Annals of Oncology

abstracts
43P
Oncoguide system - A computerized self-learning interactive
assistance system for the diagnosis and treatment of CML /
MPN and MDS
D. Hempel 1 , Y. Fischer 2
1 Institute of Clinical Hematology/Oncology, Steinbeishochschule Berlin,
Donauwoerth, Germany, 2 IOSB, Fraunhofer Institut, Karlsruhe, Germany
Background: Clinical practice guidelines (CPG) represent the current state of research.
Usually they were passive disseminations (e.g. via print media), but this doesn’t assist
the physician in the adaptation of CPG into the daily diagnostic and treatment
algorithm to the given boundary conditions (patient, equipment, medical experience).
The project aims to develop and implement a computerized interactive assistance
system for the diagnosis and treatment of CML / MPN and MDS.
Methods: To create the system experts from the medical and the technical domains
were necessary. They developed a CPG model in the form of a Unified Modeling
Language (UML) activity followed by translation of UML activities into Bayesian nets.
The future system is planned to be self-learning by weighing the decision criteria. The
knowledge-based system is implemented as a client-server architecture. The server acts
as a central data storage in the form of a database. As a client, for example, Internet
browsers can be used. The knowledge of guidelines and interviews with experts have to
be formalized in an appropriate manner. There are approaches based on an ontological
or logic-based modeling. The underlying methodology is based on approaches from
artificial intelligence, such as the Bayesian inference or machine learning methods.
Results: On the client’s side the system suggests the user appropriate decisions for the
diagnosis and further treatment of diseases. The user is navigated through the complex
recommendations of current guidelines and decision trees of the CML/MPN and MDS,
similar to a car navigation system. In contrast to common print media the system
actively supports the physician in the adaptation of CPG into the daily diagnostic and
treatment algorithm to the given boundary conditions (patient, equipment, medical
experience) and has self learning components.
Conclusions: The presented computerized interactive assistance system could help to
increase the accuracy of diagnosis, treatment and follow up of CML/MPN and MDS.
Legal entity responsible for the study: Steinbeishochschule Berlin, Institute of Clinical
Hematology/Oncology
Funding: Celgene, Novartis
Disclosure: D. Hempel: Supported by a grant of Celegene and Novartis.All other
authors have declared no conflicts of interest.
44P
Genomic profile of Li-Fraumeni syndrome patients with
adrenocortical carcinoma in childhood
F. Fortes 1 , L. Canto 2 , H. Kuasne 2 , F. Marchi 2 , P. Miranda 2 , K. Andrade 1 ,
K. Santiago 1 , S. Rogatto 3 , M.I. Achatz 1
1 Oncogenetics, A. C. Camargo Cancer Center, Sao Paulo, Brazil, 2 Neogene,
A. C. Camargo Cancer Center, Sao Paulo, Brazil, 3 Clinical Genetics, Vejle Hospital
Sygehus Lillebaelt, Vejle Sygehus, Vejle, Denmark
Background: Li-Fraumeni syndrome (LFS) is cancer predisposition disorder with a
high risk of having tumors at an early age and multiple primary tumors. LFS is an
autosomal dominant disease and germline TP53 mutations were recognized as the
main molecular mechanism responsible for the syndrome. LFS is present in 0.3% of the
South and Southeastern Brazilian population due to the occurrence of a founder
mutation, the p.R337H TP53. This mutation was initially described as tumor specific,
predisposing to pediatric adrenocortical carcinoma (ADR). ADR is a rare neoplasm
worldwide, but pediatric ADR is 10-15 times more incident in South and Southeast of
Brazil, a fact possibly linked to the presence of the p.R337H mutation. To date, the
factors that lead to the development of ADR in some children while others remain
asymptomatic have not been elucidated and only the presence of the mutation may not
be sufficient for tumor appearance.
Methods: Therefore, the aim of this study was to evaluate copy number alterations
(CNA) of positive ADR patients (N = 3) or negative (N = 1) for p.R337H mutation.
Analysis of gains and losses were evaluated by CytoScan HD Array (Affymetrix, Santa
Clara, CA, EUA).
Results: In total, 341 alterations were identified (260 gains, 55 losses and 26 LOH),
with an average number of 60 alterations in positive cases, while the negative case
carried 156 alterations. Among the alterations identified in the positive cases, five of
them were recurrent in all samples and involved 5p15.33, 12p13.33, 13q11, 15q11.2
and 19p13.3 regions. Despite the small set of samples, it is evident that positive cases
have fewer alterations compared to negative cases.
Conclusions: The apparent higher chromosome instability in negative cases
corroborates our previous results in which the presence of p.R337H mutation provides
a protective effect in patients with ADR. However, this is a preliminary study and our
hypothesis may be confirmed when new investigation in a larger number of samples
are completed.
Legal entity responsible for the study: Maria Isabel Achatz
Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Disclosure: All authors have declared no conflicts of interest.
45P
Proteomics-based system biology analyses unravel a functional
structure with prognostic value
G. De Velasco 1 , L. Trilla-Fuertes 2 , A. Gámez-Pozo 2 , M. Urbanowicz 3 ,
G. Ruiz-Ares 1 , J.M. Sepulveda 1 , R. Manneh 1 , B. Homet 1 , I. Otero 1 , P. Celiz 1 ,
F. Villacampa 4 , L. Paz-Ares 1 , J. Fresno Vara 2 , D. Castellano 1
1 Medical Oncology, Hospital Universitario Doce de Octubre, Madrid, Spain,
2 Molecular Oncology and Pathology Lab, Instituto de Investigación Hospital
Universitario La Paz, Madrid, Spain, 3 Pathology, Hospital Universitario Doce de
Octubre, Madrid, Spain, 4 Urology, Hospital Universitario Doce de Octubre,
Madrid, Spain
Background: Urothelial cancer has been traditionally classified based on histology
features. Recently, some works have proposed a molecular classification of
muscle-invasive urothelial carcinoma (MIUC) into basal and luminal subtypes. We
aimed to define molecular subtypes of MIUC and evaluate the status of several
biological processes in the tumor tissue and address its clinical value.
Methods: Tissue samples were obtained from 57 pts who underwent curative surgical
resection at “Universitary Hospital 12 Octubre” between 2006/12. We analyzed the
proteome applying a high-throughput proteomics approach to routinely archive FFPE
tumor tissue. Tryptic digests were analyzed by mass spectrometry for protein
identification using a Q-Exactive mass spectrometer. Subgroups were defined by
hierarchical clustering and random forest. Functional structure was developed using
probabilistic graphical models with local minimum Bayesian Information Criterion
and Gene Ontology Analysis. Data analysis was done using MeV, BRBArray Tools, R
and Cytoscape software suites and Uniprot (http://www.uniprot.org/) and DAVID
(http://david.abcc.ncifcrf.gov) webtools.
Results: We identified two different molecular subgroups with differential prognosis.
Systems biology analyses showed that wide protein expression assessment allows
building a functional structure where several nodes with defined biological activity were
defined. Activity measurement for each node showed differences between two subtypes
in metabolism, focal adhesion, RNA and splicing nodes. Subtypes defined by protein
expression are comparable to basal and luminal subtypes defined by gene expression.
Moreover, the focal adhesion node has prognostic value in the whole population, and
this prognostic information is independent from a predefined prognostic signature
(submitted Abstract: Proteomics profile profiling predicts poor prognosis in patients
with muscle invasive urothelial carcinoma).
Conclusions: Protein data analysis using random forest showed subgroups matching
with basal and luminal subtypes obtained by hierarchical cluster analysis. Importantly,
we were able to establish different nodes according to biological functions, with
diagnostic and prognostic value.
Legal entity responsible for the study: Research Institute i + 12
Funding: Fundacion Mutual Madrilen.
Disclosure: G. De Velasco: Advisory board for Pfizer. No Conflict of interest with the
abstract submitted.All other authors have declared no conflicts of interest.
46P
Annals of Oncology
Effect of newly synthesized progesteron derivatives on
apoptotic and metastatic pathway in MCF-7 breast cancer cells
S. Yahya 1 , M. Abdelhalim 1 , G. Elsayed 1 , A. Othman 2
1 Hormones, National Research Centre, Cairo, Egypt, 2 Chemistry, Cairo University,
Cairo, Egypt
Backgroun: Breast cancer is the second leading cause of mortality among women
worldwide. Anticancer agents consisting of hybrid molecules are used to improve
efficacy and reduce drug resistance. Alteration of different genes is involved in the
development of cancer. Consequently, novel anticancer drugs with increased selectivity
and specificity are required to overcome limitation of current drugs. A variety of
synthetic steroid derivatives have been contrived, most these derivatives can interact
with the steroid receptors because of a similarity of shape. Also, the investigation of
modified steroid derivatives condensed with various heterocyclic rings has a great
attention. Impaired apoptosis and metastasis are critical in cancer development and is
a major barrier to effective treatment.
Methods: Several progesterone derivatives were synthesized. The structure of the newly
derivatives was elucidated and confirmed using the analytical and spectral data. The
newly synthesized progesterone derivatives, compounds 1, 2, 3, 4, 5, 6, and 7were tested
for their cytotoxic effects against human breast cancer cells (MCF-7) using neutral red
uptake assay. Using QRT-PCR (Quantitative real time-polymerase chain reaction), the
expression levels of P53, P21, Cdc2, Bcl-2, Survivin, CCND1, VEGF, HIF-1α, FGF-1,
MMP-2, MMP-9, Ang-1 and Ang-2 genes were investigated.
Results: All tested compounds showed low IC50 values that were comparable to that of
tamoxifen. The most active compounds against MCF-7 cancer cell line was in the
descending order of 5 >1> 2 >6> 4 > 7 > 3. The study revealed that all newly
synthesized compounds down-regulated the expression levels of BCL-2, surviving,
VEGF, Ang-2 and MMp-9. Compound 2-7 down regulated CCND1 gene expression,
nevertheless, this was only significant in case of compounds 2, 3, and 6. However, P53
were up-regulated by compounds 3. Moreover, compound 1 significantly down
regulated MMP-2. Compoun 3 and 7 significantly down regulated FGF-1.
vi12 | abstracts Volume 27 | Supplement 6 | October 2016