Background The Center for Cancer Genomics (CCG) at the National Cancer Institute (NCI) was established in 2011 with a mission to lead the NCI efforts in generating critical datasets required to catalog the alterations seen in human tumors, coordinating data unification and sharing efforts, and supporting development of analytical tools and computational approaches aimed at improving our understanding of the large-scale, multidimensional data. CCG also has the goal of developing and applying cutting-edge genomic science to prevent cancer and better treat cancer patients, for example in the context of NCI-supported clinical trials. Currently, several large-scale cancer genome research projects fall under the CCG umbrella including those managed by The Cancer Genome Atlas (TCGA) Program Office and the Office of Cancer Genomics (OCG). In addition, the CCG support genomics analyses in collaborative projects with other NCI Divisions. One such collaboration is with the Alchemist clinical trial sponsored by DCTD. The Biospecimen Core Respository (BCR) provides CCG with support for the acquisition of cancer biopsy samples, the derivation of nucleic acid analytes, and the curation of clinical data associated with CCG-sponsored genomic studies. The current goal of cancer clinical trials is to embrace the precision medicine paradigm in which the therapeutic response of patients is tailored to the individual molecular and cellular features of the tumors being treated. The NCI has embarked on a number of precision medicine initiatives, some of which are detailed below. Exceptional Responders Initiative The main focus of this initiative is to explore the molecular basis for why 1% to 10% of patients enrolled in clinical trials of single targeted agent therapies that are otherwise deemed ?failures? respond to these agents with a complete or partial remission of their disease. The goals are to decipher the molecular factors that may explain these ?exceptional responses?. The short term goal of a pilot effort will be to determine how effectively hypotheses can be generated from this approach that lead to new therapeutic strategies. The majority of single agent cancer drugs that enter Phase I and II clinical trials fail to show adequate tumor response for continued development. However, in many of these trials there are a few (1% to 10%) patients that have a significant response to the therapy. These ?failed? trials could be very informative with regard to molecular markers that predict a positive response to these single agent therapies in a small subset of patients, thus making these ?inactive? agents useful. Even later phase clinical trials may have a few patients that experience an exceptional response, such as a complete response, that occurs in 10% or less of patients. Examples of the utility of this approach exist already (e.g., mutations predicting sensitivity to everolimus and EGFR tyrosine kinase inhibitors). The Exceptional Responders initiative envisions that this genomic approach to understanding therapeutic responses may be broadly applicable in cancer. The ability of molecular technologies to stratify tumor types has resulted in many common cancers being separated into specific subtypes that respond to therapeutic agents in very different ways. Identifying additional molecular markers that are able to predict a clinical response in subsets of patients will render future cancer treatments more precise. The complete or partial ?exceptional responses? observed in this cohort of patients treated on ?failed? trials should provide new leads for future oncologic therapies. The feasibility of the Exceptional Responders paradigm will be assessed in 100 patients for whom reliable outcome data from patients treated on clinical trials with targeted monotherapies or targeted combinations. Tumor biopsy material will be obtained from these patients as well as germline tissue, if available. The tissue will undergo next generation whole exome resequencing and, if practical, whole transcriptome resequencing. If this proves feasible, the project can be expanded to include other therapy regimens. The success of the endeavor depends on having adequate tissue for analysis, robust analytical techniques/platforms, and reliable outcome data for patients who have been treated on defined and consistent drug regimens. Tissue and clinical data could be obtained from either NCI-supported or pharmaceutical industry trials where there is reliable outcome data, and perhaps from other sources. In addition, the Exceptional Responders initiative will collect publically available sequencing and clinical data from patients with exceptional therapeutic responses. Alchemist clinical trial The Alchemist trial seeks to capitalize on a number of events have converged to create an opportunity for significant clinical advances in the treatment of subsets of adjuvant lung cancer and to take the next step in biological characterization of lung cancer on a national level. Recently, two of the NCI-supported US Cooperative Clinical Trials groups have brought study proposals forward for evaluation in the NCI Thoracic Malignancy Steering Committee. Each proposal would select resectable patients according to a biomarker validated in the metastatic setting and test for a large clinical effect. The two markers, EGFR mutation and ALK-positivity, each have an incidence of about 5%-10% in the general lung adenocarcinoma population, so each study design would require screening of about 8000 patients. These two markers are mutually exclusive, so there is particular efficiency in screening one set of patients to identify those positive for one marker or the other. Surgical specimens will be available from this trial, providing adequate tissue for extensive analysis. While most of this tumor tissue obtained from a cooperative group clinical trial would be formalin-fixed, technical advances now allow extensive sequence characterization of this material. Although this project would launch based on the EGFR and ALK biomarkers, Alchemist serves as an open platform, and it is likely that if the infrastructure were put in place, additional studies could tap into the stream of biomarker-classified patients. In particular, tissues from all patients screened for the Alchemist trial would be available for comprehensive genomic analyses, for which the patients would be consented. Patients testing negative for the EGFR and ALK biomarkers will be given standard treatment and followed as a prospective cohort, with repeat biopsies obtained upon tumor relapse. Biospecimen Core Resource (BCR) The CCG BCR serves as a centralized tissue processing center and provides the biomolecules for the Center. In addition, the BCR collects and standardizes clinical annotations. Standard Operating Protocols (SOP) governed clinical data collection, sample collection, pathological examination, biomolecule (e.g., DNA and RNA) extractions, quality control, laboratory data collection, and biomolecule distribution to the Cancer Genome Characterization Centers and the Genome Sequencing Centers. The BCR ensures that samples and data are received under appropriate human subjects review and informed consent, and also that Material Transfer Agreements represented the policies of the NIH for this project. A major prerequisite of the genomics projects within CCG was the acquisition of high quality biospecimens. To meet this need, NCI established a network of clinical sites providing high quality, clinically annotated biospecimens to a centralized quality control and processing facility. This facility is the primary interface between CCG and the Tissue Source Sites that provide samples. It must be noted that the term ?high quality? refers not only to the histological and molecular properties of the tissue, but also to characteristics such as degree and quality of clinical annotation, the existence of appropriate informed consent provisions for the intended use of the biomolecules and data, collection and subsequent distribution under an Institutional Review Board (IRB) reviewed protocol, as well as unencumbered access for research use (e.g., intellectual property restrictions). CCG management chose to establish a centralized tissue processing model to ensure that process variables are minimized until their effects on the results of molecular analyses become well understood. This centralization specifically means that all operations to process tissue and data for any single cancer studied by CCG occur at the BCR, utilizing SOPs. This minimization of variance refers to the processes of biospecimen receipt, logistical and physical management, processing into analytes (the molecular extracts from tissue such as DNA and RNA), the subdivision of tissue, and finally distribution of tissue or analytes to the research sites with rigorous QC of all intermediate and final products along the workflow.

National Institute of Health (NIH)
Research and Development Contracts (N01)
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Saic-Frederick, Inc.
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