Clinicians and scientists interested in novel contrast in breast cancer imagingNeoadjuvant chemotherapy (NAC) has an important role in the treatment of breast cancer. However, patients undergoing NAC may experience severe side effects and treatment may turn out to be ineffective. Therefore, there is a need to predict the individual response to NAC early on in the course of treatment, particularly for the non-responders, to either change the type of NAC or proceed directly to primary surgery.
The purpose of this study was to assess the early effect of NAC in breast cancer noninvasively by chemical exchange saturation transfer (CEST) MRI. To this end, we investigated the changes of amide CEST signals, associated with cytosolic proteins and peptides [1], in the tumor before and after the first cycle of NAC as a potential biomarker for response to NAC. Thus far, after informed consent, six patients were included in the study. Four patients with breast cancer were examined before and after the first cycle of NAC (around 3 weeks interval) on a 7T MR system (Phillips, Cleveland, USA) using a 28-channel bilateral breast coil (MR Coils, Drunen, Netherlands). Two patients were scanned with a 2-channel unilateral 1H/31P dual-tuned coil. After B0 shimming, CEST-MRI was performed using 4s saturation train (50% duty cycle) and a gradient-echo readout. Image acquisition included fat suppression with a short 1-2-1 spectral-spatial RF pulse to allow for a short TE of 1.4ms, a TR of 2.6ms and a flip angle of 3.6°. A FOV of 320x150x100 with a true resolution of 2.3x3.0x6.8 mm³ was obtained in 2 shots of 394ms with a 4 fold SENSE. Acquisitions resulting in a scan time of 5min30s including 32 frequency offsets. The frequency offsets associated with nuclear Overhauser effect (NOE) were not included due to lipid distortions.
CEST images were registered to the first volume using rigid registration and B0 was corrected using the WASSR method [2]. For a group comparison, a region of interest (ROI) was drawn in the tumor tissue pre-chemo and after the first cycle of chemo. The z-spectra were fitted using a three-pool Lorentzian model (water, APT and magnetization transfer (MT)) [3] to obtain the APT signal. An unpaired t-Test, with a two-tailed distribution was used to show statistical difference between the amide-CEST signal pre-chemotherapy and amide-CEST signal after the first cycle of chemotherapy. The pathological response in the resection regiment was used as gold standard. We observed a higher amide signal in tumors compared to glandular tissue, (mean signal of all patients 0.035±0.004 and 0.018±0.005, respectively). After treatment, a significant decrease in the amide-CEST signal in the tumor was seen in two patients (Figure 1). Figure 2 shows an overlay of an image from the DCE series and the calculated amide CEST signals in the first patient. Within the tumor a reduced amide signal in the post NAC amide CEST map can be observed with respect to the pre NAC amide CEST map. The Z-spectrum of that specific tumor is shown in Figure 3. So far, three patients (#1,#4,#5) have had surgery and from those patients the pathology in the resected tissue was assessed: Only patient 1 was complete pathological responder.In this feasibility study, we observed a significant decrease (p<0.05) in amide CEST signal in two out of six patients in tumor tissue (Figure 1). Of all pathology results available, the decrease in amide CEST corresponded to full responder, while the absence of decreasing amide signal corresponded to a clinically partial responder. As the remaining patients are still in treatment, the pathological response of the other patients is unknown. This preliminary data shows that amide CEST can be obtained in breast cancer and may even be evaluated as biomarker for treatment response in breast cancer. Note that in contrast to earlier CEST observations in breast cancer obtained at 3T [4], the standard deviation within the Z-spectra of our 7T data (Fig 3) is lower than the effect size, opening the way for individualized response monitoring.We demonstrated that amide CEST signals can be robustly measured in breast cancer before and after the first cycle of NAC. Significant differences in the amide CEST signal were observed between tumor and glandular tissue, and before and after NAC.