Researchers at the Swiss Institute of Bioinformatics and the Swiss
National Center of Competence in Research in Molecular Oncology in
Lausanne have developed a new test to predict how breast cancer patients
respond to chemotherapy, which could help change how treatment is
delivered in the future. In an article, 'A stroma-related gene signature
predicts resistance to neoadjuvant chemotherapy in breast cancer'(i),
published in 'Nature Medicine', Drs Pierre Farmer, Mauro Delorenzi, and
Pratyaksha Wirapati and the study team showed the potential of the
reactive stroma to modulate tumor phenotype and the clinical response to
treatment. This is a major step forward in the field as identifying
factors that influence response to cancer chemotherapy is crucial for
improving its efficacy.
The study first started when a team of clinicians, cancer biologists and
computational biologists combined their effort to address a very puzzling
question: Why breast tumors that have very similar conditions in terms of
aggressiveness (grade), invasiveness (node status) and hormone dependency
(ER status), respond differently to the same kind of chemotherapy
treatment.
"Two breast cancer patients might respond very differently to the same
type of chemotherapy although their respective tumors are very similar
from a clinical point of view," said Dr Pierre Farmer. "The reasons for
these different responses are unknown."
To help find an answer to this question, a collaborative study was set-up
within the framework of a large randomized clinical trial that involved
more than 40 different hospitals throughout Europe, including those in the
UK, France, Belgium, Netherlands, Poland, Sweden and Switzerland. It was
led by Professor HervГ© Bonnefoi of the European Organization for Research
and Treatment of Cancer (EORTC) in collaboration with the Swedish Breast
Cancer Group (SBCG), the Swiss Cancer Group (SAKK) and the Angloceltic
group (ACOG).
In this trial, biopsies were taken from each patient and sent to Professor
Richard Iggo's laboratory which was at the Swiss Institute for
Experimental Cancer Research (ISREC) in Lausanne at the time of the study,
which was to a large part sponsored by the National Center of Competence
in Research (NCCR) in Molecular Oncology. In Lausanne, the genomic
material (mRNA) of tumor samples were extracted and profiled on
microarrays(1) in order to measure the expression activity pattern of
thousands of individual genes.
Meanwhile, all patients included in the said study had a tumor biopsy
prior to receiving an anthracyclin-based chemotherapy followed by surgical
excision of the tumour - a protocol that clinicians call neo-adjuvant
chemotherapy. After the surgical intervention, pathologists analysed the
surgical specimen and determined if tumor cells were still present. This
is a way to measure the efficacy of the chemotherapy.
If no tumor cells were found, the patient was considered to be fully
responsive to the treatment (defined as "complete pathological response").
The aim of the study was to test if genomic analysis of the tumor taken
before chemotherapy treatment could allow the identification a signature
which permits the prediction of the patients who would respond to the
chemotherapy.
To achieve this task, Drs Farmer, Mauro Delorenzi, and Pratyaksha Wirapati
from the Swiss Institute of Bioinformatics developed new computational
methods to extract relevant gene patterns from the vast quantity of data
generated by the microarray experiment. "In this study, we have mined the
gene expression data in order to find a particular gene activity pattern,
or gene signature, that would be associated with how patients respond to
chemotherapy," Dr Farmer said.
Results showed that a signature measuring the biological activity of
tumor's microenvironment, also known as reactive stroma(2), predicted how
patients would respond to the treatment.
Researchers found that it is precisely the magnitude of this stroma
reaction that was predictive of a response to chemotherapy. "It was a
surprise to us to find that it was not the tumor itself but rather how
surrounding non-tumorous tissue reacts to the presence of the tumor that
was our best clue in predicting resistance to treatment," Dr Farmer
continued. "Patients who had a strong stroma reaction characterized by an
increased quantity of fibroblasts surrounding the tumor were more likely
to have a bad response to this particular chemotherapy."
"What this means is that success in treatment, having tumors shrink or
disappear altogether, is in part due to molecular differences in tumors
and their immediate surroundings," Dr Farmer continued.
Researchers hope that one day this discovery will contribute to changing
how breast cancer patients are treated. Indeed, in the future, if a
clinician learns with a simplified test that a particular woman has a high
probability of not responding to an anthracyclin-based therapy, this
clinician may consider prescribing an alternative chemotherapeutic
regimen. Moreover, this study suggests that predicting how individual
patients might respond to chemotherapy could be possible, which raises
hopes that one day, personalized medicine (3) in the treatment of breast
cancer may become a reality.
Breast cancer is the most common cancer among women around the world. In
2002, it was estimated that more than 1.1 million new cases occurred
worldwide; 636 000 in developed countries and 514 000 in developing
countries. The incidence of this disease is one out of 8 woman living in
western societies will someday be diagnosed with breast cancer; in 2002
the estimated number of deaths was 410 000 worldwide(4).
About the SIB
The Swiss Institute of Bioinformatics is an academic not-for-profit
foundation federating bioinformatics activities throughout Switzerland.
Its mission is to provide essential services and support to the national
and international life science community, through databases, software, Web
servers and core facilities, as well as teaching and research activities
in the field of bioinformatics. It has a long-standing tradition of
producing state-of-the-art software for the life science research
community, as well as carefully annotated databases including
UniProtKB/Swiss-Prot, the world's most widely used source of information
about proteins. The SIB includes world-class research and service groups
in the fields of proteomics, transcriptomics, genomics, systems biology,
structural bioinformatics, evolutionary bioinformatics, modelling,
imaging, biophysics, and population genetics in Geneva, Lausanne, Berne,
Basel and Zurich. The SIB expertise is widely appreciated and its services
are used worldwide by researchers in life sciences. isb-sib.ch
About the National Center of Competence in Research (NCCR) in Molecular Oncology
The National Center of Competence in Research (NCCR) in Molecular Oncology
is a Swiss network cancer research program, that is led by the Swiss
Institute for Experimental Cancer Research in Lausanne in close
collaboration with several partner institutes. The program is funded by
the Swiss National Science Foundation.
The principal aim of the NCCR Molecular Oncology is to strengthen basic
cancer research in Switzerland and to explore, in cooperation with
partners in different university hospitals and the pharmaceutical
industry, the possibilities for new cancer therapies that are opened up by
the NCCR research projects. The NCCR Molecular Oncology contributes to
clarifying causes of cancer development and to identifying new targets for
cancer therapies. The program particularly aims at establishing new
pathways for the translation of progress in basic cancer research into
advances in clinical oncology, through an extensive interaction between
basic researchers and clinical scientists. nccr-oncology.ch
Source
Swiss Institute of Bioinformatics
Janice Blondeau, Head of Communications
Quartier Sorge, BГўtiment GГ©nopode / CH-1015 Lausanne / Switzerland
isb-sib.ch
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