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Feb 1, 2014 (Vol. 34, No. 3)

Cancer Genomics Enters a New Era

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    Vast amounts of genomic discovery research have yet to be translated into routine clinical use. In the meantime, scientists continue to advance molecular diagnostics, building evidence to support its use in predicting the best therapeutic approaches.

    Each tumor is a unique evolutionary process with an individual genealogy. Comparing the DNA sequences of tumors with those of normal tissues typically gives little information about disease-process dynamics. RNA profiling can be enlightening, but this technique, like DNA sequencing, is complicated by enormous signal-to-noise problems.

    “Signal to noise is a major issue. Most diagnostic approaches do not even think about it or how to deal with it,” explained Lee Hood, M.D., Ph.D., co-founder and board member of Integrated Diagnostics and co-founder and president of the Institute for Systems Biology.

    “Blood illustrates disease dynamics in a way that diseased tissue cannot, for you can follow disease progression and therapeutic response,” added Dr. Hood. “That is an enormous benefit in evaluating disease onset and progression. In cases where a clean phenotype separates disease from normal, blood proteins will be the disease diagnostic of the future. In the end, proteins are the biomarkers closest to the biological action.”

    Three million lung nodules are identified annually, 600,000 of which fall into an intermediate category. Surgical results indicate that 50–60% of intermediate-category tumors are benign nodules, creating unnecessary system costs.

    Integrated Diagnostics’ Xpresys Lung molecular-blood test provides noninvasive, objective information for assessing pulmonary nodules. The test is intended to measure the relative abundance of 13 proteins across multiple lung cancer disease pathways. These proteins, selected from almost 400 candidates, constitute a panel that can identify 60–70% of benign nodules, eliminating unnecessary surgical intervention.

    The 13 proteins map into three major disease-perturbed networks for small cell lung cancer. These pathways reflect the biological disease process. After additional optimization and validation, these biomarkers may allow observation of disease progression and therapeutic response.

    “I believe that in five years, blood diagnostics are going to be the key disease diagnostics,” asserted Dr. Hood. “Furthermore, these diagnostics have the ability to stratify complex diseases into subgroups to better gauge therapeutic reactions.”

    Dr. Hood predicted that a new medicine is coming: “In 10 years, every patient will be surrounded by a virtual data cloud with billions of data points. We will learn how to reduce that data dimensionality for each individual to discover their internal, external, and environmental stimuli to optimize their health. In the beginning it will be crude, but with time it will become more powerful.”

    According to Dr. Hood, the new medicine will be predictive, personalized, preventive, and participatory—or “P4,” to be succinct. “Molecular diagnostics will provide the tools to identify and predict disease. Systems approaches will generate preventive drugs or vaccines, plus the focus on wellness will be a powerful preventive. ‘Participatory’ is the largest challenge. All stakeholders have to accept this new transformation of medicine.”

    “It is a very exciting time in diagnostics. We are right at the beginning of a revolution and it is going to be really transformational,” concluded Dr. Hood.

  • Integrated Genomic Analyses

    Lung cancer is particularly amenable to genomic-based therapies. Work substantiating this observation has been carried out by Trever Bivona, M.D., Ph.D., an assistant professor of medicine/hematology-oncology at the University of California, San Francisco (UCSF). According to Dr. Bivona, UCSF’s Helen Diller Family Comprehensive Cancer Center has been using whole exome and transcriptome deep sequencing for nearly a year to systematically identify molecular biomarkers of response and resistance to specific targeted therapies in lung cancers.

    Data are synthesized in a clinical time frame and used to direct the mechanism-based treatment of lung cancer patients, after the research-grade test results are validated in a CLIA setting.

    The approach provides a comprehensive and unbiased view of the genetic architecture of each individual patient’s tumor, and can unlock the genetic secrets of tumor initiation and progression. This enables a context-specific understanding of the molecular pathogenesis along with biologically precise, individualized therapies that improve patient outcomes.

  • Barriers to Acceptance

    Barriers slow the translation of discovery work into clinical application. Next-generation sequencing (NGS) platforms present bioinformatics challenges that the modern pathology laboratory is not equipped to deal with. And with the exception of the large teaching hospitals, there are very few community physicians that have a great degree of facility with genomics.

    “If you do not understand the tests underlying the diagnostic, it is not going to be part of the evidence base that you use to make therapeutic choices. We have a huge job in front of us to train physicians so they understand the value of ’omics in the context of clinical care,” explained Elaine R. Mardis, Ph.D., professor of genetics and molecular microbiology at the Washington University School of Medicine and co-director of the university’s Genome Institute.

    Reimbursement remains a confusing landscape. Some single-gene tests—for example, EGFR mutations for lung cancer—are standard-of-care and covered under insurance. Larger tests that look at multiple, hundreds, or all genes need to demonstrate clinical efficacy, and to be packaged into a palatable bite for payers. All of these parameters need to be satisfied for the successful introduction of genomics as an element for routine cancer patient care.

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