Genetic testing in melanoma: an interview with Dr. Diane McDowell, US Medical Affairs Lead, Oncology GSK -
Interview by April Cashin-Garbutt , BA Hons (Cantab)
insights of industry Dr. . Diane McDowell US medical Affairs Lead, Oncology GSK please can you give a brief history of genetic tests?
Genetic testing, commonly used process of looking for changes in genes or chromosomes of a person that may be associated with diseases or specific conditions i predates President Richard Nixon declared war against cancer with the passage of the 1971 National cancer Act ii
the first genetic tests helped to detect abnormalities in genes unique causing rare inherited disorders such as cystic fibrosis iii , sickle cell anemia and Tay-Sachs disease. iv in the 1980s, researchers began to better understand the role of genes in cancer v , with the first genetic test for breast cancer and ovarian cancer being introduced in the mid 190s vi
in recent years, the variety of tests has greatly expanded. ii With genetic testing today, medical professionals can determine the risk of developing certain diseases a person, confirm suspected diagnosis, detect when an individual can pass a genetic mutation to its children, or filter out patients who are unlikely to respond to certain therapies i for diseases such as melanoma.
What conditions is an available genetic test for?
Today, genetic testing is available for more than 2,000 rare and common diseases. viii Although oncology is an area that has received a significant amount of attention and research funding, experts predict that in the long term, immunology, central nervous system diseases infectious and cardiovascular disease are active research areas in the field of genetic testing and personalized medicine.
Why is the application of genetic testing for melanoma occurred most recently?
over the past 20 years, growth in the knowledge of the molecular biology and cancer genetics has not only enriched our understanding of how tumors develop, but we also taught that each tumor is the same. We have known for some time that genetic mutations can affect the way cells grow and divide. Some mutations can cause cells to grow out of control, which can lead to cancer. i
In order to apply genetic testing for melanoma, it was necessary to first gain an understanding of the genetic mutations associated with this particular illness. 02 marked a turning stage IV melanoma point when "Mutations in the BRAF Gene gene in human cancer" was published in the journal Nature . viii
The research, funded by the Cancer Genome Project Trust Sanger Institute Wellcome, studied the MAP kinase (MAPK) and describes the somatic activating mutations of the BRAF protein in melanoma ix , allowing cancer cells to grow and spread. Thank you to these early research, we can now genetically differentiate at least three subtypes of tumors associated with melanoma, the most common being those with BRAF V0 mutations.
Can tests genetic current for melanoma to determine the two types of mutations - inherited and acquired
cancers such as melanoma may be inherited (germline) mutations or those somatic, or acquired environmental factors ;? still other mutations may have no identifiable cause. x
The research identified high-risk susceptibility genes thought to be associated with melanoma, including CDKN2A, CDK4 and associated BRCA1 protein (BAP -1). xi Although the test is available to determine germline mutations in CDKN2A, xii such mutations are rare xiii and there are no clinical utility clear for this. Test
There are two main molecular signaling pathways that can contribute to somatic development of melanoma. activated protein kinase mitogen (MAPK) pathway and the phosphoinositide 3-kinase (PI3K) paths xiv As mentioned above, the MAPK pathway, which is dysregulated in many melanomas, contains genes such that BRAF and RNA that may be somatically mutated. xv
About half of all people with metastatic melanoma have a BRAF V0 mutation. BRAF V0E mutations V0K and represent approximately 70 percent and 23 percent, respectively, of patients with V0 mutation, xvi and can be detected in a tumor through genetic testing. Such a test approved by the FDA is the THxID® - BRAF, for which GSK has worked with the in vitro diagnostics company bioMérieux.
What percentage of melanoma cases are caused by acquired mutations linked to sun exposure?
Over 0 percent of melanoma cases have been linked to sun exposure. xvii Only about 10 percent of melanoma cases can be attributed to germline genetic mutations that are passed through a family from generation to generation. xviii xix
At what stage are genetic tests for melanoma usually done?
The National Clinical Practice Guidelines in Oncology Comprehensive Cancer Network® recommend for melanoma genetic testing be performed at diagnosis of metastatic melanoma.
If a health care provider contemplates the treatment of a patient with a metastatic melanoma with a targeted therapy, they must be tested to determine if their tumor shows a mutation in the gene.
once the melanoma mutation of a patient has been identified, they may find that they are a candidate for a targeted therapy with this particular mutation. xx
What genetic testing results can have impact?
Patients receiving a positive diagnosis for a specific mutation in their melanoma tumor can work with their doctor to identify specific targeted therapies that may be available and decide on a treatment plan that is best for them.
a better understanding of the molecular basis of melanoma presented a great opportunity for new and more targeted approaches for the treatment, reducing the number of patients who can not take real advantage for therapy.
combinations of targeted therapies, such as combining Tafinlar® (dabrafenib) and Mekinist® (trametinib) which was approved by the FDA in January 2014, will be an important part of the personalized medicine strategy results from genetic testing.
what do you think the future for genetic testing in melanoma and how GSK plan to add to that?
Our belief is that science and technology continue to evolve, the future of genetic testing to expand beyond a single test for a single transformation to a multi-complexed evaluate an approach large number of genes simultaneously.
One of the biggest breakthroughs in technology terms is the reduction of the execution time and the cost of sequencing, which may eventually help to identify other genes of interest to inform personalized treatment for patients.
genetic test will also have a greater role in the pharmaceutical industry R & D, as well; a 2013 analysis by McKinsey found that, at present, almost half of active preclinical and Phase I in the pharmaceutical pipeline associated the diagnosis, especially in oncology, immunology and CNS. Oncology is one of the most active areas of research for genetic testing and personalized medicine. xxi
When we Tafinlar® (dabrafenib) and Mekinist® (trametinib) on the market, we took a very scientific approach and focus combined agents in phase I before receive confirmation of Phase II data. We now see this trend continues, with mixed programs that start much earlier in Phase I.
At GSK, we design studies of populations with very specific patient in mind that most of chance to get some kind of therapeutic benefit. At the heart of this ensures that we can effectively identify these patients using the right type of diagnosis.
About Dr. Diane McDowell
After medical school, Diane completed a general surgery residency at the Medical School and a fellowship in surgical oncology at Fox Chase Cancer Center of the University of Tulane.
After a year in private practice as a general surgeon and breast cancer, Diane moved to Bristol-Myers Squibb, where she worked as Director of US Medical Affairs focusing on the breast and cancer liver.
she served as the European headquarters BMS temporary illness Zone Head for Oncology in the EU markets on melanoma and CML before moving to Global Medical Affairs, where she concentrated on lung cancer.
before joining GSK, Diane was a director of global clinical research at Bristol-Myers Squibb and was responsible for melanoma and lung cancer trials.
Currently, Diane is the leader of medical affairs in the United States for both Tafinlar® (dabrafenib) and Mekinist® (trametinib) for GSK.
A native of Pittsburgh, Pennsylvania, Diane now lives in Philadelphia with her husband and son.
where readers find more information?
For more information on genetic testing in cancers like melanoma, there are a number of organizations with useful information, including the National Cancer Institute of the National Institutes of Health and the National Institute for human genome research at the National Institutes of Health.
i American Cancer Society. "The genetic testing for cancer: What you need to know." Http://www.cancer.org/acs/groups/cid/documents/webcontent/002548-pdf.pdf. Accessed Page 2 March 17, 2014.
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ii National Cancer Institute. "1971 National Cancer Act" http://dtp.nci.nih.gov/timeline/noflash/milestones/M4_Nixon.htm. Accessed Page 1 June 9, 2014.
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iii National Institute for Human Genome Research. "genetic testing rules." Http://www.genome.gov/10002335. Accessed Page 1 June 9, 2014.
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iv science Progress. "A brief history of genetic testing." Http://scienceprogress.org/08/05/a-brief-history-of-genetic-testing/. Accessed Page 2 June 9, 2014.
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v Cancer Research UK "Stalking the BRCA genes." http://scienceblog.cancerresearchuk.org/2012/02/28/high-impact-science-tracking-down-the-brca-genes-part-1/. Accessed June 9, 2014.
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iv Myriad Genetics "Brief History of Myriad." Https .: //www.myriad.com/about-myriad/history/. Accessed June 9, 2014.
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viii Nature. "Mutations of the BRAF gene in human cancer." Http://www.ncbi.nlm.nih.gov/pubmed/22453012. Accessed June 9, 2014.
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xi Gangadhar, Tara., Schuchter, Lynn. "Explosion recent progress in melanoma mangament catalyst for change in the future direction of research" 1. June 2014. http://am.asco.org/recent-explosion-progress-melanoma-management-catalyst-change-future-directions-research. Accessed on page 2 9 June 2014
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xiii Robert, C. Rouiller, J., C. Kannengiesser et al. "Study of BRAF mutations in melanoma and nevi mutation patients germline CDKN2A gene in the" Journal of Clinical Oncology. 06 . http://meeting.ascopubs.org/cgi/content/short/24/18_suppl/10075.Accessed June 16, 2014.
xiv Vultur A, J Villanueva , Herlyn M. "targeting BRAF in Advanced melanoma: a first step towards Manageable disease." Clin Cancer Res 2011: 1658 :. 63
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xv Banerji, U., Affolter, A. Judson, I., et al. "BRAF mutations and RNA in melanoma :. potential relationship to clinical response to HSP0 inhibitors". Mol Cancer Ther 08.
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xvi JA Jakob, RL Bassett, CS Ng , et al. "State NRAS Mutation is an independent prognostic factor in metastatic melanoma." Cancer. 2012; 4014-23.
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xvii Kumar, K., Angelini, S., Czene, K. "BRAF mutations in melanoma metastatic A possible association with clinical outcome." Clin Cancer Res . August 9, 03; 3362
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xix Cancer Network NCCN comprehensive national clinical practice Guidelines in oncology (NCCN Guidelines®):... Melanoma version 3 ;. 2014
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xxi McKinsey and Company. "personalized medicine :. The way forward ".
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