The principal goals of NAC in breast cancer are to reduce tumor volume and to provide an opportunity to monitor an individual patient’s response and tailor her therapeutic regimen. Such adaptive therapy requires a minimally invasive means to distinguish responders from non-responders early in the course of treatment .
Monitoring response to NAC by CE-MRI was studied in various studies and showed that its accuracy to predict pathologic complete remission has a moderate sensitivity. Recently, the idea that DWI and MRS might be able to compensate has been raised .
The aim of this work was to study the value of the functional non-contrast-based MR imaging sequences as DWI and the MRS in the follow-up of the response to NAC in the breast cancer patients before surgery.
To our knowledge, there is paucity in the literature about this subject and most of the articles studied only solitary functional sequence. Comparative works between these non-contrast-based MR sequences were not potential.
Regarding the enhancement parameters in the current study, after completion of NAC, the maximum relative enhancement decreased and the time peak of contrast uptake was increased in responders while there were no significant changes in non-responders. Regarding the dynamic curve patterns, changes were noted between the typical malignant phenotype and the less aggressive phenotype in responders. These results were in agreement with a study by Wang et al.  where the maximum relative enhancement of responders decreased significantly, and time peak of contrast uptake increased significantly (P < 0.001), while in non-responders there was no significant change (P > 0.05). Dynamic signal intensity–time curves tended to significantly flatten after NAC in responders (type I occupied 63.9%), with no significant change in non-responders.
In this work, the ADC value as a single parameter to predict pCR achieved 78.95% sensitivity, 83.33% specificity and 80.65% total accuracy. The additive role of DWI to conventional DCE-MRI enhanced the diagnostic indices to 89.47% sensitivity, 83.87% total accuracy (compared to 73.68% and 77.42%, respectively, in case of DCE-MRI alone). A study by Gao et al.  combined data from 20 studies and stated that for assessing pCR after NACT, DWI could be a valuable tool with 89% sensitivity and 72% specificity.
In the current work, a cutoff ADC value of 1.043 × 10−3 mm2/s presented the best statistical indices’ to distinguish responders from non-responders with a sensitivity of 96.9%, specificity of 66.7% and total accuracy of 87.2%. A study by Fangberget et al.  showed that an ADC cutoff value of 1.42 × 10−3 mm2/s (at b = 750 s/mm2) was suggested as the optimal value with a sensitivity and specificity to distinguish pCR after chemotherapy of 88% and 80%, respectively.
A study by Park et al.  elicited that after 3–6 cycles of NAC, the best cutoff for differentiating pCR from non-pCR was a 54.9% increase in the ADC value, which could reach 100% sensitivity and 70.4% specificity. El bakoury et al.  assumed a cutoff value of 20% increase in the ADC value after the first cycle of chemotherapy as indicative of pCR.
Pereira et al.  observed significant early increase in the ADC value in responders that precedes reduction in tumor size measured at CE-MRI.
Sharma et al.  also believed in significant correlation between the increased ADC value and the treatment response.
On the contrary, Woodhams et al.  and Elbakoury et al.  stated that the increase in ADC did not correlate with the change in the size of the tumor that was measured at the CE-MRI and pathological response.
The study analysis presented the idea that the post-NAC MRI in most of the responders were characterized by fading of the bright signal on the high b-value DWI-MR images and a slightly bright signal on the ADC maps, which was indicative of apparently free diffusion of water molecules and subsequently low ADC values.
However, one of the major limitations of DWI was encountered which was its low spatial resolution so small cancer foci, including DCIS and scattered foci of invasive lobular cancer, sometimes was not that obvious at DWI.
The current study suggested a cutoff value of 0.36 mmol/l to target the tCho peak and it presented 71.0% sensitivity and 71.4% specificity. The diagnostic indices of choline peak as single parameter to predict pathological complete remission post-NAC showed 78.95% sensitivity and had the highest specificity (91.67%) and PPV (93.75%). The statistical indices were enhanced when the diagnostic performance of the dynamic post-contrast curve and MRS was combined in the post-NAC patients to reach up a value of 78.95% sensitivity, 91.67% specificity and 83.87% total accuracy (compared to 73.68%, 83.3% and 77.42%, respectively, in case of DCE-MRI alone).
Baek et al.  stated that at first follow-up tCho concentration changes were not significantly different between patients achieving pCR and those not achieving pCR. However, at second follow-up tCho decreased by 100% in patients achieving pCR (versus 67% in patients not achieving pCR, P = 0.01).
Moreover, Tozaki et al.  concluded that the tCho changes after the second cycle may be more sensitive than changes in the tumor size to predict the pathological response.
Baek et al.  also reported that with responders there was an average reduction of 50% in tCho level after one or two cycles of NACT (compared to 14% in non-responders) and the mean percentage lesion size reduction was 18% (compared to 15% in non-responders).
The results of these studies were in agreement with the current work: The early metabolic changes were more evident than the changes in tumor size. Also, after completion of NAC, MRS choline peak was reduced in 85% (n = 113) and remained stationary in 15% (n = 20) with reduced mean MRS choline peak post-NAC to 0.36 in responders versus 0.95 in non-responders.
On the contrary, a limited data set presented by Bolan’s study  that focused on the early changes in tCho levels measured 1–4 days after starting chemotherapy where the early decrease in the tCho after chemotherapy initiation presented a poor predictive ability for pCR or radiologic response.
Few studies attempted to compare the evaluation of post-NAC response using both of MRS and DWI techniques, where the resultant data showed mixed values. Mountford et al.  showed that MRS provided substantial prognostic information, slightly more than that provided by volume measurements. They also noted ADC mapping after the second course of NAC did not contribute significantly toward detecting early response.
In another study, Shin et al.  found that the post-NAC percentage changes in two parameters of the MRS (absolute and normalized tCho integral) in the pCR group were significantly higher than in the non-responder group (P = 0.020 and 0.023) but the change in tCho SNR was not significantly different between the two groups. They also reported that the percentage change of the ADC value in the pCR group was significantly higher than that in the non-pCR group (81.3% vs. 12.6%; P < 0.001). The post-treatment ADC value in the pCR group (1.43 × 10−3 mm2/s) was significantly higher than that in the non-pCR group (1.10 × 10−3 mm2/s) (P = 0.003). They found that combination of the MRS and the DWI parameters did not provide additional predictive value compared with the predictive value of a single parameter.
These results were in agreement with the results of the current work; the mean post-treatment (i.e., post-NAC) ADC value in the pCR group (1.3 × 10−3 mm2/s) was higher than that in the non-pCR group (0.95 × 10−3 mm2/s). But on the contrary, the present study showed that the combination of the MRS and the DWI parameters increased the sensitivity and the diagnostic accuracy of the dynamic post-contrast MR imaging in its role in following up response of neo-adjuvant chemotherapy in reported cases of breast cancer and achieved 89.47% sensitivity and 87.10% accuracy compared to 73.68% and 77.42%, respectively, in case of the solo assessment of the post-contrast dynamic curve.
Previously, when the size of the cancer showed no significant regression, the intensity of the contrast uptake was the criterion to rely upon to check response to therapy and so the presence of benign behavior of contrast uptake and the decreased signal intensity in spite of the stationary size of the tumor were considered response to the therapy. The current work showed cases that presented with no enhancement of the breast cancer on post-contrast MRI yet, on DWI and MRS, the findings suggested non-responder case and the pathology report after the surgery confirmed the data presented by the non-contrast functional MR sequences.
Tozaki et al.  assessed the change of the integral value of tCho after the first cycle of NAC in comparison with measurements of the ADC value in seven patients. The change of the tCho showed a positive correlation regarding the change in the lesion size (r = 0.91, P = 0.01). However, no correlation was observed between the change of the ADC value and the change in the lesion size (r = 0.45, P = 0.32). They concluded that MRS after the first cycle may be more sensitive in predicting pathological response(s) than DWI.
In another study by Bathen et al. , sixteen patients were evaluated who returned for a follow-up MRS after the first cycle of chemotherapy; eight of them were defined as responders and another eight as non-responders. The reduction in tCho SNR was significant for both responders (P = 0.025) and non-responders (P = 0.012). The DWI technique was described in the study, but no discussion or conclusion was made about the result and predictive value of the DWI.
In the current study, the increase in the ADC value post-NAC is associated with the reduction or normalization of the MRS choline peak, and this was considered as an indicator for the detection of responders that could achieve pCR. The current study presented 24 patients who achieved pCR for both breast and axilla: 16 patients had an increase in the ADC value with normalized MRS choline peak that was a true positive indication for pCR, four patients with stationary MRS choline and reduced ADC value and another four patients with increased ADC value and stationary MRS choline peak that was false positive for residual malignancy.
The study may be limited by: (1) the use of 1.5 Tesla magnet MRI machine for the performance of the functional MR imaging especially DWI and MRS which require higher values (≥ 3 T) to achieve accurate assessment of the tumor size/extension and consequently provide more accurate estimation of the ADC values and the height of the choline peak. (2) There is an element of operator variability in application of ROI for the ADC value or acquisition voxel placement at MRS.