According to the present analysis, there were no differences of ADC values between the investigated BC types. Therefore, ADC cannot predict hormone receptor status of BC. This finding is very important.
The clinical importance of different BC molecular subtypes is without any questioning . There are distinctive differences in prognosis and therapy in accordance to BC immunohistochemical subtype . So, the BC type with expression of estrogen and progesterone receptors and low expression of proliferation marker Ki 67, namely Luminal A type, has the best prognosis with a 5-years overall survival rate of 95.1% to 78.5% of triple negative type [10, 47]. This is also caused by the possibility of endocrine hormone therapy as a treatment option. Luminal B type is defined by the presence of estrogen and progesterone receptors with additionally a high proliferation rate compared to Luminal A. Her2-enriched type is defined by the expression of the oncogene human epidermal growth factor receptor, which stimulates proliferation and inhibits apoptosis . Importantly, it can be targeted by an antibody treatment, namely trastuzumab, which shows the utter importance of this receptor . Lastly, the triple negative type is defined by the absence of any of these receptors, resulting in the worst prognosis and limited treatment options .
Previously, it was shown that ADC values are associated with cellularity and tumor microstructure . Beyond sole cellularity, ADC values are associated with important histopathology parameters, reflecting proliferation potential (Ki 67) and tumor suppressor genes p53 [49, 50]. However, some immunohistochemical features of angiogenesis were not associated with ADC values . In short, there is ongoing debate which features of tumors can be predicted by imaging.
There are inflicting published results regarding, whether ADC values can also reflect immunohistochemical features in BC. So, in some single center studies, there were reports that Her2-positive tumors have slightly higher ADC values compared to negative tumors . However, Choi et al. could not identify an influence of the Her 2 status on the ADC values . In another study by Montemezzi et al., Luminal A type showed the highest ADC values compared to all other subtypes (0.924 × 10−3± 0.033 mm2/s) . According to other authors, triple negative type showed the highest ADC values [25, 38]. In a first multi center study comprising 661 patients, no significant differences were reported between BC subtypes corroborated by the present results .
Presumably, the reported differences in previous investigations were caused by different scanner technology, measurement, and patient samples. For example, it is a known fact that mucinous carcinoma alone has distinctive higher ADC values due to the histopathology which seems to be more important than the immunohistochemical subtype .
So, the present analysis can harmonize these reported differences that no significant differences of ADC values between molecular subtypes of BC can be assumed.
ADC values are reflective of tumor microstructure with a moderate inverse correlation of the cellularity of tumors [6-9]. Presumably, the histopathologic differences of the molecular subtypes are not strong enough that they can be reliably predicted by DWI.
There are other reports highlighting the importance of necrosis on ADC values which was the only independent influencing factor of the ADC values . These relationships resulted in the highest ADC values of the triple negative type because of the high rate of necrosis.
Our results are also in accordance with a recently published meta analysis suggesting that ADC cannot predict outcome to neoadjuvant radiochemotherapy of BC .
Yet, there is clear evidence that ADC values can aid in the discrimination between benign and malignant tumors which was shown in a recent meta analysis . So, ADC values can nevertheless aid in important clinical decision making despite the present negative results.
There are some inherent limitations of the present study to address. Firstly, the meta- analysis is based upon published results in the literature. There might be a certain publication bias because there is a trend to report positive or significant results; whereas studies with insignificant or negative results are often rejected or are not submitted. Secondly, there is the restriction to published papers in English language. Thirdly, the study investigated the widely used DWI technique using 2 b-values. However, more advanced MRI sequences, such as intravoxel incoherent motion and diffusion kurtosis imaging might show a better accuracy in discriminating BC phenotypes [57, 58]. Yet, there are few studies using these sequences and thus no comprehensive analysis can be made.