- Email: [email protected]
Challenges of Dealing With Next Generation Sequencing for Hereditary Cancer in Clinical Practice
Annals of Oncology 23 (Supplement 9): ix34, 2012 doi:10.1093/annonc/mds375
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
abstracts
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
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: [email protected]
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
abstracts
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
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: [email protected]