In this study, [18F]NaF-PET/MRI was found feasible for monitoring hormonal therapy response in breast cancer bone metastases, as reflected by the significant SUV and Ki decreases, and the changes in MRI parameters consistent with the response. In current standard of care, monitoring of MBC treatment response mainly relies on tumour size measurements on CT/MRI according to RECIST 1.1. However, this is restricted to solid soft tissue lesions and bone metastases may only be assessed qualitatively as non-target lesions and are consistently difficult to evaluate for response. Increasing lesion density on CT, because of sclerosis, constitutes a sign of therapy response, but bone metastases frequently escape detection on baseline CT, and the appearance of sclerotic bone metastases on follow-up CT may therefore be misinterpreted as appearance of new lesions and progressive disease.
[18F]Fluoro-deoxy-glucose (FDG)-PET/CT constitutes another means for assessment of therapy response that also includes bone metastases [10]. Quantification on FDG-PET utilizes several PET biomarkers, such as the tumour SUV, metabolic tumour volume and total lesion glycolysis, which are parameters for therapy monitoring of various cancers including breast cancer [8]. In breast cancer patients, SUV changes on FDG-PET/CT have been applied for assessment of therapy response [11]. SUV measurements are easy to perform, robust, reproducible and are therefore widely used. However, true quantitative assessment of a particular tracer is not possible on static PET examinations [12]. The rate at which the tracer changes its concentration in the tissues throughout the PET examination may instead be quantified by means of a dynamic acquisition [13]. Time activity curves are derived, representing kinetic data of the tissues, and by kinetic modeling different models may be tested for the best fit to the data, and the various transport rate constants for that model can be calculated. Further, parametric images may be generated.
Doot et al. previously applied kinetic analysis on [18F]NaF-PET in MBC patients with bone metastases and showed that the fluoride transport and Ki provided a robust method to assess therapy response in bone metastases [14]. In the present study, [18F]NaF-PET/MRI was utilized to quantify the Ki, SUVmax and SUVmean along with MRI quantitative parameters to assess hormonal therapy response in skeletal metastases. In contrast to SUV, routinely measured on static whole-body PET, quantification of [18F]NaF-influx rate Ki requires dynamic PET acquisition, which is not part of clinical routine because of the additional time requirements and the need to be started simultaneously with the tracer injection and continued for about 45 minutes. Together with the subsequent whole-body examination, every patient therefore needs to occupy the PET/CT scanner for a longer time. The introduction of new multidetector ring systems, allowing for fast simultaneous PET acquisition of the whole body, may however permit dynamic examinations of some patients with maintained throughput. Dynamic PET imaging of bone with the use of [18F]NaF is therefore a very attractive technique, as it gives an insight into the physiologic basis of “bone tracer kinetics”. The bony trabeculae account for 80% of the surface area of bones and hence, of the bone turn-over. The diffusion of [18F]NaF from the capillaries into the bone extracellular fluid provides an evidence of the chemisorption of fluoride crystals at the new mineralization sites on the bone. The fluoride ions are exchanged with hydroxyl ions in the hydroxyapatite crystals and form stable fluoro-apatite present in healthy bone [15]. In previous studies, testing several models to assess fluoride kinetics, a compartment model applying non-linear regression, was found the most accurate for this quantification [16]. In our study, fluoride kinetics was assessed by two-tissue compartment model with non-linear regression to quantify the four kinetic parameters K1-k4 and their changes correlated with those of SUVmean, and SUVmax [17]. The decreases in SUVmean, SUVmax and Ki were found consistent with response to hormonal therapy and in line with the patients´ clinical response. As expected, the changes in Ki, i.e. from baseline to follow-up, correlated with those of SUVmax and SUVmean. Despite of the fact that we investigated merely three patients, lesion-based statistical analyses were possible due to the large number of bone metastases. In the lesion-based analysis, the changes in Ki, SUVmax and SUVmean were also consistent with therapy response, except for one metastasis.
To the best of our knowledge, previously for therapy monitoring, the diagnostic accuracy of PDFF and R2*, derived from Dixon MRI and ADC derived from DWI have not been studied in bony metastases in breast cancer patients. DWI with ADC mapping improves MRI evaluation of treatment response by providing quantitative functional assessment of cellularity, and can especially be important when intravenous contrast-enhancement is not possible. DWI is currently incorporated in many MRI routine protocols and has for some applications substituted contrast-enhanced MRI [18]. Bolan et al., studied 9 women with gynecological cancers to assess the effect of hormonal therapy on the bone marrow using Dixon MRI. An increased PDFF in the vertebral bone marrow (p = 0.04) and in the femoral neck (p = 0.03) has previously been observed after 6 months of therapy compared to pre-treatment [19]. The combined information from bone marrow PDFF and multi-peak fat corrected R2* may even offer improved diagnostic accuracy in detection of skeletal changes such as in osteoporosis [20].
We found that MRI showed changes in ADC, PDFF and R2*, consistent with response, although only R2* reached statistical significance. In the lesion-based analysis, 11/17 of the metastases showed a relative increase in ADC at follow-up, consistent with decreased cellularity in the metastases because of cell death and development of tumour necrosis. The rise in ADC occurs in parallel with increased water diffusivity in areas of necrotic tissue post-therapy suggestive of successful treatment. Conversely, in the remaining 6/17 metastases, ADC at follow-up was lower than at baseline, which is not an expected result of favourable therapy response, and therefore not as easily explained. This could be due to a return of normal fatty bone marrow in the tumour VOI, or possible because of a sclerotic reaction as a part of the osteoblastic healing mechanism may be due to denosumab. Further, because of their lower water content, the sensitivity of DWI for sclerotic bone lesions is lower, which constitutes a potential pitfall [18].
As the present DWI protocol was only based on three b-values (50, 400 and 800), for purpose of reducing the acquisition time, the intra-voxel incoherent motion (IVIM)-derived perfusion fraction and associated pseudo-diffusion were not estimated in our study. Compared to the overall tumor water content, the fraction of blood flow is very small. IVIM, includes the microscopic movement of water molecules due to both diffusion and capillary perfusion. The perfusion component is significant at small b values and can be estimated from DWI sequences acquired with a range of high and low b-values [21].
While all patients at follow-up showed an overall increase in PDFF, the lesion-based analysis showed an increase in 11/17 metastases except in 6/17 lesions, which conversely showed a decrease. In clinical practice, the use of Dixon technique for PDFF quantification can potentially cause misinterpretation when in-phase and opposed-phase images are visually compared, since lesions consisting of pure fat exhibit no or little signal drop-out on opposed-phase images. Measured PDFF values will therefore be inaccurate or heavily influenced by fat-water ambiguity [22]. Further, a substantial spatial heterogeneity of PDFF, related to the contents of red and yellow bone marrow, is also found to exist in the different parts of the skeleton [19]. This normal variation can potentially obscure treatment response assessment based on PDFF. Like PDFF, the patient-based analysis of R2* data were consistent with therapy response. Lesion-based analysis for 15/17 metastases showed an increase of R2*, reflecting an osteoblastic reaction in the metastases, as new bone formation takes place, which increases the microscopic susceptibility effects [20].
In conclusion [18F]NaF PET/MRI proved feasible for monitoring of hormonal therapy response in breast cancer bone metastases, as reflected by the parallel significant decreases in SUV and Ki, and of the changes in the MRI parameters ADC, PDFF and R2*, consistent with the response although only R2* reached statistical significance. This warrants further assessment in a larger patient population.