Cancer Research in Switzerland - Krebsliga Schweiz

150
recurrence of the disease, we addressed the recognition of
leukaemic stem cells by NK cells. This is a small subpopulation
of malignant cells that is implicated in the development
and persistence of leukaemia.
Results of these studies demonstrated that NK cell therapy,
together with the use of pharmacological anti-
neoplastic drugs, should be considered as an innovative
combinatorial approach for treatment of leukaemia. The
important outcome of our project is the translational
“bench to bedside” clinical trial initiated in 2008 at University
Hospital Basel. Altogether, the results of our studies
contributed to a better understanding of the specific
NK cell-leukaemia interactions and to the development of
novel approaches towards curing human leukaemia.
Project coordinator
Prof. Dr. Aleksandra Wodnar-Filipowicz
Basel Stem Cell Center of Competence
Medizinische Fakultät
Universität Basel
Klingelbergstrasse 61
CH-4056 Basel
Phone +41 (0)61 265 33 87
aleksandra.wodnar-filipowicz@unibas.ch
Zaman Khalil | Monitoring of angiogenesis-related
molecules during first line chemotherapy with
bevacizumab and pegylated liposomal doxorubicin
for advanced stage breast cancer: A substudy of
the SAKK 24/06 trial (OCS 02029-02-2007)
The anti-angiogenic drug Avastin ® is currently used in the
treatment of different malignancies including breast cancer.
Until now, no identified factor had been identified
predicting benefit from Avastin ® . Many angiogenesis associated
molecules are detectable in the blood of patients
with cancer. We monitored prospectively six angiogenesis
related factors in patients with advanced stage breast
cancer treated with a combination of Avastin ® and pegylated
liposomal doxorubicin (PLD) in a phase II trial of
the Swiss Group for Clinical Cancer Research (SAKK).
Methods
Patients received Caelyx ® and Avastin ® every 2 weeks for
a maximum of 12 administrations, followed by Avastin ®
monotherapy until progression or severe toxicity. Blood
samples were collected at baseline, after 2 months of
therapy, then every 3 months and at treatment discontinuation.
Enzyme-linked immunosorbent assays were used
to measure vascular endothelial growth factor (VEGF),
placental growth factor (PlGF), matrix metalloproteinase-9
(MMP-9) and soluble VEGF receptors, sVEGFR-1,
sVEGFR-2 and sVEGFR-3. The natural log transformed (ln)
data for each factor was analyzed by analysis of variance
(ANOVA) model to investigate differences between the
mean values of the subgroups of interest (where a=0.05),
based on the best tumour response.
Results
132 samples were collected in 41 patients. The mean
of baseline MMP-9 levels was significantly higher in patients
with tumour response (p=0.0202, log fold change=
0.8786) or disease control (p=0.0035, log fold change=
0.8427) compared to those with disease progression.
Higher MMP-9 level was also a predictor of better progression-free
survival (p=0.0417, hazard ratio=0.574,
95 % CI=0.336–0.979), even when other prognostic factors
were considered in a multivariate cox proportional
hazards model (p=0.0266). MMP-9 level allows to distinguish
two groups in the treated population, one with
higher levels and longer progression-free survival and the
other with lower levels and rapidly progressing cancer
during treatment (p=0.0408).
The mean level of baseline sVEGFR-1 was significantly
lower in patients with disease control than those with progression
(p-value=0.0008, log fold change=–1.0289).
No strong correlation was shown for the other factors
measured.
Conclusions
Higher baseline levels of MMP-9 could predict better efficacy
of the combination of Avastin ® and Caelyx ® and a
longer progression free survival.
Clinical implications for the patients
Only a limited number of patients with breast cancer benefit
from the association of Avastin ® with their chemotherapy.
If our exploratory results are confirmed in the future,
MMP-9 could allow a better selection of the patients
who will benefit from Avastin ® and consequently improve
the benefit/risk ratio of this controversial treatment.
Project coordinator
Dr Khalil Zaman
Centre pluridisciplinaire d’oncologie (CePO)
Centre hospitalier universitaire vaudois (CHUV)
Rue du Bugnon 46
CH-1011 Lausanne
Phone +41 (0)79 556 78 01
Secrétariat +41 (0)21 314 01 68
Fax +41 (0)21 314 02 00
khalil.zaman@chuv.ch
Zhong Xiao Yan | Investigating tumour-derived
methylation DNA in circulation as markers for non-
invasive screening, early diagnosis, monitoring and
determination of the prognosis of breast cancer
(OCS 01993-02-2007)
The discovery of cell-free DNA in plasma and serum samples
offers new diagnostic possibilities in two crucial areas
– prenatal genetic diagnosis and cancer detection.
In the prenatal area, we have recently shown that both
cell-free foetal DNA and foetal cells in maternal blood
could be used for non-invasive prenatal diagnosis regarding
genetic diseases and pathological pregnancies. We
were able to detect cell-free foetal DNA earlier, more frequently
and in greater amounts than foetal cells in the
maternal circulation. In the cancer area, we have found
that a high level of cell-free DNA in plasma was elevated
in breast cancer and was related to tumour size and distant
metastases, suggesting a potential for clinical applications.
In order to develop a non-invasive blood test, we intend
to identify breast cancer-related DNA methylation
changes in tumour tissues as tumour biomarkers. DNA
methylation analysis is a rapidly developing field. However,
studies demonstrating its usefulness are still limited
due to the fact that no one technique is superior. A new
quantitative high-throughput MassCLEAVE TM assay (Sequenom)
based on MALDI-TOF MS system enables dis-