Cancer Biomarkers The Promises and Challenges of Improving Detection and Treatment (2007) / Chapter Skim
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2 Methods, Tools, and Resources Needed to Discover and Develop Biomarkers
2 Methods, Tools, and Resources Needed to Discover and Develop Biomarkers
Pages 29-72
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From page 29... ...
. As a result, there has been a flood of new data and renewed interest in discovering novel biomarkers for use in drug development and patient care.
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From page 30... ...
However, identifying biomarker patterns or specific changes in genes or the products of gene expression in tumors is only the beginning of the process to develop cancer biomarkers. Before a candidate biomarker can be put into use, it must undergo several stages of confirmation, validation, and qualification for use (Wagner, 2002; Feng et al., 2004; Ransohoff, 2004, 2005; Simon, 2005; De Bortoli and Biglia, 2006)
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From page 31... ...
For example, in the drug development process, biomarkers can play a role at many different stages, from early, exploratory research to surrogacy for a clinical endpoint in large clinical trials, and the required degree of validation increases along that continuum (Table 2-2; see also Table 1-2)
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raloxifene can reduce the risk of invasive breast cancer without significantly reducing the incidence of ductal carcinoma in situ, a preinvasive lesion with potential to develop into invasive cancer (NSABP, 2006)
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The design, conduct, and interpretation of randomized clinical trials to assess medical interventions place high importance on ensuring that the treated and untreated patient populations are similar in every respect except for the treatment to avoid biases that could affect the outcome and thus the conclusions drawn from the results. However, most research on molecular markers for diagnosis or prognosis entails observational studies, in which it is difficult or impossible to ensure or even fully assess the similarity of the comparison groups, and which are much more likely to result in biased conclusions as a result.
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THE NEED FOR NEW, INNOVATIVE TECHNOLOGIES If the full potential of cancer biomarker-based tools in early detection, treatment, and drug development is to be realized, it will be important to optimize efforts to discover and validate putative biomarkers. Progress in biomarker discovery and development is directly dependent on the capacities of the technologies available.
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Metabolomics entails the study of metabolic responses to drugs, environmental changes, and diseases via identification of small-molecule metabolite profiles; that is, it attempts to measure the metabolic consequences of altered genes and protein expression. 1The Human Genome Project was an international research project to map each human gene and to completely sequence human DNA.
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, but much work remains to be done. There is a significant need for new and improved technologies for biomarker discovery and development, particularly in the field of proteomics.
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The Protein Structure Initiative (PSI) , a $600 million, 10-year venture funded by the National Center for Research Resources of the National Institute of General Medical Sciences, is a recent example of an NIH program that explicitly funded technology development in the initial phase of the project.
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has also recently launched new funding initiatives for proteomics research, noting that "current proteomic technology approaches are insufficient to reliably and reproducibly discover, identify, and quantify peptides and proteins of clinical significance for cancer" from complex patient samples. The NCI's Clinical Proteomic Technologies Initiative for Cancer program is a 5-year $104 million program that includes two funding opportunities for proteomics technology development: Advanced Proteomic Platforms and Computational Sciences (DHHS, 2005)
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focused on the development of novel, long-range technologies to support cancer research. The Program funded research through contracts instead of grants, allowing for enforcement of deadlines for specific milestones along the research track in order for researchers to
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are selected to be technically continue to receive funds. UIP management actively recruited the interest and involvement of investigators from disciplines that have not traditionally received support from NCI and assembled interdisciplinary research teams focused on cancer detection technologies, including nanotechnologies (IOM, 2003; NCI, 1999)
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The involvement of multiple federal agencies is important, as no single agency is likely to have the needed expertise to address all issues, but it will be important for one agency to take the lead in organizing intra-institutional efforts. Given NCI's current funding level and recent initiatives and interest in biomarker discovery and development, it may seem an obvious choice for the lead agency for this endeavor, but to date it has not yet developed an adequate overarching leadership strategy.
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. However, despite the common funding source, these biobanks BOX 2-2 Examples of Current NCI-Supported Specimen Resources • Cooperative Human Tissue Network • Tissue Array Research Program • Cooperative Breast Cancer Tissue Resource • Cooperative Prostate Cancer Tissue Resource • Clinical Trial Cooperative Group Human Tissue Resources • AIDS and Cancer Specimen Resource • The Cancer Family Registries • The Breast Cancer Intergroup of North America Specimen Resource • The Human Cancer Biospecimen Core Resource (for the Cancer Genome Atlas Pilot Project)
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. Nonetheless, in 2005, NCI established the Office of Biorepositories and Biospecimen Research with the objective of improving and standardizing biobanking activities and to facilitate the establishment of a National Biospecimen Network (NCI, 2006b)
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For example, it is important to develop consensus on common data elements for collecting patient information and to make this information and samples easily accessible to researchers. NCI's Early Detection Research Network has made considerable progress in this regard and provides a good model for how to proceed with other biospecimen collections (NCI, 2005, Figure 2-1)
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The committee notes that some privately established biorepositories have been quite successful in dealing with some of the issues that NCI is grappling with, and much could be learned from their example. The Multiple Myeloma Research Consortium Tissue and Data Bank is a prime example (Box 2-3)
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From page 46... ...
NIH should also initiate and sustain funding of biorepositories that are created in conjunction with large cohort studies and clinical trials, and use of these prospectively collected samples should be encouraged for validating biomarkers. When clinical trials end or funding for cohort studies is not renewed, the ability to maintain the biorepositories created in conjunction with the study is often lost (Goodman et al., 2006)
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However, MMRC is currently working on a $6 million, 3-year genomic sequencing project, the Multiple Myeloma Genomic Initiative, and plans to release all data generated from the project into the public domain. The long-term goal of MMRC is to make all data from every project accessible to the public.
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For example, validating a surrogate endpoint requires costly and lengthy clinical studies. As such, companies inevitably find it cheaper and faster to directly measure the primary endpoint of interest for a particular drug than to first validate the surrogate marker (Fleming, 2005)
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, and collaborative efforts have already been successful in biomarker development as well. For instance, the HIV Surrogate Markers Collaborative Group, established through multiple partnerships among academia, industry, and government, confirmed the usefulness of HIV RNA as a surrogate marker for testing new anti-HIV drugs.
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semiconductor suppliers develop next-generation production tools and facilitated manufacturer supplier communication and collaboration. It also encouraged semiconductor manufacturers to come to consensus about future needs, so that equipment manufacturers were held to just one set of industry specifications rather than different standards for each company.
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with the goal of improving cancer therapeutics and patient outcomes through biomarker development and evaluation. The OBQI aims to facilitate the codevelopment of diagnostic-therapeutic combinations and to reduce the time and cost of drug development by shortening clinical trials through enriched patient populations more likely to respond to therapies.
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All DNA contributions were anonymous, voluntary, and obtained with informed consent. SNP data were regularly validated by internal quality control assessment and by external auditors; the estimated validation rate of both internal and external analysis was 95 percent.
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A more cooperative and comprehensive approach that attempts to leverage and integrate all available data could have an enormous impact on the field. Such efforts could lead to better biomarkers for the entire spectrum of cancer health care, from early detection and disease classification to drug development and treatment planning and monitoring (Bast et al., 2005; Dalton and Friend, 2006)
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DEMONSTRATION PROJECTS TO DEVELOP BIOMARKERS FOR DRUGS ALREADY APPROVED Most drugs are effective in only a fraction of the patients who receive them (Spear et al., 2001)
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Major Foci: • Validate predictive, preclinical animal model biomarkers to reduce the cost and time of preclinical safety studies • Provide public access to validated tools • Provide potential early indicators of clinical safety in drug development and postmarket surveillance • Provide new tools for FDA to assist in regulatory decision making Example -- Warfarin Pharmacogenetics Project: Improper dosing of warfarin causes unnecessary health care spending and trauma for patients. Genetic variation contributes significantly to dosing variability.
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An umbrella legal counsel was set up so that projects could be quickly and efficiently initi ated using a nonprofit research consortium. Key Features: • No real infrastructure or standing staff -- mostly outsourcing and borrowing/sharing • Biomedical research-focused mission, research focused by-laws and charter • Pooling of talent, experience, and required specialized consortia skills • Antitrust protection • Independent data handling and release • Execution of desired regulatory standards Serious Adverse Events Consortium In April 2006, the FDA approached the PBRC to develop and lead an industry-driven, nonprofit consortium focused on drug-induced seri ous adverse events (SAEs)
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Furthermore, these efforts are not coordinated or unified through data sharing or by a common strategy. Federal agencies and other funders should therefore support demonstration projects to discover and develop biomarkers that can predict the safety and effectiveness of FDA-approved oncology drugs in individual patients,
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Another potentially informative case of how pharmacogenomics might be used to predict the effectiveness of a drug is a body of work undertaken to understand the variability in response to the antiestrogen tamoxifen in breast cancer patients (Box 2-8)
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Furthermore, much of the heterogeneity among cancer patients can be traced to differences in the specific pathways that have been modified in each tumor. Decades of research have gradually led to the identification and delineation of the pathways that control these vital cell functions, and recent advances in developing molecularly targeted therapies, like imatinib and trastuzumab, are derived from that increased understanding of signaling pathways.
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Endoxi fen is present at about 10-fold higher concentrations than 4-OH-Tam, and the concentration of endoxifen varies a great deal among breast cancer patients. Much of this variability appears to be due to the genetic differences in CYP2D6, the main enzyme that generates endoxifen.
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On October 18, 2006, the FDA's Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science recommended that the FDA revise tamoxifen's drug label to include a warning that postmenopausal women who are CYP2D6 poor metabolizers and are taking tamoxifen to treat breast cancer have an increased risk for breast cancer recurrence. The subcommittee also recommended that the label should include a warning that certain antidepressants may reduce tamoxifen's effectiveness.
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. An annual report from the President's Cancer Panel concluded that "the translational research infrastructure is inadequate to enable the work that needs to be done; resources must be committed to develop the tools and workforce required.
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. Although not a traditional NIH funding focus, several recent initiatives have been undertaken to foster translational research.
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Indeed, NCI has noted that the development of new diagnostic tests, cancer treatments, and other interventions that benefit people with cancer and people at risk for cancer will rely on strong translational research collaborations between basic and clinical scientists to generate novel approaches (NCI, 2006d)
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From page 65... ...
NCI in particular should actively encourage and facilitate interaction between biomarker developers and clinical trials groups to enable this prospective collection of patient samples. Collectively, these strategies could lead to better biomarkers for the entire spectrum of cancer health care, from early detection and disease classification to drug development and treatment planning and monitoring, and they could bring personalized medicine closer to being a reality.
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2004. Dose density in adjuvant chemotherapy for breast cancer.
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2004. Mass spectrometry as a diagnostic and a cancer biomarker discovery tool: Opportunities and potential limitations.
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2006. NCI's translational research uncoordinated, advisors say.
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2005. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.
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Presentation at the meeting of the National Cancer Policy Forum, Washington, DC. MMRC (Multiple Myeloma Research Consortium)
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1997. Evolving concepts in the systemic drug therapy of breast cancer.
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2002. Overview of biomarkers and surrogate endpoints in drug development.
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