The biospecimen as the key to personalizing medicine - Future Medicine

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Personalized Medicine (2007) 4(4), 385–387. 385 part of. The biospecimen as the key to personalizing medicine. Carolyn Compton. National Cancer Institute,.
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E DITORIAL

The biospecimen as the key to personalizing medicine ‘In personalized medicine, biospecimens take center stage as the critical link between the biology of the patient and the patient’s disease and the design of a customized treatment plan that encompasses both’ Carolyn Compton National Cancer Institute, Room 10A31, 31 Center Drive, Bethesda, MD 20892-2580, USA Tel.: +1 301 402 1762; E-mail: comptcar@ mail.nih.gov

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In contrast to generic one-size-fits-all approaches, modern medicine aims to address the specific manifestations of the specific disease in the specific patient. Never before, however, has medical science had the technological capability to define all of these in such exquisite molecular detail. The development of powerful, high-throughput molecular technologies has made it possible to envision an era of medicine in which molecular analysis will define susceptibility to disease, classify disease by molecular profile and delineate potential treatment targets on which customized therapeutic regimens will be based. Altogether, this vision of personalized medicine is compelling and foresees the ability to treat patients with more specificity and efficacy but fewer adverse events, to more accurately determine disease predisposition in healthy individuals, and to pre-empt disease initiation or progression in a targeted fashion. The concept drives most of the major strategic initiatives of the National Institutes of Health and the National Cancer Institute (NCI), and it is the principle behind recently drafted congressional bills such as the ‘Genomics and Personalized Medicine Act of 2007’. As evidenced by the recent report from the US Secretary of Health and Human Services entitled ‘Personalized Health Care’ [101], the transformation of clinical imperatives by the integration of scientific and technological advances to patient care is both inevitable and imminent. Patient biospecimens, such as cells, tissues, blood and serum, have long been central to the practice of medicine as the key to patients’ pathobiology and the source of analytes for diagnosis. In personalized medicine, biospecimens take center stage as the critical link

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between the biology of the patient and the patient’s disease and the design of a customized treatment plan that encompasses both. The analysis of tumor tissues, for example, would reveal the specific constellation of aberrant molecular elements that would constitute potential targets for highly directed therapeutic intervention. Validation of approaches based on this paradigm, patient- and disease-specific molecular analysis data, must be derived from biological specimens in an accurate and reproducible manner. This, in turn, requires that the biospecimens themselves be annotated, collected, processed and, if necessary, stored and/or distributed according to standards that ensure their quality. In short, the reliability of the molecular data derived from patient specimens is dictated by the quality of the specimens from which they were derived; the well-known aphorism for the worst-case scenario being ‘garbage in, garbage out’. In point of fact, the era of personalized medicine has already begun. The first steps have been taken in the evolution of tumor classification, disease prognosis, molecularly targeted treatment and response to therapy based on molecular features. These represent some of the most important advances in cancer medicine over the past decade, but their development has been utterly dependent on the availability of highquality biospecimens. Illustrative examples of the key role of biospecimens in developing and validating targeted therapies for tumors are described below: • Using tumor specimens from the NCI Cooperative Breast Cancer Tissue Resource, investigators demonstrated that the HER-2/Neu receptor is amplified in 20–30% of breast cancer cases. An antibody developed to this receptor (trastuzumab or Herceptin®) was found to be effective against breast cancers with HER-2/neu overexpression and is now standard of care for such tumors; • Molecular profiling studies performed on biospecimens representing a variety of different tumor types found that a mutant form of KIT, a protein related to BCR-ABL, is responsible Personalized Medicine (2007) 4(4), 385–387

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for the progression of gastrointestinal stromal tumors (GISTs). From this observation, it was hypothesized that imatinib mesylate or Gleevec®, a drug targeting the BCR-ABL protein that had originally been developed for the treatment of chronic myelogenous leukemia, could be used to treat GISTs. Subsequent clinical trials confirmed that the drug has unprecedented effectiveness in this disease and is now standard treatment for this tumor type; • Gefitinib or Iressa®, a commercially available anticancer drug that had been designed to target the epidermal growth factor receptor (EGFR), which was thought to contribute to lung cancer, was found to be clinically effective in only approximately 10% of lung cancer patients. Using samples of tumor tissue from strong responders, it was found that these cancers carried specific EGFR mutations and that this genetic marker could be used to predict Iressa responsiveness. Advanced technologies for molecular analysis are now exquisitely sensitive and specific, and many have the capacity for high throughput. Thus, the capacity to perform the type and amount of molecular profiling needed for personalized medicine is within reach. However, these very same improvements in molecular analysis technology have significantly raised the bar for molecular analyte quality and standardization. Powerful technologies that can detect minute molecular shifts in a biologic sample with great accuracy demand increased rigor in biospecimen acquisition and handling to achieve reproducible results. It is not clear whether enough biospecimens of sufficient quality currently exist to support research using these technologies and, if not, what is being doing to address this problem. Finally, the usefulness of biospecimens for the types of translational research needed to move medicine into the personalized era may also be limited by variation in the ways biospecimens are annotated with clinical data and consented for scientific use. Even biospecimens of the highest physical quality will be of little or no use in translational research if they lack high-quality clinical and pathological data or are not properly consented. The associated clinical data obtained from medical records must be accurate, complete and standardized across biospecimen collections in order to facilitate studies that link molecular profiles to patterns of disease progression and outcome. The integrity and quality of associated clinical and pathological data are becoming

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increasingly important as the research community sets its sights on answering the bigger questions in cancer with larger, population-scale studies. ‘…improvements in molecular analysis technology have significantly raised the bar for molecular analyte quality and standardization.’

Biospecimen collections have been stored by individual laboratories, private companies, community hospitals, academic medical centers and government institutions for various objectives since the mid-nineteenth century. According to an authoritative analysis published by RAND Corporation in 1999, there are over 300 million biospecimens stored in hundreds of biorepositories across the USA [1]. That number is probably far greater today. However, the full potential of these repositories as scientific resources has never been realized because the biorepositories employ widely varying procedures for quality control, storage, annotation and patient consent. This variation makes it difficult, or even impossible, for the research community to compare and validate results derived from the use of these biospecimens. Both within the USA and internationally, there are a number of ongoing efforts to create large-scale resources in which biospecimens are collected, stored and distributed under a new system of standards, quality control, data sharing and access. Increased patient participation in building these biospecimen collections will depend upon the implementation of guarantees of medical record privacy, legislation and enforcement of protections against genetic discrimination and the creation of very clear informed consent guidelines for the use of biospecimens and their data. Examples of largescale biobanking efforts that are addressing these challenges include: • UK National Cancer Tissue Resource, which comprises a large-scale network of acquisition and processing centers for tumor biospecimens; • UK Biobank, which is recruiting up to half a million participants between the ages of 45 and 69 years to contribute blood samples, lifestyle details and medical histories to create a large biospecimen resource for epidemiological studies; • Biobank Japan, which is creating a large-scale DNA repository, with blood samples and associated clinical information from over 300,000 individuals;

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Biospecimens and personalized medicine – EDITORIAL

• Kaiser Permanente, which has launched a large-scale campaign among more than 2 million subscribers with the goal of soliciting 500,000 volunteers to provide blood or saliva specimens for genetic analysis to study how lifestyle, environmental factors and genes interact to contribute to diseases such diabetes, asthma and cancer; • US Department of Veterans Affairs, which has launched a pilot project to gather 100,000 biospecimens, with the aim of linking certain diseases to the genetic makeup of the biospecimen donors. With its large patient base and well-established electronic health-record system, the Veterans Affairs is well positioned to successfully expand this effort. ‘The development of powerful, high-throughput molecular technologies has made it possible to envision an era of medicine in which molecular analysis will define susceptibility to disease, classify disease by molecular profile and delineate potential treatment targets on which customized therapeutic regimens will be based.’

The NCI has recently led several efforts to establish best practices for biospecimen resources, which will help to ensure that the quality standards for the research needed to further personalized medicine are recognized and implemented throughout the research enterprise, thereby furthering personalized medicine. These include the establishment of the NCI Office of Biorepositories and Biospecimen Research; the development of the National Biospecimen Network Blueprint (providing a framework of recommendations for standardized informed consent, privacy of Health

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Insurance Portability and Accountability Act-protected patient information, biorepository operating procedures, researcher access to biospecimens, and quality control for data and specimens); hosting of the first International Summit on Harmonization of Biorepositories; and issuance of the Draft First-Generation Guidelines for NCI-supported Biorepositories, now revised in accordance with public comment and renamed NCI Best Practices for Biospecimen Resources [102]. While large biorepositories are clearly increasing in number and incorporating standardized procedures for biospecimen and data handling, much work remains to be done to achieve the vision of national and/or global resources that can support the scale and precision of molecular analyses needed to accelerate progress towards personalized medicine. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Bibliography 1.

Eiseman E, Haga SB: Handbook of Human Tissue Sources. A National Resource of Human Tissue Samples. RAND, Washington, USA (1999).

Website 101. US Department of Health and Human Services:

Personalized Health Care: Opportunities, Pathways, Resources (2007) www.hhs.gov/myhealthcare/ 102. Office of Biorepositories and Biospecimen Research http://biospecimens.cancer.gov

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