Cancer Research in Switzerland - Krebsliga Schweiz

was to explore whether sequential conversion of 17b-
estradiol to 2-ME is an intrinsic growth inhibitory pathway
that counteracts/suppresses the ER-dependent proliferative
actions of 17b-estradiol.
Results
Growth studies using ER-positive breast cancer cells revealed
that estradiol has a biphasic effect on their growth,
with proliferative and inhibitory effects at low (physiologic)
and high concentrations respectively. Importantly,
studies with ER-negative cells and ER antagonists show
that the proliferative phase is ER-dependent, whereas the
inhibitory effects of estradiol are mediated via conversion
of estradiol to 2ME. Molecular and gene-silencing studies
provide evidence that the inhibitory effects of estradiol
are mediated by 2-ME via upregulation of p21, a negative
regulator of cell cycle.
Potential Implications
Because 2-ME, an endogenous non-estrogenic oestrogen
metabolite, counteracts/suppresses the proliferative/carcinogenic
actions of estradiol, this non-estrogenic and
non-carcinogenic oestrogen metabolite could be employed
for the prevention of breast cancer. Metabolic disorders
and inter-individual differences in estradiol metabolism
might affect the balance between the proliferative
and anti-proliferative pathways and define the potential
risk for an individual to develop breast cancer. Moreover,
assay of 2-methoxyestradiol or the key enzymes responsible
for 2-ME formation, i. e. catechol-O-methyltransferase,
in biopsy tissues may serve as a diagnostic marker
in women with potential risk of oestrogen associated
breast cancer. Finally, in postmenopausal women using
hormone replacement therapy, 2-ME could be employed
for prevention of cardiovascular disease without increasing
the risk of cancer. Finally, the presence of the negative
regulatory metabolic pathway may also help explain the
protective effects of oestrogens and the deleterious effects
of oestrogens plus medroxyprogesterone on breast
cancer in the recently concluded Women’s Health Initiative
(WHI) study, as medroxyprogesterone inhibits the
formation of 2-hydroxyestradiol, the precursor of 2-methoxyestradiol.
Project coordinator
Prof. Dr. Raghvendra K. Dubey
Klinik für Reproduktions-Endokrinologie
UniversitätsSpital Zürich
Frauenklinikstrasse 10
CH-8091 Zürich
Phone +41 (0)44 255 86 08
raghvendra.dubey@usz.ch
Frattini Milo | Characterization of EGFR deregulation
and EGFR downstream cascade in colorectal cancer
patients, and relationship to new targeted therapies
(OCS 01921-08-2006)
Colorectal cancer (CRC) is the second leading cause of
cancer-related death in Western countries. Newer therapeutic
options for treating metastatic CRC (mCRC) include
targeted biological therapies, with those against epidermal
growth factor receptor (EGFR) showing promising
data. Cetuximab and panitumumab are two monoclonal
antibodies that block EGFR and, therefore, block its activation
and the transduction cascade of mitogen signals.
EGFR-targeted therapies have significantly increased the
follow-up of affected patients but are effective only in 10-
20 % of cases. In addition, they are quite toxic and expensive.
Objective
As no molecular markers able to predict the efficacy of
EGFR-targeted therapies were available at the time, the
overall goal of this research project was to better understand
the significance of deregulation of EGFR (the target)
and/or proteins of its downstream signalling cascade
(PTEN, KRAS, BRAF, PIK3CA), on EGFR-targeted therapies
response in CRC patients.
Methods and procedure
A series of patients with mCRC were identified in Ticino
and then treated with cetuximab or panitumumab. Patients’
tissue specimens were evaluated for EGFR gene
status by fluorescence in situ hybridization, for PTEN protein
expression by immunohistochemistry and for KRAS,
BRAF and PIK3CA mutational status by direct sequencing.
A series of 44 patients with primary CRC and paired distant
metastatic lesion were investigated with the same
markers.
Results
In our cohort, we found that a normal gene status of
EGFR, the presence of KRAS mutations, BRAF mutations,
PIK3CA mutations and the PTEN loss of expression all represent
independent predictive markers of resistance to
EGFR-targeted therapies, because they occurred only in
patients who experienced no response to these drugs. By
comparing the molecular profile of primary tumour with
that of the metastatic lesion, we observed some differences,
especially at EGFR gene status level, thus indicating
that it should be better to perform analyses of metastatic
specimens than analyses of primary tumours.
Recommendations and patient benefit
Our results were subsequently confirmed by other studies
and therefore concurred with the definition of KRAS as a
molecular marker that has to be tested before considering
the use of cetuximab or panitumumab as a treatment. The
international agencies FDA and EMA approved KRAS
testing as a prerequisite before drug administration. The
other markers, due to either low frequency of alteration or
to lack of standardized methodologies, are currently on
stand-by. Therefore, at least 30 % of patients (characterized
by KRAS mutation) are not treated with drugs and
can be addressed with new combinatorial treatments or
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