Hybrid ¹⁸F–FDG PET/MRI might improve locoregional staging of breast cancer patients prior to neoadjuvant chemotherapy

This prospective single center study was approved by the institutional review board. Informed consent was waived by the institutional review board. Women with biopsy-proven primary invasive breast cancer with a tumor larger than 2 cm (cT2-4 N0) and/or a pathologically confirmed lymph node metastasis (cT1-4 N+) undergoing NAC between February 2015 and June 2016 were consecutively considered for inclusion [19]. Exclusion criteria were pregnancy, presence of distant metastases at diagnosis or contra-indications for PET/MR imaging (such as known allergies for the contrast agents used or severe claustrophobia).

Conventional pre-NAC imaging consisted of FFDM and US of the suspicious breast lesion(s) and ipsilateral axilla. Breast cancer diagnosis and initial cTNM-classification were based on conventional imaging combined with pathology of pre-treatment core needle biopsies. If suspicious axillary lymph nodes were visualized, US-guided core needle biopsy of the most suspicious lymph node was performed. Reports of all conventional imaging exams and pathology reports were written in accordance with the Dutch Breast Cancer Guidelines [3].

After the decision to start NAC by a multidisciplinary tumor board in a newly diagnosed breast cancer patient, a PET/MRI breast protocol was performed prior to treatment initiation. Results concerning clinical tumor status (cN) and clinical nodal status and metastatic status (cN) on PET/MRI were compared to cT and cNstatus based on FFDM, US and MRI (the MR images made with PET/MRI were first interpreted separately, blinded for PET images). The percentage of patients with a modified treatment plan based on PET/MRI findings was analyzed.

Blood glucose levels had to be <10 mmol/l after a fasting period of at least 4 h. All PET/MR images were obtained after intravenous injection of a bodyweight adapted ¹⁸F–FDG dose (2 MBq/kg bodyweight) followed by a resting period of 45–60 min. All scans were performed from diaphragm to top of the humeral head on the same 3.0 T Biograph mMR integrated PET/MRI system (Siemens Healthcare, Erlangen, Germany) using a dedicated bilateral 16-channel breast radiofrequency coil (Rapid Biomedical, Rimpar, Germany) while patients were placed in a prone position and with both arms above their head.

The MR imaging protocol consisted of a two-dimensional T2-weighted turbo spin-echo sequence without fat suppression, a diffusion weighted imaging (DWI) sequence with fat suppression and a dynamic contrast enhanced T1-weighted sequence with fat suppression. As contrast agent, Gadobutrol (Gadovist®, Bayer Health Care, Germany) was used. It was automatically injected through a catheter in the antecubital vein at a 0.1 mmol/kg bodyweight, followed by a saline flush.

Parameters used for T2-weighted imaging consisted of a 340 mm field of view (FOV), a voxel size of 0.9 × 0.8 × 3.0 mm, 46 slices, 6410 milliseconds repetition time (TR), 83 milliseconds echo time (TE), 5 min 28 s acquisition time, turbo factor 11 and 80 degrees flip angle in transverse plane. For DWI a 320 mm FOV, voxel size of 1.7 × 1.7 × 4.0 mm and 24 slices were used and b-values 50, 400, 800 and 1000 s/mm² were acquired. For T1-weighted imaging, a 340 mm FOV, 0.9 × 0.9 × 1.2 mm voxel size, 128 slices, 10 degrees flip angle, 4.77 milliseconds TR, 1.78 milliseconds TE and 9.02 min acquisition time for a normal size breast were used. Magnetic resonance images were assessed by a dedicated breast radiologist with seven years of experience, blinded for PET results, using the descriptors of the American College of Radiology MRI BI-RADS lexicon [20].

The PET scanner has an axial FOV of 258 mm. All PET images were iteratively reconstructed and automatically attenuation corrected with the implemented 4-compartment model attenuation map (μ-map). All PET images (one bed position) were acquired within 11 min of the initial activity measurement. PET images were evaluated by a dedicated nuclear medicine physician with four years of experience. A lesion was characterized as malignant if it showed a focally increased FDG uptake compared to the surrounding breast tissue. After initial separate assessment, both imaging specialists performed a consensus reading of both PET and MRI images and a combined conclusion was drawn.

To determine clinical tumor (cT) stage on conventional imaging, number of breast lesions (unifocal or multifocal) and size (largest diameter of the largest malignant breast lesion in one view) were measured on FFDM and US. For clinical nodal (cN), staging number and location of suspicious lymph nodes were determined on US. Characteristics of a suspicious axillary lymph node on US included diffuse cortical thickening, focal cortical mass and/or thickening and loss of the fatty hilum [21].

To determine cT-stage on MRI, also a number of breast lesions and tumor size were assessed on MRI. To determine size on MRI, the largest diameter of the largest breast lesion proven to be malignant was measured on the T1-weighted MRI sequence at peek enhancement (i.e., first dynamic phase after contrast injection) in one view. For determining cN-stage, number and location of suspicious lymph nodes were assessed on MRI. The following criteria were considered suspicious: irregular margins, inhomogeneous cortex, perifocal edema, absent fatty hilum, asymmetry, and absence of chemical shift artifacts [22‐24].

To determine cT-stage on PET/MRI, the diameter of the tumor was measured on MRI, as described above, as diameters are not clinically measured on PET. Therefore, tumor size was always the same on MRI and PET/MRI. Yet, uni- or multifocality was determined on both modalities (pathologically proven malignant hotspot on PET or pathologically proven suspicious lesion on MRI). For determining cN-stage, number and location of suspicious lymph nodes were assessed on both modalities. A lymph node was characterized as malignant on PET if an abnormal focal FDG accumulation was present in combination with high visual uptake intensity (VUI) compared to background tissue, as recommended by the European Association of Nuclear Medicine [17, 25].

If any distant metastasis was detected in the FOV of any imaging modality (a lesion outside the breast tissue and lymph nodes like a bone or lung) and also proven PET positive and/or pathologically confirmed malignant, patients were considered M1, if not they were considered M0.

Neoadjuvant chemotherapy generally consisted of four cycles of 3-weekly doxorubicin and cyclofosfamide, followed by four cycles of 3-weekly docetaxel in case of an ER+ and/or HER2 overexpressed tumor, or 12 cycles of weekly paclitaxel in case of a triple negative tumor. In patients with HER2 overexpressed tumors, trastuzumab was added. After NAC, breast conserving surgery (BCS) or mastectomy and surgery of the ipsilateral axilla (sentinel lymph node biopsy in case of N0 and axillary lymph node dissection in case of N+) was performed. Postoperative radiotherapy of the breast was always performed after BCS. Chest wall and periclavicular irradiation were performed when patients had a cN1 (≥4 suspicious nodes), cT1-2ypN+, c/ypT3N+, c/ypT4 or c/ypN2–3 status. Solitary chest wall irradiation was performed in case of irradical breast surgery. The internal mammary chain (IMC) was irradiated in case of a PET-positive or a pathologically proven tumor-positive lymph node in IMC.

On conventional imaging, mean tumor size was 33 mm and one patient had a multifocal tumor. After MR imaging, four patients had a multifocal tumor (all pathologically proven) and mean tumor size on MRI was 37 mm. Hybrid PET/MRI did not find additional multifocal tumors meaning that clinical tumor stage, based on the size of the primary tumor measured only on MRI (not on PET) and number of breast lesions (multifocality, measured on both MRI and PET), did not differ from MRI alone (Table 2 and Appendix Table 3). Hence, PET/MRI did not provide diagnostic advantages compared to MRI alone for breast tumor staging, nor did it result in treatment plan changes.

According to conventional imaging, 12 out of 40 patients were considered cN0 and 28 patients cN+. In six out of 40 patients, lymph node status changed based on PET/MRI findings. In these six patients number and location of lymph node hotspots on PET, combined with their morphology on MRI, resulted in confirmation of diagnosis and change in treatment plan.

In three patients, MRI showed an enlarged IMC node. PET/MRI confirmed malignancy of this node by showing focally enhanced FDG-uptake in the IMC node in these patients, making additional PET/CT imaging or tissue sampling superfluous. In another patient a suspicious IMC node with focally enhanced FDG-uptake was seen. No suspicious IMC node was described on MRI at first. The final combination of PET information with MRI morphology completed diagnosis and changed the treatment plan. In all four patients the IMC was incorporated in the radiotherapy field.

One patient had five axillary FDG hotspots suspicious for lymph node metastases on PET/MRI, whereas initially only two were seen on US (of which one was proven to be malignant by tissue sampling) and no lymph nodes suspicious for metastases were described on MRI alone. Combining PET information with MRI, all five lymph nodes were marked as suspicious for metastases. As a consequence, chest wall and periclavicular area were added to the radiotherapy field. Image examples are shown in Fig. 1.

One patient had three axillary lymph nodes suspicious for metastases on PET/MRI compared to more than three on US and MRI. Final clinical decision by the multidisciplinary tumor board was to consider three lymph nodes to be suspicious for metastases. The chest wall and periclavicular area were, therefore, excluded from the radiotherapy field. Images are shown in Fig. 2.

PET/MRI confirmed and changed metastatic status in two patients. In both cases a sternal bone metastasis was found. In one patient a sternal bone abnormality was detected by the radiologist on MRI. PET/MRI confirmed malignancy by showing focally enhanced FDG-uptake of this bone abnormality, making additional PET/CT imaging or tissue sampling superfluous. In the other patient the bone lesion was not described in the MRI report at first. In both cases a hotspot on PET combined with morphologic information on MRI completed diagnosis. In retrospect, the bone metastasis of the second patient was visible as a subtle abnormality on T2-weighted MR images. In both patients the treatment plan was adjusted. In both cases a whole body PET/CT was acquired consecutively and did not show other distant metastases. Both patients are being treated curatively (oligometastatic breast cancer), and the sternal bone will be additionally irradiated.