Download the ESMO 2012 Abstract Book - Oxford Journals

abstracts
how can medical oncologists deal with
the new wave of genetic information
about their patients?
33IN CHALLENGES OF DEALING WITH NEXT GENERATION
SEQUENCING FOR HEREDITARY CANCER IN CLINICAL
PRACTICE
K. Claes
Center for Medical Genetics, Ghent University Hospital, Ghent, BELGIUM
Next generation sequencing is one of the most significant technological advances in
the biological sciences of the last 20-30 years. These recent advances have brought a
paradigm shift in how medical researchers investigate both rare and common
disorders. The ability to generate enormous amount of sequence data in a short time
at an affordable cost makes this approach ideal for a wide range of applications from
1) sequencing a panel of genes associated with a particular disease, 2) all coding
regions (« exome sequencing ») to 3) the entire human genome. However, while the
technology promises to reduce the cost of sequencing an entire human genome to
less than US$1000, one must question the diagnostic utility of complete genome
sequencing for routine clinical testing, given the many interpretive challenges posed
by this approach. Knowing that in 5-6% of the breast cancer patients analysed for the
coding regions of BRCA1/2 variants of unknown clinical significance (VUS) are
identified, several thousands of VUS are being found by whole exome sequencing
whereby the coding region of more than 20,000 genes are investigated. These,
individually rare, VUS potentially have a negative impact on the individual
concerned as they create greater uncertainty. Currently, large scale implementation of
functional assays is not a realistic option in diagnostic settings. Therefore, at present,
to our opinion, for familial cancer syndromes, it appears that next-generation DNA
sequencing may provide the greatest benefit to routine clinical testing by enabling
comprehensive multigene panel sequencing. This should provide an advantage over
traditional Sanger-based sequencing strategies while limiting the total test output to
sets of genes with known diagnostic value. The finding of a deleterious mutation in
such genes guarantees the patient the possibility of adequate clinical management
and follow up according to (international) established guidelines.
During the presentation we will discuss the current and near future state of clinical
testing approaches for the best known and most frequent familial cancer syndromes
and explore what (bioinformatic, quality control metrics and other) challenges must
be addressed in order to extract diagnostic value from whole-exome and
whole-genome sequencing for hereditary cancers.
Disclosure: The author has declared no conflicts of interest.
34IN IS IT NECESSARY TO SCREEN EVERYBODY FOR INHERITED
CANCER? WHEN, WHY AND HOW
E. Levy-Lahad
Shaare Zedek Medical Center, Hebrew University Medical School, Medical
Genetics Institute, Jerusalem, ISRAEL
Individuals who inherited mutations conferring high cancer risks should ideally be
identified before they ever develop cancer. Such mutation carriers stand to reap the
greatest benefit from surveillance and prevention measures. This begs the question of
the optimal means of identifying such carriers. Currently, carriers are usually
identified after they have already been diagnosed with cancer, representing a lost
opportunity for prevention, or through a family history of cancer. Identification of
carriers based on family history is limited by sufficient family size, sufficient
information on family history of cancer, and familial communication about cancer
diagnoses, and especially about results of genetic testing. We will present data on
BRCA1/BRCA2 testing in the general Ashkenazi (European) Jewish population,
which has common BRCA1/BRCA2 mutations, as a model for comprehensive
genetic screening. In particular, we will discuss our findings that approximately half
of BRCA1/BRCA2 families do not have significant family history, so that many
carriers would not be identified without a general screening program. There are both
technical and ethical challenges to such an approach, and these will be discussed.
Disclosure: The author has declared no conflicts of interest.
35IN HOW CAN CANCER RISK AND GENETIC PREDICTION
MODELS HELP ONCOLOGISTS IN THE CLINICS?
D.G.R. Evans
Regional Genetic Service, St Mary’s Hospital, Manchester, UNITED KINGDOM
There are two forms main outputs of risk prediction models. These are the likelihood
of a patient harbouring a mutation in a cancer predisposition gene and the likelihood
of developing specific cancers. Whilst there are a number of these models for
different cancer types, the most well developed area is that of breast cancer. An
oncologist treating a breast cancer patient may be influenced in discussing treatment
options by future risks of contralateral breast cancer and ovarian cancer. Entry into
treatment trials such as those of targeted treatments with PARP inhibitors may also
be influenced by genetic testing for BRCA1 and BRCA2. Finding a mutation in
BRCA1/2 may also influence treatment choices including risk reducing surgery.
Outputs of genetic risk for BRCA1/2 will usually drive the offer of mutation
screening if the likelihood exceeds 10% although this is currently 20% in the UK.
Models include computer based: BRCAPRO, BOADICEA, Tyrer-Cuzick and paper
scoring systems such as the Manchester system. There have been numerous
validations of the models which show that they all perform reasonably well. The
breast cancer risk element is most used for unaffected women and in the context of
family history have only really been validated through one study where the
Tyrer-Cuzick model was the best performer. Incorporation of genetic testing
information from Single Nucleotide Polymorphisms (SNPs) and mammographic
density is likely to improve the precision of these models in the near future.
Disclosure: The author has declared no conflicts of interest.
36IN NEW TREATMENT APPROACHES IN HEREDITARY CANCER:
THE ROUTE TOWARDS PERSONALIZED CARE
E. Vilar
Department of Clinical Cancer Prevention, U.T. - M.D. Anderson Cancer Center,
Houston, TX, UNITED STATES OF AMERICA
Patients diagnosed with tumors arising on the basis of hereditary cancer syndromes
represent a relatively small fraction from the total of cancer cases. However, the
risks to develop different types of tumors among carriers highlight the need to
develop surveillance strategies and preventive interventions to decrease the burden
of cancer in this population. The specific molecular characteristics displayed by
these tumors make them ideal candidates to identify new targets and implement
not only personalized cancer treatments but also targeted chemoprevention
strategies. In addition, hereditary tumors have served as a model to gain further
knowledge in the molecular biology of cancer and to develop targeted drugs.
The best example in this context is the case of PARP inhibitors and breast and
ovarian tumors arising in families diagnosed with Hereditary Breast and Ovarian
Cancer Syndrome (BRCA 1 and 2 mutations). In this presentation we will review
the most recent research advances on target identification and drug development
for hereditary cancer syndromes with a special emphasis in hereditary
gastrointestinal cancers.
Disclosure: The author has declared no conflicts of interest.
37IN CONCLUSIONS AND PERSPECTIVES
Annals of Oncology 23 (Supplement 9): ix34, 2012
doi:10.1093/annonc/mds375
R. Catane
Division of Oncology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL
The aim of this session was to familiarize practicing oncologists with the concept of
modern genetics and its implication for the daily practice. As busy oncologists, we
are inundated with information, and unfortunately the important new genetic facts
related to oncology are frequently presented with code words and acronyms, that
make the information unusable. It is hoped that such regular session, in which expert
geneticist would give us the needed genetic knowledge, coupled with “user’s manual”,
will make us better medical oncologists. Moreover, we will be able to pass on the
required information to our patients, and be in a vantage position to present them
the oncology guidelines.
Disclosure: The author has declared no conflicts of interest.
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com