Towards patient tailored cancer treatment supported by molecular imaging
IMPACT: IMaging PAtients for Cancer drug selecTion - Metastatic Breast Cancer

Current patient work-up, including conventional imaging and pathological
assessment of just one single biopsy, might be insufficient to identify
metastatic breast cancer patients, who possibly benefit from first-line
anti-hormonal or anti-HER2 therapy. As receptor conversion of the tumor is
found quite frequently and molecular heterogeneity can occur within one
patient, up-to-date whole body information is necessary to determine estrogen
receptor (ER) and/or human epidermal growth factor receptor 2 (HER2) receptor
status and subsequently guide therapy decision. With molecular imaging via PET
this information can be obtained in a non-invasive, patient friendly way.
Furthermore, to improve and individualize treatment and be able to identify
(new) drug targets and biomarkers, sampling of venous blood, circulating tumor
cells (CTC) as well as circulating tumor DNA and molecular characterization of
one metastasis at the beginning and, if feasible, of an additional biopsy
during therapy, is necessary.

The primary objective is to evaluate the clinical utility of experimental PET
scans, in the setting of metastasized breast cancer (MBC) at first
presentation.
Secondary objectives:
- The relation between progression free survival (PFS, defined as time from
start of treatment until moment of documented tumor progression or death) to
either positive or negative baseline 18F-FES-PET, 89Zr-trastuzumab-PET and 2
week 18F-FDG-PET.
- The relation between DNA sequencing and RNA expression analysis (including
miRNA analysis) of the biopsy and venous blood samples to all molecular,
imaging (standard and experimental) and clinical follow-up data (treatment
response and survival).
- The relation between miRNA analysis of the baseline biopsy and a venous blood
sample at baseline, and all other molecular, imaging and clinical follow-up
data.
- The relation between peptide profiling of new baseline biopsy and venous
blood samples (baseline and day of standard response assessment) and all other
molecular, imaging and clinical follow-up data.
- The assessment of molecular changes of primary biopsy, new baseline biopsy
and (optional) biopsy taken during treatment and the relation to all other
molecular, imaging and clinical follow up data.
- To compare CTC enrichment approaches and relate CTC count and ER/HER2 status
of CTCs at baseline to all molecular, imaging and clinical follow-up data.
- The assessment of circulating tumor DNA analysis at baseline, day of early
18F-FDG-PET and standard response assessment to the molecular findings of the
available biopsies and venous blood samples, as well as to all imaging and
clinical follow-up data.
- The relation between peptide profiling of the baseline biopsy and venous
blood samples (baseline and day of standard response assessment), and all other
molecular, imaging and clinical follow-up data.
- The relation between circulating miRNA analysis (baseline) and all other
molecular, imaging and clinical follow-up data.
- The quantification of the cost-effectiveness of the experimental imaging
(baseline 18F-FES-PET and 89Zr-trastuzumab-PET; 2 week 18F-FDG-PET) as
described in paragraph 7.4.6.
- The assessment of impact of biopsy procedure and molecular imaging (both at
baseline), as well as quality of life assessment before and during therapy.

This will be a multicenter prospective observational cohort study in
non-rapidly progressive MBC patients eligible for first-line systemic therapy.
200 consecutive patients will be recruited in the VUMC, UMCN, ERASMUS MC and
UMCG.
After successful eligibility screening, all patients will undergo i) a biopsy,
according to standard clinical care, but with additional tissue gain for DNA
sequencing, RNA expression analysis (including miRNA analysis) and peptide
profiling, ii) investigational pre-treatment FES- and 89Zr-trastuzumab PET,
iii) sampling of venous blood for routine assessments, 89Zr-activity
measurements, for CTC analysis (baseline), circulating miRNA analysis
(baseline), peptide profiling (baseline & day of standard response assessment),
circulating tumor DNA analysis (baseline, day of early 18F-FDG-PET & day of
standard response assessment), as well as for germline DNA collection
(baseline). Subsequent treatment will be based on the routine biopsy and/or
performed molecular imaging. QoL assessment will take place at baseline, 6-7
and 12 (+/-1) weeks after treatment start. Treatment response will be evaluated
after 2 weeks as early response assessment (with 18F-FDG-PET) and routinely at
8 weeks (day 56 ± 3) after treatment start (with CT). If feasible, another
biopsy for molecular analysis will be taken during therapy.

In this study the patients will optimally make 4 (maximum 5) extra visits to
the hospital: Screening procedure (visit 1); 18F-FES-PET and 89Zr-trastuzumab
tracer injection (visit 2, possibly on 2 following (working)days);
89Zr-trastuzumab-PET (visit 3); 18F-FDG-PET for early response monitoring
(visit 4).
After staging (by standard clinical procedures and additional whole body
molecular imaging) 3 treatment groups will be formed. All 3 treatment groups
will potentially benefit from this study design due to a more correct selection
of the treatment and/or an additional treatment option, which would have been
withheld after conventional staging. The additional PET scans (18F-FES-PET,
89Zr-trastuzumab and 1x 18F-FGD-PET) implement a radiation burden of about 31
mSv including the low dose CT for attenuation correction. This radiation burden
is justifiable in this category of patients with metastatic cancer, by the
information that can be obtained from this study, which will have direct
consequences for diagnostic and therapeutic decision-making. Patients may
experience side effects of the new tracers. Until now no side effects of
18F-FES have been registered. Three times, a side effect in terms of a
hypersensitivity reaction has been observed using 89Zr-trastuzumab. Appropriate
precautions have been taken to reduce the risk of such an event. The risk of
(additional) tumor biopsies is considered low with a small risk on
significant/major complications (0 to 1.6%) or death (0 to 0.48%). The risk of
blood draws for molecular analysis is considered negligible. As the methodology
of DNA sequencing, RNA profiling (including miRNA analysis), peptide profiling,
CTC and circulating tumor DNA analysis is experimental, we are currently unsure
about the potential benefit patients can derive from this information and we
clearly emphasize the experimental nature of this part of the protocol.