Background
Breast cancer (BC) is the most common noncutaneous malignancy among women, representing four in ten female cancer survivors in the United States [
1]. Different imaging modalities such as mammography, ultrasound, and magnetic resonance imaging (MRI) play an essential role in the diagnosis and local staging of BC. According to the literature, imaging not only can document breast lesions but also can predict histopathological features of BC [
2‐
5]. For instance, Seo et al. reported that the human epidermal growth factor receptor 2 (HER2)-positive subtype of BC was associated with a higher BI-RADS (Breast Imaging Reporting and Data System) category [
2]. Some authors also indicated that several imaging features can provide information about proliferation potential or expression of Ki-67 in BC [
5]. Szabo et al. reported that rim enhancement on dynamic MRI was associated with high expression of Ki-67 and poor prognosis of BC [
5]. Furthermore, numerous studies analyzed associations between diffusion-weighted imaging (DWI) and histopathological features in BC, including associations between apparent diffusion coefficient (ADC) and expression of Ki-67 [
4,
6,
7]. However, the reported data were mixed. Whereas some authors found significant correlations between ADC and Ki-67 in BC, other did not [
8‐
13]. For example, Li et al. observed a moderate statistically significant correlation between ADC and Ki-67 (
r = − 0.566,
p = 0.025) [
8]. Similar results were also reported by Mori et al. [
9]. These authors suggested that ADC would be practical to use for estimating the Ki-67 labeling index [
9]. However, Aydin et al. could find only a weak negative correlation between ADC and Ki-67-values in BC (
r = − 0.279;
p = 0.029) [
10]. Finally, some authors did not identify statistically significant correlations between these parameters [
11‐
13]. Similarly, data about relationships between tumor grade and ADC were also inconsistent. These facts question the possibility to use ADC as a surrogate marker for proliferation activity in BC in clinical practice. The purpose of the present study was to provide evidence-based data regarding associations between ADC and expression of Ki-67 as well tumor grade in BC.
Discussion
This is the first multicenter study about relationships between ADC and histopathological features such as expression of Ki-67 and tumor grade in BC. Overall, it addresses a key question of whether imaging parameters can reflect clinically relevant histopathological findings. If so, then imaging, in particular ADC values, can be used as surrogate markers for tumor biology in BC.
Ki-67 is a well-established biomarker in BC [
20,
21]. According to the literature, Ki-67 before and after neoadjuvant chemotherapy can predict the prognosis for patients with BC [
21]. Furthermore, pretherapeutic Ki-67 is associated with pathological complete response after neoadjuvant chemotherapy in patients with BC [
22]. In addition, Ki-67 is associated with overall and disease-free survival of patients with BC [
23]. Therefore, it can be important in clinical practice to predict expression of Ki-67 on the basis of imaging.
ADC reflects diffusion of water molecules in tissue [
24,
25]. Recently, a meta-analysis identified inverse correlations between ADC and cell count in several malignant and benign tumors [
25]. Furthermore, it has been shown that ADC was associated with expression of Ki-67 in different lesions [
26]. Several mechanisms may explain this association. Ki-67 is a nonhistone nuclear protein synthesized throughout the whole cell cycle except the G
0 phase [
27,
28]. Cytoplasmic proteins and cytoplasmic viscosity increase during mitosis [
29]. These factors may influence water diffusion and ADC. Additionally, water diffusion may be affected by intracellular mitotic membranes.
As mentioned above, numerous prior studies investigated the role of ADC values in BC diagnosis and treatment. However, the reported results regarding associations between ADC and histopathology were inconclusive. Interpretation of prior results is complicated by differences in study design and analysis. The published radiological studies used different values of Ki-67 expression to discriminate tumors with low and high proliferative activity. For example, in the study of Zhuang et al., a Ki-67 level of ≥ 14% was considered to indicate high proliferation, and < 14% was considered to indicate low proliferation [
30]. Some other studies used a threshold value of 20% [
15,
16] or defined more than two Ki-67 categories. For example, De Felice et al. categorized Ki-67 expression as follows: low Ki-67 (≤ 14%), intermediate Ki-67 (15–30%), and high Ki-67 (≥ 30%) [
13]. According to the meta-analysis of Petrelli et al., based on data of 64,196 patients, a Ki-67 cutoff > 25% is associated with a greater risk of death than lower expression rates [
31]. Therefore, a reevaluation of the previous studies on associations between ADC and Ki-67 expression was needed.
The present study suggests that ADC cannot be used as a surrogate marker for proliferation activity in BC. In fact, although ADC values between tumors with high expression of Ki-67 (≥ 25%) differed from those with low levels of Ki-67 (< 25%), the calculated specificity and sensitivity were too low. This applied also for several alternative thresholds of Ki-67 expression ranging from 10% to 50%. Similar results were also observed for distinguishing low-grade and intermediate/high-grade tumors. Statistical analysis identified that grade 1 lesions had higher ADC values than grades 2 and 3 tumors. However, the ROC analysis showed that a possible use of ADC for discrimination of tumor grade in BC has very low specificity and sensitivity. Furthermore, we found that DCIS had statistically significant higher ADC values than IDC and ILC. However, ADC values also overlapped also overlapped distinctly in these subtypes. Therefore, use of ADC does not provide specific information regarding tumor biology in BC that can be used reliably in clinical practice.
The present study is the largest to date on this topic, to our knowledge. However, it has some limitations. The involved patients were investigated with use of different MRI equipment with different technical parameters, such as field strength, DWI sequences, and b-values. This may broaden the range of ADC values in the study and may have influenced our results. Furthermore, the patient samples consisted predominantly of only three tumor subgroups, namely DCIS, IDC, and ILC. Our study identified that associations between ADC and Ki-67 were different in several subtypes of BC. Moreover, the calculated correlation coefficients for IDC, DCIS, and ILC in our study differed significantly from those for mucinous carcinoma (
r = 0.035,
p = 0.892) reported by Onishi et al. [
32]. Presumably, associations between ADC and Ki-67 or tumor grade may be different in other subtypes of BC such as tubular or medullary carcinomas. However, the included tumors represent the most frequent subtypes of BC, whereas other carcinomas are rarer. We did not analyze possible associations between ADC and other clinically relevant biological features in BC, such as hormonal receptor status and/or HER2 status. This interesting aspect is a goal of further studies.
Availability of data and materials
The data that support the findings of this study are available from the corresponding author, but restrictions apply to the availability of these data, which were used under license for the present study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of the corresponding author (AS).