Evaluation of a high-resolution dedicated hanging breast PET guided biopsy device for breast cancer diagnosis.

Biopsy of breast lesions is increasingly being performed with a variety of
anatomical imaging techniques. Primary tumour 2-[F-18]-fluoro-2-deoxy-D-glucose
(18F-FDG) uptake in breast cancer is significantly higher in tumours with
prognostically unfavourable characteristics. An important aspect of improved
tumour visualisation using functional imaging, e.g. positron emission
tomography (PET) imaging, could be the evaluation of heterogeneity in 18F-FDG
uptake. The assessment of intratumoural 18F-FDG uptake may enable tumour
sampling from the area with the highest 18F-FDG uptake (i.e. highly
proliferative area). This might be particularly interesting in patients treated
with neo-adjuvant chemotherapy, in whom pre-treatment biopsies are used for
determination of the chemotherapeutic regimen. Uptake of 18F-FDG can also be
helpful in the detection of radiographic occult lesions or discriminating a
benign process such as scar from malignancy. A consortium of investigators,
participating in the European Project MAMMOCARE, has developed a prototype
breast biopsy device that is incorporated in a dedicated high-resolution PET
breast scanner. This study will investigate the safety and accuracy of this new
PET-guided biopsy device.

The primary objective of the present study is to assess the feasibility and
safety of a newly developed PET-guided breast biopsy system in breast cancer
patients.

This is a prospective observational feasibility study.

Standard clinical protocol:
Patients will be prepared following a 6-h fasting period on the day of the
conventional 18F-FDG PET/CT scan. A PET/CT (Philips Gemini Time-of-flight,
Eindhoven, The Netherlands) will be used. The patient will be administered
between 180-240 MBq 18F-FDG intravenously, according to standard protocol.
PET/CT will be acquired at approximately 50 minutes after administration of
18F-FDG. First, a PET/CT of the thorax will be performed with the patient in
prone position with hanging breasts. Subsequently, a whole body PET/CT will be
performed with the patients in supine position.

18F-FDG PET-guided biopsy protocol:
After the conventional PET/CT scans, patients with demonstrated 18F-FDG-avid
breast lesions will be transferred from the Nuclear Medicine department to the
MAMMOCARE intervention room at the sixth floor (room number 6B.21). In here,
18F-PET-guided biopsies will performed by the Radiologist and Nuclear physician
based on the following protocol (Figure 1):

Three biopsies, which is standard clinical practise at the NKI-AVL, of the
primary breast tumour are performed. Two biopsies are taken from the area with
the highest 18F-FDG uptake and one biopsy is taken from the tumour border using
a commercial 9-gauge vacuum-assisted needle (Eviva, Hologic, IN, USA).

As safety check, a hydromarker will be inserted to indicate the biopsy
location. Mammograms can visualise if the biopsy location (hydromarker)
correspond to the location of the tumour. Furthermore, the hydromarker is
needed as orientation point to insert the 125I-marker.

Finally, a dose calibrator will be used to measure the presence and quantity of
18F-FDG in the breast biopsy specimens.

Radioactive 125I-seed placement:
A radioactive 125I-seed (similar to those used in brachytherapy of the
prostate) will be placed, under ultrasound guidance, in the breast near the
hydromarker in order to mark the location of the primary tumour. 125I has a
half-life time of 60 days and is a 27 keV source of gamma radiation. This
radioactive 125I marker can be visualised using ultrasound, X-ray and CT.
Intra-operatively it can be detected with a gamma probe. This method enables
surgical localisation of the primary tumour after neo-adjuvant chemotherapy
because of the long half-life time of the radioactive 125I marker. This is part
of the standard clinical workflow in these patients.

Mammography:
Directly after 125I-seed placement, all patients undergo mammograms in three
different orientations (MLO, ML, CC) in order to locate the 125I-seed in vivo.
This is part of the standard clinical workflow in these patients.

Histopathology examination of breast biopsies:
Primary tumour characterisation is determined by assessing the ER, PR, HER2,
MIB-1 (Ki67), and AR status of the breast biopsies. The pathologist will
evaluate the breast biopsies within 48 hours to check whether enough tumour
tissue is obtained for standard gene-expression and molecular subtyping
analysis. An additional ultrasound-guided breast biopsy is planned as back-up
in case the PET-guided breast biopsies do not contain enough tumour tissue for
pathological analysis. This additional ultrasound-guided breast biopsy
procedure is planned a few days after the PET-guided biopsy. This additional
biopsy procedure is cancelled when pathological analysis shows that enough
tumour tissue is obtained.

Burden and risks associated with participation:

-Participation in this study does not involve a significant risk for the
patient or personnel, but the patients do need to stay 2 hours longer in the
hospital after their PET/CT scan.

-Additional radiation:
Patients receive an additional mammogram in one direction, which cause an
additional radiation exposure of 0.3 mSv. This is within the normal reach of
diagnostic procedures and no side effects or risks are expected.

The involved staff receives additional radiation exposure, because they have to
stay near the patient during the biopsy procedure. A worst case scenario of
radiation exposure is calculated (ANNEX 1 in study protocol: Berekening
uitwendige stralingsbelasting medewerkers).
The additional total body radiation exposure after 20 patients is 0.9 mSv, and
the radiation exposure of the hand is 1.6 mSv.
In reality, the radiation dosage to the personnel is limited by using proper
lead shielding and distance during the biopsy procedure, while the personnel is
not handling the biopsy needle.

-Biopsy needles:
The biopsy needles are thicker than the biopsy needles used in case of
ultrasound-guided breast biopsies. 9-gauge needles are used instead of 14-gauge
needles. These thicker needles can cause a higher risk for hematomas. These
thicker needles are the same needles which are used in the NKI-AVL for
stereotactic biopsies. Therefore, the Radiologist has experience using these
needles and knows that these biopsy needles are safe to use.

-There is a low risk that the targeted biopsy region does not contain tumour
cells, which means that the patients have to come back for a second biopsy.
This risk is minimized by including breast cancer patients who have a
relatively large tumour (stage II or III), which should make it relatively easy
to perform a biopsy of the tumour

Benefit with participation

-The PET/CT scan for these patients will be scheduled within 1 week time
instead of 2 weeks.

- Biopsies will be taken of the area with the highest 18F-FDG uptake. The
benefits associated with this are still unknown. It is expected that this area
of the tumour has the highest proliferation, and therefore, this tumour tissue
is potentially ideal for the gene-expression and molecular subtyping analysis
in order to determine the neo-adjuvant chemotherapy treatment.
Histopathological analysis of breast biopsies taken from the breast tumour area
with the highest proliferation may potentially lead to a more adequate
personalised treatment.