Cancer Research in Switzerland - Krebsliga Schweiz

Regarding new genes, in collaboration with Riccardo
Dalla Favera’s group in New York we identified the tumour
suppressor gene TNFAIP3/A20, an inhibitor of the NFkB
pathway, as being frequently deleted and mutated, especially
in MALT lymphomas (Novak et al., Blood 2009).
We also studied the relationship between immunogenetics
and genomic lesions in splenic MZL (Rinaldi et al., British
Journal of Haematology 2010). Splenic MZL express
mutated (M-) or unmutated (U-) immunoglobulin heavy
chain (IGHV) genes. We combined SNP arrays and IGHV
sequencing in 83 cases. Clinical features and outcome
were similar between U- and M-IGHV cases. Recurrent lesions
frequency was higher in U-IGHV cases, including
poor prognosticators. Frequencies differed among cases
bearing individual VH genes or lambda light chains. We
also studied the role of antigen stimulation in splenic
MZL (Zibellini et al., Haematologica 2010). The occurrence
of stereotyped B-cell receptors was investigated in
133 SMZL (26 HCV + ) and compared with 4,414 HCDR3
sequences from public databases. Sixteen SMZL (12 %)
showed stereotyped BCR; 8 % of SMZL sequences
retrieved from public databases also belonged to stereotyped
HCDR3 subsets. Three categories of subsets were
identified: 1) “SMZL-specific subsets”; 2) “Non-Hodgkin’s
lymphoma-like subsets”; and 3) “CLL-like subsets”.
Immunoglobulin 3D modelling of 3 subsets revealed similarities
in antigen binding regions not limited to HCDR3.
Conclusions
We identified the different patterns of genomic aberrations
in MZLs, thus aiding differential diagnosis. We identified
a lesion predicting a poor outcome in splenic MZLs,
which could be useful to better manage patients. Also, we
identified a new gene strengthening the NFkB pathway as
an important therapeutic target for these patients. Splenic
MZLs present distinctive features in terms of immunogenetics.
Additional studies are ongoing, and data will be reported
in the future.
Project coordinator
Dr. Francesco Bertoni
Laboratorio di oncologia sperimentale
Istituto oncologico della Svizzera italiana (IOSI)
Via Vincenzo Vela 6
CH-6500 Bellinzona
Phone +41 (0)91 820 03 67
Fax +41 (0)91 820 03 97
frbertoni@mac.com
Bohlius Julia | Individual patient data meta-analysis
on the effects of erythropoiesis-stimulating agents in
cancer patients (OCS 02146-10-2007)
Patients with cancer have an increased risk for anaemia,
which may negatively impact their quality of life (QoL).
Erythropoiesis-stimulating agents (ESAs) reduce anaemia
in cancer patients and may improve QoL, but there are
concerns that ESAs might increase mortality.
Study aim
We collected patient data from randomised controlled trials
to evaluate the effect of ESA on mortality and survival
in patients with cancer and to identify subgroups of patients
that may benefit from ESAs.
Methods
We identified randomised controlled trials comparing
epoetin alfa, epoetin beta or darbepoetin alfa plus red
blood cell transfusions versus transfusion alone, for
prophylaxis or therapy of anaemia in patients with cancer
receiving chemotherapy, radiotherapy or no anticancer
therapy. Study investigators from eligible trials were invited
to collaborate and submit raw data of their studies.
Main analyses were defined in a peer-reviewed protocol
and a statistical analysis plan. A steering committee consisting
of clinicians and methodologists reviewed results
and agreed on their interpretation. The raw patient-level
data were meta-analyzed by independent statisticians at
two academic departments, using fixed-effects and random-effects
meta-analysis. Primary endpoints were onstudy
mortality, defined as duration of ESA study plus 1
month follow-up, and overall survival, defined as the
longest follow-up available. Analyses were conducted
separately for all patients with cancer regardless of anticancer
therapy and for patients receiving chemotherapy.
Tests for interactions were used to identify differences in
effects of ESAs on mortality and survival for pre-specified
subgroups.
Findings
A total of 13,933 patients with cancer from 53 trials were
analyzed: 10,411 patients were scheduled to receive
chemotherapy, 799 radiotherapy, and 737 radiotherapy
combined with chemotherapy. 1,690 patients received no
anticancer treatment during the ESA study, and 266 received
other treatment modalities. 1,530 patients died on
study and 4,993 overall. Including all patients with cancer
regardless of anticancer therapy, ESAs increased on-study
mortality (hazard ratio [HR] 1.17; 95 % confidence interval
[CI] 1.06–1.30) and worsened overall survival (HR
1.06; 95 % CI 1.00–1.12), with little heterogeneity between
trials (I 2 0 %, p=0.87 and I 2 7.1 %, p=0.33, respectively).
Restricting the analysis to patients receiving chemotherapy,
the HR for on-study mortality was 1.10 (95 %
CI 0.98–1.24) and 1.04 (95 % CI 0.97–1.11) for overall
survival. There was little evidence of a difference between
trials of patients receiving different cancer treatments (p
for interaction=0.42).
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