Early monitoring of trastuzumab +/- pertuzumab therapy with 18F-choline PET/CT in patients with advanced disease breastcancer.

Trastuzumab (Herceptin) +/- pertuzumab (Perjeta) in combination with docetaxel
(Taxotere) is being used in the treatment of HER2/neu receptor positive
advanced disease breastcancer. At present patients treated with trastuzumab +/-
pertuzumab are monitored using conventional morphological techniques, i.e.
CT-scans. Routinely, the first follow-up CT-scan is performed after twelve
weeks of therapy and compared to the initial pre-therapy scan. According to
morphological RECIST criteria targetlesions do or do not respond to therapy. In
the case of a non-responder alternative strategies need to be considered. In
the meantime these patients have been treated with an ineffective therapy,
causing serious side effects. Most important side effect of trastuzumab and
pertuzumab is potential cardiotoxicity. Taking into consering these potentially
serious side effects, earlier follow-up than at 3 months seems to be mandatory.
This is where nuclear medicine comes into play with functional techniques
rather than morphological. PET/CT is a hibrid technique that combines both a
functional and a morphological approach and is expected to allow monitoring as
early as after 2 or 3 weeks of trastuzumab +/- pertuzumab therapy .

[11C]-choline is a radiotracer of choline phospholipid metabolism in cell
membranes. Choline is an essential amino acid needed for the synthesis of cell
membrane phospholipids, and has both anabolic and katabolic pathways. Normally
these pathways are in balance, but in rapidly dividing cancer cells the
anabolic pathway is dominant, being the solid base for [11C]-choline PET/CT
imaging. There is good uptake of [11C]-choline in HER2/neu receptor positive
breast cancer lesions, that seems to decrease in patients responding clinically
to trastuzumab therapy. This seems to make [11C]-choline an ideal radiotracer
for the early response monitoring of trastuzumab and pertuzumab therapy in
these patients.

The use of the short lived [11C] label demands for PET/CT facilities in close
proximity to the cyclotron that is producing the radiotracer. The longer lived
[18F] label allows transportation to sites more remote from the producing
cyclotron, and is at present commercially available and being used in the
routine staging and restaging of patients with prostate cancer. Application in
breast cancer patients has been anecdotal so far, but seems possible because
biodistribution of [18F]-choline and [11C]-choline is nearly identical.

Because of this anecdotal experience with [18F]-choline in breast cancer
patients, we are planning to perform a pilotstudy in a relatively low number of
patients in order to investigate if [18F]-choline uptake will decrease after 2
to 3 weeks of trastuzumab +/- pertuzumab therapy in morphologically responding
patients (as noted after 12 weeks on a CT-scan). In addition, we would like to
sort out if responders can thus be discriminated from non-responders. The
results of this pilotstudy will be used to design a definite study involving a
sufficient number of patients in order to determine a cutoff value for the
decrease in [18F]-choline uptake that can discriminate responding from
non-responding patients.

In this pilotstudy we are planning to investigate in a relatively low number of
patients if [18F]-choline uptake will decrease after 2 to 3 weeks of
trastuzumab +/- pertuzumab therapy in morphologically responding patients (as
noted after 12 weeks on a CT-scan). In addition, we would like to sort out if
responders can thus be discriminated from non-responders.

The study design is that of a prospective pilotstudy that can suit the routine
diagnostic and therapeutic work-up of patients with HER2/neu receptor positive
advanced disease breast cancer. Patients will have an initial [18F]-choline
PET/CT study (PET/CT study No. 1) that will be repeated after 2 to 3 weeks of
trastuzumab +/- pertuzumab (and docetaxel) therapy (PET/CT study No. 2). The
initial [18F]-choline PET/CT study can be combined with a contrast enhanced
diagnostic CT when there is a high suspicion upon distant metastases. Of course
all patients will be evaluated and treated according to existing criteria.

A total number of 20 evaluable patients that will have completed the entire
research protocol is anticipated. Taking into account premature withdrawal of
patients from the study, we anticipate a total number of 45 PET/CT studies in
approximately 23 patients. From historical data on the incidence of HER2/neu
receptor positive advanced disease breast cancer in the participating hospitals
we can estimate the total duration of the pilotstudy to be one to one and a
half years. The participating hospitals are the Bronovo hospital in The Hague,
the Reinier de Graaf hospital in Delft, the Catharina hospital in Eindhoven and
the NKI/AVL in Amsterdam. We are planning to restart the pilotstudy in november
2013.

The burden associated with participation comprises of two additional studies
for which Brovono patients will have to travel to Delft where an intravenous
access is to be instituted. Patients from Eindhoven and Amsterdam can have
their studies done in their respective hospitals. When there is a high
suspicion upon distant metastases, the initial [18F]-choline PET/CT study can
be combined with a contrast enhanced diagnostic CT for which an intravenous
access is mandatory as well.
The radiotracer [18F]-choline, that will be used in both PET/CT studies, will
be administered in very low tracer amounts that probably will not cause any
adverse side effects.
However PET/CT studies do have a radiation burden. In the literature an
effective equivalent dose of approximately 10 mSv was reported for
[18F]-choline PET studies (no CT). In this study dating from 2002 less
sensitive PET scanners were being used than nowadays. Using present modern
PET/CT scanners a dose reduction of approximately 60% can be achieved, enabling
an effective equivalent dose of 4 mSv per study and 8 mSv for a study including
a low dose CT (PET/CT). In case of both an initial and follow-up PET/CT scan,
the total effective equivalent dose administered extra to the patients is 16
mSv. For comparison: the radiation burden of a contrast enhanced diagnostic CT
is 8 to 20 mSv per scan, depending on the protocol being used. The extra
radiation burden of 16 mSv may lead to an increased risk for developing a
second tumor in the participating patients. However, the latency time of such
an effect is probably much longer than the average life expectancy of these
patients.