically relevant cutoff points for Ki-67 expression. In 2011, the 12th St. Gallen Expert Consensus panel classified ER-positive (ER+) breast cancer as Luminal A with Ki-67 levels below 14%, and Luminal B (HER2 negative) with higher scores.[22] The 2013 update raised the cutoff to 20%, which highlighted its relevance for predicting survival outcomes in the ER + cohort.[232425] Another study demonstrated the prognostic importance of Ki-67 expression levels of 25% or higher in predicting mortality, based on their review of over 64,000 breast cancer patients.[26] In our study, we additionally evaluated the relation between the metabolic parameters and Ki-67 index by keeping the cutoff value of 25% and found a statistically significant difference between the low (≤25%) and high (>25%) Ki-67 groups.
The retrospective design and small sample size are the major limitations of this study, besides the nonconsideration of molecular subtypes of the carcinoma breast. However, despite these limitations, the results of our study are identical to the published literature as well as the meta-analyses. Through this study, we propose the cutoff value for the Ki-67 index of 25% as a threshold to decide the potential aggressiveness of the primary breast malignancy. However, future prospective studies are needed to establish this hypothesis.
Conclusion
Metabolic parameters measured on 18F FDG PET/CT show a potential role in the determination of the Ki-67 index in carcinoma breast.
Conflicts of interest
There are no conflicts of interest.
Nil.
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