With the development of new lines of cancer treatment options, various diagnostic imaging modalities are emerging accompanied by new strategies and guidelines to predict early tumor response to NAC and to assess the burden of residual disease [9,10,11,12].
The current study included 81 patients who have completed the full NAC course. Assessment of response was performed in reference to the previously described MRI shrinkage patterns by Kim et al. [6].
The combined response evaluation proposed by the authors showed significantly better agreement with histopathology than the evaluation based on RECIST 1.1 alone. Contrast-enhanced mammography is less expensive and less time consuming and may even have a chief advantage over MRI as it can assess the true extent of residual tumors associated with microcalcifications [1, 13, 14].
After NAC, some histopathological changes may occur in the tumor bed with an overall reduction in size and the amount of viable tumor cellularity giving the different post-NAC shrinkage patterns described by Kim et al. [6, 15]. Some tumors may show concentric shrinkage patterns, while others may disintegrate or fragment into discrete foci which are difficult to measure. In some other tumors, a fibrous stroma may persist in the original tumor bed. This fibrous stroma may show subtle enhancement giving a false impression of poor response to NAC as there will be no change in tumor diameter [16]. Knowing the shrinkage pattern helps in the accurate assessment of residual disease before conservative surgery [6, 17].
Goorts et al. stated that a possible explanation for the better prediction of pathological response by MRI halfway through NAC than after NAC is that taxanes might suppress MRI enhancement irrespective of the cytotoxic activity, as reported by Schrading et al. And since in Goorts et al. patient’s cohort, taxanes were also only given during the second half of treatment, this could be a plausible explanation; however, their study also showed that this might be false negative, especially when lobular carcinomas are classified as complete responders. Furthermore, the two triple-negative tumors classified as type 0 were both true negatives [16].
Kim et al. stated that types III and I shrinkage patterns were more frequently observed in the pathological responder group, and type IV was more frequently noted in the non-responder group [6]. Our results were in agreement with Kim et al., where 17/24 (70.8%) of type 1 shrinkage pattern and 8/9 (88.8%) type 3 shrinkage pattern were responders. On the other hand, solitary lesions showed the most favorable response to NAC where 6/26 (23%) lesions showed a complete radiological response and even the remaining 20/26 (77%) with the residual disease showed type 1 concentric shrinkage pattern making conservative surgery more amenable. On the other hand, replaced lesions showed the least favorable response where 7/10 (70%) lesions showed persistent diffuse enhancement ending up with a modified radical mastectomy (MRM).
We then assessed the accuracy of CESM in the evaluation of residual disease; once using the RECIST 1.1 and another time using the combined response evaluation approach (Table 4). This was performed in correlation with the postoperative histopathology results.
Morphologic measurement of change in tumor size in response NAC helps assess therapeutic effectiveness through the use of the RECIST 1.1 [7]. Since the publication of the RECIST, several reports have been published regarding its low reliability in evaluating responses. The RECIST 1.1 mainly depend on tumor size alterations and they do not express other morphologic (tumor necrosis, hemorrhage, and cavitation), functional, or metabolic changes that may occur with NAC [10]. Forner et al. stated that when applying RECIST alone in the assessment of response to NAC, tumor necrosis and partial tumor response can be missed [18]. Magnetic resonance imaging has long been considered the most promising imaging modality in assessing response NAC, as it not only provides accurate tumor size assessment but also gives us information about the change in tumor enhancement pattern reflecting the functional change in tumor cells [19]. However, since breast MRI and CESM show similar performance and are based on similar principles, we proposed a new assessment approach based on both size assessment and enhancement pattern using CESM.
In reference to the postoperative histopathology results of the 81 patients included in the current study, 60/81 lesions were responders (Miller-Payne grades 3, 4, and 5). Using the combined response evaluation approach, 57/60 patients (95%) were classified as responders, while by using RECIST 1.1 alone, only 46/60 patients (76.7%) were classified as responders. The combined response evaluation approach showed higher sensitivity and positive and negative predictive values compared to the evaluation based on RECIST alone.(95%, 87.6%, and 81.2 % compared to 76.6%, 86.7%, and 50% respectively). The specificity of the RECIST evaluation was slightly higher than the combined approach (66.9% as compared to 61.6%). Both methods of radiological evaluation coincided with postoperative pathology in predicting PCR in 20/21 (95.2%) lesions, with an additional 1 false-positive and 1 false-negative case. Pathology of the false-positive responder showed areas of fibrosis and hyalinosis entangling breast lobules leading to a decreased contrast uptake, yet with residual viable tumor cells. False-negative responders were significantly more in the RECIST 1.1 evaluation than in the combined approach (14 compared to 3 non-responders respectively) as the overall loss of tumor cells was not always expressed as a change in tumor size. Another explanation to the false-positive cases was also suggested in previous studies stating that the residual tumor may shrink when fixed in formalin after surgical removal giving a false impression of size reduction [20, 21].
The overall reported diagnostic indices of the combined approach matched some reported results for MRI in the same context and mismatched others. For example, in a meta-analysis performed by Yuan et al., MRI showed a high specificity (90.7%) and relative lower sensitivity (63.1%) in predicting pathologic complete remission after NAC while in another study, MRI showed a sensitivity of 100%, a specificity of 50%, a PPV of 83.3%, and an NPV of 100% [22, 23]. Thus, both overestimation and underestimation were previously observed and reported [24].
Many studies have presented correlation coefficients between size measurements assessed by MRI compared to pathological tumor size measurement [25,26,27]. In an analysis of these studies by Lobbes et al., the median correlation coefficient was calculated and found to be 0.698, with a range of 0.21–0.982 [24]. In the current study, the overall correlation between size measurements assessed by CESM compared to pathological tumor size was 0.921 (P < 0.001). The correlation coefficient achieved by CESM in our study was significantly higher than that recorded for MRI in the meta-analysis by Lobbes et al [24].
In recent studies, it was observed that the accuracy of breast MRI to assess residual disease and predict pCR depended on breast cancer subtypes. For example, it was observed that MRI was able to predict pCR more accurately in patients having HER2-positive tumors when compared to HER2-negative tumors. In the latter case, a higher false-negative rate was observed [24].
HER2-negative and hormone receptor-positive cancers and lesions showing non-mass-like enhancement are more likely to show residual disease as small foci or scattered cells after NAC, leading to underestimation of residual disease extent at MR imaging, and the diagnostic results of MR imaging should be used with caution in surgical planning [28].
Loo et al. also concluded that response monitoring using breast MRI is accurate in patients having triple-negative or HER2-positive tumors. However, they found it was inaccurate in ER-positive/HER2-negative subtypes [29].
In the current study, the overall accuracy of CESM in assessing the 41 patients with hormone receptor-positive/HER2-negative tumors was 88.9%. Five out of these 41 patients achieved pCR; CESM was able to predict pCR in 4 out of 5 patients with only one false positive case.
In a study by Chen et al., the results indicated that the diagnostic accuracy of MR imaging is better in HER2-positive than in HER2-negative cancers, with a size discrepancy of 0.5 ± 0.9 cm versus 2.3 ± 3.5 cm (P = .009) [28]. These results suggest that patients with HER2-negative hormone receptor-positive disease are the poorest candidates for MR imaging evaluation [28].
In the current study, the mean size discrepancy for the HER2-positive tumors was 0.5 ± 0.7 cm versus 1.1 ± 1.2 cm for HER2-negative tumors (P < 0.001). Note the smaller size discrepancy achieved by using CESM in evaluating the residual disease in Her2-negative tumors compared to the MR evaluation in the Chen et al. study [28].
The present study had some limitations. The combined response evaluation approach carries the limitation of being subjective, which raises the need for the introduction of non-subjective methods in the evaluation of the change in the intensity of enhancement by CESM. However, the inter-observer variability between the different readers was excellent (kappa 0.960). Patients were only evaluated by CESM before and after completion of NAC. During the course, the evaluation was based on clinical and ultrasound assessments. The authors did not want to subject the patients to unnecessary irradiation before validating the efficiency of CESM to assess response. In a future application, it is necessary to do a limited CESM examination of the affected breast to predict early response.
