Search Results - EGA European Genome-phenome Archive

Genomic Profiling of Rare Tumors

Utilizing the rare and unique patient samples provided by Pattern Medicine, LLC, MD Anderson will molecularly characterize rare cancer samples, and potentially generate a collection of preclinical models to enable identification of novel therapeutic targets and concepts, as well as evaluation of innovative treatment strategies.

Study phs003916

Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program –Sarcoma, Kidney, and Liver Cancers

The goal was to complete whole exome sequencing (WES) and RNA sequencing (RNA-Seq) on patient derived xenograft samples. Cancer in children is rare with approximately 15,700 new cases diagnosed annually in children 21 years or younger in the U.S. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be 'cured' of their disease, and 5-year Event-Free Survival (EFS) exceeds 80%. Consequently, the number of patients that can be enrolled in phase I/II clinical trials is small, and most patients will have been extensively treated, hence drug/radiation resistant. Thus, preclinical studies that accurately translate into effective clinical therapy are an essential component of pediatric drug development. Our group has contributed to studies in the Pediatric Preclinical Testing Program (PPTP) and Pediatric Preclinical Testing Consortium (PPTC) that have led to clinical studies through Children's Oncology Group (COG). Of importance, we have developed and characterized over 330 Patient Derived Xenografts (PDX), developed from tumors both at diagnosis and relapse, that can be used to facilitate pediatric drug development as directed by FDA under the Research to Accelerate Cures and Equity for Children Act (RACE for Children Act).

Study phs003160

NCTN: Phase III Randomized Study of Sorafenib Plus Doxorubicin versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) (CALGB-80802)

Study ID: CALGB-80802NCT Number: NCT01015833 Alliance for Clinical Trials in OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: Phase III Randomized Study of Sorafenib plus Doxorubicin versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) (CALGB-80802)Trial Description: This randomized phase III trial studies sorafenib tosylate and doxorubicin hydrochloride to see how well they work compared with sorafenib tosylate alone in treating patients with liver cancer that has spread to nearby tissue or lymph nodes or has spread to other places in the body. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving sorafenib tosylate together with doxorubicin hydrochloride is more effective than sorafenib tosylate alone in treating liver cancer. Data presented in the following publication(s): PMID 31486832 Disease type(s): Gastrointestinal Neoplasm - Liver and Hepatobiliary CancerClinical Dataset(s) included:NCT01015833-D1 (PMID 31486832): Dataset NCT01015833-D1 is the only dataset associated with PubMed ID 31486832. This dataset contains baseline characteristics, treatment arm and number of cycles, treatment discontinuation reasons, hepatitis status, toxicity, and survival data.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004239

Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

Study phs003641

Integrating Circulating Tumor DNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer

DNA was isolated from pre-treatment and mid-treatment plasma samples and matched germline samples from patients undergoing chemoradiation therapy for stage IIB-IIIB non-small cell lung cancer. Sequencing libraries were hybrid captured using custom selector pools designed to target genes frequently mutated in non-small cell lung cancer prior to ultra-deep next generation sequencing.

Study phs003947

Dynamic Evolution of Fibroblasts Revealed by Single Cell RNA Sequencing of Human Pancreatic Cancer

Understanding the constituents of the pancreatic ductal adenocarcinoma (PDAC) microenvironment may illuminate more efficacious targets for treating this aggressive malignancy. However, the compositional changes occurring in untreated and treated PDAC relative to both normal and inflamed pancreas have not been well characterized. To provide a more comprehensive understanding of the PDAC tumor microenvironment relative to the non-cancerous pancreas, we performed single-cell expression profiling (10X Genomics Chromium) on samples of upfront resectable PDAC, FOLFIRINOX-based treated PDAC, chronic pancreatitis, and normal pancreas specimens from 19 patients. Spatial gene expression profiling (10X Genomics Visium) was performed to gain additional insight into cell populations. Our analysis revealed that fibroblasts are central mediators of cell-cell communication in both inflamed and malignant settings and defined unique roles for these cell populations in different disease contexts.

Study phs003751

Blood and Marrow Transplant Clinical Trials Network - A Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell/Myeloma Fusions (BMT CTN-1401-BioLINCC)

Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To compare response at one year post transplant between participants receiving dendritic cell/myeloma vaccine along with granulocyte macrophage colony-stimulating factor (GM-CSF) and lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF.Background: The advent of combination biologic therapy for multiple myeloma (MM) has significantly improved patient outcomes. Induction therapy followed by consolidation with autologous hematopoietic stem cell transplantation (auto-HCT) prolongs progression-free survival in patients with MM. The addition of post-transplant lenalidomide maintenance therapy further extends the duration of remission. However, the vast majority of patients ultimately experience disease progression due to the emergence of resistant disease. The development of strategies to enhance the durability of post-transplant response remains a major unmet need in the field. Since MM is associated with immune suppression, the development of cancer vaccines is being investigated in MM with the goal of stimulating tumor-specific immunity. Dendritic cells (DC) are the most potent antigen-presenting cells that prominently express costimulatory signaling necessary for optimal T-cell activation, cross-presentation of antigen to reactive CD8 T cells, and the development of primary immunity. The BMT CTN developed a personalized cancer vaccine in which patient-derived tumor cells are fused with autologous monocyte-derived DCs. The BMT CTN-1401 study examined the efficacy of the DC/MM fusion vaccine in conjunction with lenalidomide maintenance therapy after auto-HCT, compared with maintenance alone.Participants: Participants with symptomatic MM were eligible if they were 18-70 years old, were candidates for auto-HCT, had a Karnofsky Performance status of ≥70%, had >20% plasma cells in the bone marrow aspirate differential A total of 140 participants were randomized. 68 participants were randomized to the vaccine arm, 37 to the lenalidomide plus GM-CSF arm, and 35 to the lenalidomide alone arm.Design: BMT CTN-1401 was a phase II, multicenter, open label trial. All participants underwent bone marrow aspiration following enrollment. Myeloma cells were isolated, preserved, and for participants randomized to the vaccine arm, used for vaccine generation. All participants received standard-of-care induction therapy and auto-HCT conditioned with melphalan. Participants were randomized approximately 2 months post-transplant. Participants were randomized in a 2:1:1 ratio to the vaccine arm (DC/MM vaccine, GM-CSF, plus lenalidomide), or one of two control arms (lenalidomide plus GM-CSF or lenalidomide alone). All participants began maintenance lenalidomide between day 90 and 100 post-transplant at a dose of 10 mg a day for 28 days of a 28-day cycle. On day 1 of cycles 2, 3, and 4 of lenalidomide maintenance, patients assigned to the vaccine arm underwent subcutaneous administration of the DC/MM fusion vaccine along with 100 μg GM-CSF administered subcutaneously adjacent to the vaccine site on days 1 to 4. Participants randomized to the control arms received either lenalidomide alone or lenalidomide with GM-CSF at the same dose and schedule as the vaccine arm.The primary outcome was a comparison of participants in complete response (CR)/stringent CR (sCR) at 1-year post-transplant between the vaccine and control arms. The primary immunologic endpoint of the study was a comparison of the percentage of circulating multiple myeloma–reactive T cells between participants in the vaccine and control arms. PFS (progression-free survival) and OS (overall survival) were secondary endpoints of the study.Conclusions: There was not a statistically significant difference in the percentage of participants achieving complete response 1-year post-transplant in the vaccine arm compared to the control arms.

Study phs004718

NCTN: Postoperative Chemotherapy With or Without Bevacizumab for Patients With Stage II or III Rectal Cancer (E5204)

Study ID: E5204NCT Number: NCT00303628 ECOG-ACRIN Cancer Research GroupSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 5-Fluorouracil, Leucovorin and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Pre-operative Chemoradiation (E5204)Trial Description: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating rectal cancer. This randomized phase III trial is studying combination chemotherapy to see how well it works with or without bevacizumab in treating patients who have had surgery for stage II or stage III rectal cancer. Clinical data presented in the following publication(s):PMID 31852811 Disease type(s): Gastrointestinal Neoplasm - Colorectal CancerClinical dataset(s) included:NCT00303628-D1 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D1, contains baseline characteristics, stratification factors, surgery information, treatment, second primary cancer and efficacy data. NCT00303628-D2 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D2, contains toxicity data. NCT00303628-D3 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D3, contains PRO Bowel function/uniscale data. NCT00303628-D4 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D4, contains PRO FACT-Diarrhea Data. NCT00303628-D5 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D5, contains PRO FACT/GOG-Ntx Data. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004621

Establishment and Genomic Validation of Novel Patient-Derived Xenograft Models for Drug Discovery in Gastrointestinal Stromal Tumor

This dataset contains targeted next-generation sequencing data generated with the Illumina TruSight Oncology 500 (TSO500) assay from six gastrointestinal stromal tumors (GIST) and matched patient-derived xenograft (PDX) models established at Fox Chase Cancer Center (Philadelphia, PA). GIST are most commonly driven by activating mutations in KIT or PDGFRA, and this study focused on KIT-mutant tumors. All PDXs were derived from metastatic patient tumors previously treated with one or more tyrosine kinase inhibitors (TKIs). PDXs were maintained through series of passages and represents in vivo models of differential TKI sensitivity. The dataset represents a detailed comparison of mutational profiles between primary tumors and corresponding PDXs across passages, enabling studies of genomic stability, resistance mechanisms, and the evaluation of novel therapeutic strategies in GIST.

Study phs004185

The Electronic Medical Records and GEnomics Network Genomic Risk Assessment (eMERGE IV)

The eMERGE (electronic MEdical Records and GEnomics) network enrolled ~25,000 individuals not typically involved in research in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report along with recommended actions. The GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports and was returned to participants, their providers, and their EHR. The network is examining the uptake of care recommendations after return of results.Children's Hospital of Philadelphia (CHOP)The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP) with the primary goal of translating basic research findings to medical innovations. The mission of CAG is to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders. We aim to discover genetic causes for the most prevalent diseases of childhood including ADHD, asthma, autism, diabetes, epilepsy, obesity, schizophrenia, pediatric cancer, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. Our participants are recruited from the CHOP Health Care Network, which includes over 50 sites throughout Pennsylvania and New Jersey, 100% of which use Epic EMR system. This constitutes the country's largest pediatric integrated delivery system, supporting >1.1 million visits/year within the primary and specialty care networks, community-based inpatient pediatric and neonatal programs, a rehabilitation hospital, and a home care service. It provides acute- and well-care to patients in urban, rural, and suburban settings.Cincinnati Children's Hospital Medical Center (CCHMC)CCHMC has proposed ambitious initiatives for eMERGE IV. The major goals are to generate, return as appropriate along with clinical recommendations, individualized genomic risk assessments that include polygenic risk scores for 2500 minority participants ascertained on dyads (mother/child) and extended to families (dyad + biologic father, siblings). The informatics initiatives include integration of electronic medical records and development, implementation and evaluation of clinical decision support at two different hospital systems, one pediatric and one adult. Participant preferences, education needs, and ethical and social implications will be studied throughout the 5 year period. Columbia UniversityColumbia University in partnership with the New York-Presbyterian hospital has a long and strong tradition of patient-centered research and community engagement in the urban, medically underserved communities of Washington Heights and Harlem in Northern Manhattan, and has established Precision Medicine as a major university-wide initiative (PMI), of which eMERGE is a vital program. We possess broad and deep expertise in clinical genetics, genomics, informatics, EHR phenotyping, systems biology, public health, and ELSI, including return of genetic results and secondary findings to diverse patients. Columbia will share lessons learned in linking EHR and sequence data for genomic decision support, developing scalable genomic education methods and assessing the impact of returning genetic results on patients, families, and clinicians. We are poised to contribute novel comprehensive risk prediction and management solutions for diverse patients as part of eMERGE IV efforts.Icahn School of Medicine at Mt. Sinai (Mt. Sinai)Mt. Sinai investigators have been at the center of many NHGRI-led genomic research (GSP, PAGE) and genomic medicine (eMERGE, CSER, IGNITE) consortia. Building on our decade-long track record in genomic research, clinical trials, and genomic medicine in diverse, underserved patients from New York City, we propose to develop new frameworks to bring genomic risk into clinical care to promote health equity. In addition to genomic discovery and risk prediction, we are creating analytical and data resources, and digital health applications tailored to diverse populations, as part of the eMERGE IV Network. The Mt. Sinai team is composed of clinicians and scientists who work closely with community members and industry partners to develop flexible and innovative strategies to bring leading-edge research into clinical care. Having recently announced a large institutional investment to scale the integration of genomics and artificial intelligence into patient care, Mt. Sinai is poised to contribute to eMERGE IV's mission to implement and learn from genomic risk assessment in clinical care. Mt. Sinai's team will contribute to progress in multiple areas across eMERGE, including developing and deploying electronic phenotypes; discovering new genotype-phenotype associations; and facilitating the communication of genomic results to patients and their healthcare providers.Mass General BrighamThe eMERGE IV Clinical Center at Mass General Brigham leverages a large biobank, clinical data in the electronic health records (EHR) for >6 million patients from the largest integrated health care provider in New England, advanced bioinformatics expertise, prior leadership in PRS development, established expertise in returning genomics results, and experience using information technology to transform clinical processes and assess medical, behavioral and economic outcomes. We have developed highly specific machine learning algorithms for e-phenotypes and implemented eMERGE algorithms for multiple phenotypes and have considerable experience in developing decision support tools and analyzing outcomes that can be leveraged to study the integration of PRS data into clinical practice. We will test the hypothesis that PRS will allow us to stratify eMERGE participants based on genetic risk for common complex traits. We will focus on coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer and depression in GWAS populations and validate multi-ethnic PRS in the Mass General Brigham Biobank and eMERGE III dataset. We will conduct an analysis of the effect of disclosing results to high risk participants to determine how personalized results changed patient outcomes in laboratory values, risk reduction behaviors, or health care utilization.Mayo Clinic (Mayo)The goal of Mayo eMERGE investigators is to leverage the electronic health record (EHR) for genomic discovery and to implement genomic medicine to improve health care outcomes, working closely with other eMERGE sites and the Mayo Center for Individualized Medicine. In eMERGE I we used genotype data and electronic phenotyping algorithms for genomic discovery. In eMERGE II we conducted a clinical trial of disclosing a polygenic risk score (PRS) for coronary heart disease (CHD) and placed pharmacogenomic variants in the EHR with linkage to clinical decision support (CDS). In eMERGE III, we returned actionable findings from targeted sequencing of 68 genes and collaborated with a Federally Qualified Health Center (FQHC) to bring genomic medicine to an under-represented population. In eMERGE IV, as part of the Genomic Risk Assessment & Management Network, we will test the hypothesis that individuals at high polygenic risk for common diseases will have a higher uptake of risk reduction measures than those at lower risk. We will build on our prior work in genomic discovery, EHR integration and return of results (RoR) to develop and validate PRS and combine these with clinical risk scores and family history to compute comprehensive risk profiles for 2500 individuals. Our prior work in disclosing a PRS for CHD to research participants as part of a comprehensive risk profile enables us to efficiently expand the approach to other common diseases that pose a significant public health burden. To assess the utility of PRSs, we will recruit 1800 adults and 200 adolescents from Rochester MN and 500 adults from Phoenix AZ. DNA will be sent for CLIA-certified genomic testing and we will calculate ancestry specific PRSs for each participant. Individualized risk estimates will be reported to participants and health care providers (HCPs) and placed in the EHR with linkage to CDS that includes guideline-based risk-management information. For participants who are at significantly higher polygenic risk of developing at least 1 of the diseases, results will be disclosed in-person by a HCP followed by assessment of outcomes including new tests ordered, risk reduction measures, and changes in modifiable risk factors. We will examine the economic, behavioral and psychosocial implications of returning PRS. Our focus on PRS for common cardiovascular diseases brings genomic medicine to the population. We will continue our partnership with Mountain Park Health Center, a FQHC serving low-income, minority communities in Phoenix AZ, to address concerns about health disparities in the context of genomic medicine.Northwestern University (NU)Northwestern University is dedicated to translational genomics, with a strong focus on unified, interdisciplinary research bridging the informatics, clinical, basic science, and bioethics domains. Over the phases of eMERGE, Northwestern has applied this interdisciplinary approach to study the feasibility, utility, outcomes, and effectiveness of EHR-linked genomic information as a member of the network. Particular areas of focus include: novel informatics approaches to integrate genomic results into EHR systems; development of open-source, EHR-based phenotyping algorithms to empower translational research across a variety of clinical domains; and studies of participant, patient, and provider interaction with EHR-based genomic results. In phase IV of eMERGE, Northwestern is building on this expertise to develop, deploy, and evaluate systems of EHR-based, genomics-guided clinical risk assessment and management tools across a variety of common, impactful conditions. Northwestern's cross-disciplinary approach to this work is empowered by an innovative smartphone app to consolidate outreach, enrollment, engagement, return of results, and dissemination of health education materials surrounding genetic risk and risk management. Focusing recruitment on community-based clinics, Northwestern aims to engage participants from communities that, though not traditionally included in academic research settings, could benefit significantly from these risk management approaches. By combining expertise in informatics and EHR integration with innovative return-of-results strategies rooted in behavior theory, Northwestern aims to provide valuable data on accuracy, utility, and uptake of genetic risk assessment as the field moves towards integrating genetic risk scores into clinical practice.University of Alabama at Birmingham (UAB)Our eMERGE team aims to bring our experience and expertise in research with medically underserved (>75%) populations to identify genomic signatures of common diseases, conduct genomic risk assessments within the clinical workflow and where appropriate, pre-treat at-risk patients with common diseases including diabetes, chronic obstructive pulmonary disease, obesity, coronary artery disease and prostate cancer. Our aims will also allow us to develop genomic risk assessments, and address challenges involved in bringing genomic medicine into routine medical care. Working with the eMERGE network, we will select the eleven diseases of public health impact and select polygenic risk scores for clinical implementation. We will conduct an ethical legal social implications (ELSI) study, to explore patient perspectives on the use of family history and polygenic risk scores for estimating disease risk among Alabama Genomic Health Initiative (a statewide cohort) participants. The results will inform the development of consent, educational materials, and a communication strategy to enhance recruitment and retention of eMERGE participants. Recruiting over 75% of patients from medically underserved communities, we will incorporate genomic risk, family history, and clinical data to identify high-risk patients, recommending risk reduction recommendations in concordance with practice guidelines. For high-risk patients, we will deploy clinical decision support and present the genomic risk assessments and risk reduction recommendations. We will assess three outcomes: uptake of recommendations (implementation outcome), adherence to clinic visits (engagement outcome), and surrogates of disease/control (clinical outcome; e.g. blood sugar, cholesterol). We bring our expertise and experience to collaborate with the eMERGE investigative team to leverage the power of genomics to prevent disease.University of Washington (UW)The eMERGE IV Northwest partnership includes clinicians, scientists, and professionals in other fields from University of Washington (UW) Medicine, UW Health Sciences, the Fred Hutchinson Cancer Research Center, and the Brotman Baty Institute for Precision Medicine. The eMERGE IV Northwest partnership aims to evaluate the use of genomic information in the health care of diverse participants at the University of UW. Our site is expected to lead work on the prediction of colon cancer, glaucoma, and cardiovascular disease; other conditions expected to be studied include diabetes, liver disease, high cholesterol, and osteoporosis. Working with our eMERGE colleagues, we will aggregate, into a single score that informs about the risk of a disease, a participant's polygenic test information, which looks at variants from across the genome, as well as other known risk factors, such as personal and family medical history, environmental and social determinants, and physical and lab results. This score would let clinicians know which patients might benefit from screenings or other interventions to reduce the risk of disease or make an early diagnosis. In addition to experts specializing in each of the medical conditions that are the focus of the Northwest site, leaders in health economics, and in the ethical and societal aspects of genomics and health care will also be part of the research team. Medical, as well as economic, outcomes will be measured. Stakeholder engagement will be encouraged to obtain comments from participants and their families.Vanderbilt University Medical Center (VUMC)Vanderbilt University Medical Center has embraced Personalized Health and Healthcare as a key pillar of our Research Strategic Plan. This institutional commitment has taken multiple forms including the development of key infrastructure resources (the institutional Biobank (BioVU); the program in preemptive pharmacogenetic testing; the genotyping and sequencing core) and support of faculty in key disciplines such as genomics, informatics, ethics, privacy science, and clinical pharmacology. VUMC's team has contributed importantly to progress in multiple areas across eMERGE, including developing and deploying phenotype algorithms; developing and managing the genotype quality control pipeline for the network (eMERGE I); discovering new genotype-phenotype relations in VUMC and cross-network datasets; actively participating in the PGx clinical implementation project, community consultation, and return of results initiatives; developing methods to resolve tensions between data access and individual privacy; developing sampling methodology for the CERC survey; and developing new software tools for the field, including for developing and validating phenotypes, de-identification and for the phenome-wide association study paradigm (“PheWAS”)eMERGE Network Coordinating Center (CC)Vanderbilt University Medical Center has been the coordinating center of the eMERGE Network since inception. During this phase of eMERGE we have partnered with the Broad Institute to to add expertise in large-scale genotyping, cloud computing, and genomic data analysis and management, and with Duke University to leverage its proficiency in the implementation of patient-oriented family history tools and delivery of risk assessments. To meet the needs of the Network, the CC continues to serve NHGRI, the Network, and its members in all coordination, communication, and collaboration functions while providing a nationally visible home for eMERGE authored tools and scientific productivity. The CC is also assisting the Network with selecting and validating polygenic risk scores (PRS) for approximately eleven complex diseases and developing genomic risk assessments (GRAs) which combine the PRS with other clinical risks, family history, and monogenic risks. Finally, The CC will coordinate a prospective study for 25,000 participants which calculates clinical and genomic risks for participants and their providers. In addition to providing the genotyping and PRS reporting services, we will develop with the Network scalable EHR-based methods to assess uptake of risk-reduction recommendations and clinical impact.

Study phs003905

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined with Nivolumab and Ipilimumab for Patients with Resected MMR-p Colorectal and Pancreatic Cancer

Phase 1 study for patients with resected PDAC after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic colorectal cancer who have exposure to 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with poly-ICLC adjuvant in combination with nivolumab and ipilimumab.

Study phs003425

Genomic Landscape and Preclinical Therapeutic Insights Developed from Xenograft, Organoid, and Cell Line Models in the NCI's Patient-Derived Models Repository

Patient-derived xenografts (PDXs), organoids (PDOrgs), and two-dimensional cell cultures (PDCs) are powerful tools for translational cancer research. The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR) features preclinical models from primary and metastatic lesions across a broad array of solid tumors, including rare and pediatric cancers, each annotated with genomic data as well as clinical information about the patient from whom the model originated (https://pdmr.cancer.gov). We used these models to demonstrate stable propagation of genomic aberrations over multiple passages, to evaluate patient-specific tumor heterogeneity, and to examine the relationship of the preclinical activity of a panel of approved and investigational anticancer agents in PDXs and PDOrgs to known levels of therapeutic activity in the clinic.

Study phs003984

Comprehensive Genomic Data Deposition for Pancreatic Cancer Precision Medicine Studies: Clinical Trials NCT02451982 and NCT02648282

This submission includes specimens from 89 pancreatic cancer patients at Johns Hopkins Hospital, comprising 41 surgically resectable and 48 locally advanced pancreatic cancer (LAPC) cases. These samples originate from two clinical studies, NCT02451982 and NCT02648282, following the Johns Hopkins Medical Institution Institutional Review Board-approved registry protocol at the Pancreatic Cancer Precision Medicine Center of Excellence Program. Written consent for specimen use, obtained from participants in the original studies, covers additional research, including this one. Biopsy specimens collected through endoscopic ultrasound-guided fine needle core biopsies or surgically resected tumors are included. NCT02451982 is a platform trial evaluating immunotherapy combinations for surgically resectable pancreatic ductal adenocarcinoma in the neo-adjuvant and adjuvant settings. It investigates the GVAX pancreatic cancer vaccine with immune-boosting cyclophosphamide, exploring immune cell trafficking and the impact of PD-1 blocking. NCT02648282 focuses on the efficacy and safety of combining cyclophosphamide, pembrolizumab, GVAX, and stereotactic body radiotherapy (SBRT) in locally advanced pancreatic cancer, with an emphasis on anti-tumor activity. Both studies provide valuable insights into innovative pancreatic cancer treatment approaches.

Study phs003600

NCTN: A Non-Randomized Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed High Risk Hodgkin Lymphoma (AHOD0831)

Study ID: AHOD0831NCT Number: NCT01026220Children's Oncology Group (COG)Submitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Non-Randomized Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed High Risk Hodgkin Lymphoma (AHOD0831)Trial Description: This phase III trial is studying how well giving combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed Hodgkin lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells. Clinical data presented in the following publication(s):PMID 31180135Disease type(s): Hematopoietic Neoplasm/Lymphoma - Hodgkin LymphomaClinical Dataset(s) included:NCT01026220-D1 (PMID 31180135): There is one dataset for AHOD0831's primary publication 31180135. This dataset contains patient demographics, baseline characteristics, PET results, and survival endpoints. This dataset is presented at patient level and includes one record per patient.You are encouraged to view the PDF data dictionaries found in the "Documents" tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004161

Multi-Modal Single-Cell, Spatial, and Genomic Analyses of Human Non-Small Cell Lung Cancer Brain Metastases

We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of 12 treatment-naive non-small cell lung cancer (NSCLC) primary tumors (PTs) and 31 treatment-naive NSCLC brain metastases (BMs). In total, we recovered 277,206 cell transcriptomes in 43 samples. Single-nuclei suspension from frozen NSCLC metastases were generated using methods published in Slyper et al. (Nature Medicine, 2020, PMID:32405060) with modifications. The tissue was first cut in 20 µm sections using a cryostat and stored on dry ice until the next step. Then the tissue was put on wet ice and washed once with 5 ml PBS to remove OCT. After this step nuclei were extracted by vigorous pipetting in salt-tris buffer with Tween-20 (TST) followed by a high-volume wash in salt-tris buffer (ST). Nuclei were counted and 10,000-14,000 and were loaded using a Chromium controller (10X genomics) and Chromium Single Cell 5' Reagents (V1.1 and V2). Complementary DNA libraries were generated according to manufacturer's instructions, with the modification of one additional cycle of amplification. Matched single nuclei T cell receptor (snTCR) sequencing libraries were prepared from amplified cDNA libraries using either Chromium Single Cell V(D)J Enrichment Kit for human T cells Reagent Kit, v1.1, or single cell human TCR amplification kit. Final snTCR sequencing libraries were prepared using Single Index Kit T Set A for V1.1 libraries or Library construction kit and Dual Index Kit TT set A for V2 libraries. Sequencing libraries were quantified using Tapestation D5000 reagents and a 2200 TapeStation and pooled for sequencing. Pool matched low pass whole-genome sequencing (lp-WGS) was performed in addition to snRNA-seq to improve the identification of the malignant and non-malignant cell compartments. Nuclei from snRNA-seq sample preparations were collected by centrifugation (500g, 5 min), snap frozen after removing excess ST buffer, and stored at -200C until further processing. If insufficient nuclei (0C for 9 minutes. Adapters were not diluted, and the optional PCR (5 cycles) and cleanup were performed. After library cleanup with AMPure beads (Beckman Coulter, Brea, CA), libraries were quantified with Tapestation D5000 HS tapes (Agilent) and stored at -200C until sequencing.Using multiplexed immunofluorescence in an independent cohort of treatment-naïve pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features that strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

Study phs003865

NCORP: Vitamin D and Breast Cancer Biomarkers (CALGB-70806)

Study ID: CALGB-70806NCT Number: NCT01224678 Alliance for Clinical Trials in OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCORP: Vitamin D and Breast Cancer Biomarkers (CALGB-70806)Trial Description: RATIONALE: Vitamin D may help prevent breast cancer.PURPOSE: This randomized clinical trial is studying vitamin D and breast cancer biomarkers in female patients. Clinical data presented in the following publication(s):PMID 33849913 Disease type(s): Breast Neoplasm - Breast Neoplasm, MiscellaneousNon-neoplastic Disorder - Non-neoplastic Disorder, MiscellaneousClinical Dataset(s) included:NCT01224678-D1 (PMID 33849913): Dataset NCT01224678-D1 is one of 2 datasets associated with PubMed ID 33849913. This dataset contains baseline and change in breast density, baseline characteristics, change in Vitamin D levels, and off treatment reasons.NCT01224678-D2 (PMID 33849913): Dataset NCT01224678-D2 is one of 2 datasets associated with PubMed ID 33849913. This dataset contains data presented in the safety analyses.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004250

Disentangling the Effect of Black/African Ancestry from Confounding Variables on Colorectal Cancer Biology

This study examined the effect of African ancestry on AI assisted computation of tumor infiltrating lymphocytes (TIL%) scores from hematoxylin and eosin stained whole slide images (WSI) assembled from three cohorts: 1.) African vs. European ancestry WSI downloaded from the TCGA-COAD-READ database; 2.) African vs. European ancestry WSI assembled from three US medical centers; 3.) Nigerian WSI assembled from a single Nigerian medical center. There were 33 African ancestry WSI suitable for analysis in the TCGA cohort and 48 African ancestry WSI in the independent US cohort. In addition to self-described African ancestry, the additional independent covariables were: 1.) Mismatch repair enzyme-deficient/ microsatellite instability-high vs. MMR-proficient/MSI-Low +microsatellite stable (MMR-d/MSI-H vs. MMR-p/MSI-L+MSS); 2.) Categorical age at diagnosis/resection (75 y); 3.) Sex (Male vs. Female); tumor location (Right vs. Left + Rectum); tumor stage (I+II vs. III+IV), tumor grade [G1+ G1/G2+G2 vs. G2/G3 +G3+mucinous (regardless of G)]. For the 242 TCGA cohort there were 241 parallel whole transcriptome data generated from parallel frozen tumor samples. For the independent US cohort there were 87 parallel targeted whole exome transcriptome data generated from the same formalin fixed paraffin embedded (FFPE) block. The TCGA and independent US cohort computed TIL% scores were correlated separately with CIBERSORTx derived total lymphocyte and T-cell abundance scores, and with CXCL10 and CCL5 gene expression values. mRNA gene expression count data (from STAR processing of the RNA-sequence data) and WSI for the subjects used in this study are available from the Genome Data Commons (GDC).

Study phs004622

Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer: DNA and RNA Sequencing

This randomized phase II trial studies how well paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. All participants in this study were female. RNA sequencing (RNA-Seq) data from the same patients were previously published under phs001863. This comprehensive dataset (phs003801) includes all data published under phs001863 and new RNA and DNA data for patients in CALGB 40603.

Study phs003801

Germline Sequence Variation in Cancer Genes Among Rwandan Breast and Prostate Cancer Cases

Inherited genetic information can reduce cancer risk and mortality using protocols for patient ascertainment, testing, counseling, prevention, and treatment. For example, carriers of germline BRCA1/BRCA2 or Lynch Syndrome mutations are at increased risk of breast, ovarian, prostate, endometrial, colorectal, and other cancers. Genetic testing is of clinical value because many mutations are actionable in reducing risk or determining appropriate treatment regimens. There is growing evidence that inherited genetic mutations represent a large proportion of cancer cases in sub-Saharan Africa (SSA). It is also well known that most cancer genetic testing data does not represent the racial and ethnic diversity of the US or global population. Despite the high proportion of cancer cases diagnosed at an early age and late stage, as well as the potential for interventions to reduce cancer risk and death by using genetic tools, genetic testing, counseling, and clinical management protocols have largely not been widely developed in SSA. In order to develop and evaluate the potential for genetic testing in SSA, we propose to undertake a proof of concept feasibility study of hereditary cancer that will contribute data on the prevalence of hereditary cancer mutations in SSA and inform the development of SSA-specific guidelines for cancer genetic testing. In this study, we undertook a pilot evaluation of research genetic testing and counseling in breast and prostate cancer cases in Rwanda that involved genetic testing of breast and prostate cancer cases.

Study phs003927

DNA Repair Capacity for Lung Disease Risk Assessment

A focus of this work was to address the extent to which susceptibility for lung cancer varies by gene-environment-phenotype interactions involving DNA repair capacity and differences in risk from environmental stressors. GWAS from a subset of subjects from the Lovelace Smokers Cohort and New Mexico Lung Cancer cohort were used to derive polygenic risk scores for DNA repair pathways (nucleotide excision, base excision, single strand break, non-homologous, homologous recombination). Logistic regression analysis was used to examine the association between polygenic risk score and lung cancer status. Polygenic risk scores were grouped by quartiles. Only diminished base excision repair was associated with increased risk for lung cancer at the 25-50% quartile and approached significance at the 50-75% quartile.

Study phs004063

National Cancer Institute Multi-Ancestry Genome-Wide Association Study of Kidney Cancer (NCI-3)

The National Cancer Institute (NCI) multi-ancestral genome-wide association study (GWAS) of kidney cancer ("NCI-3") was performed by NCI to further investigate common genetic variants associated with risk of kidney cancer and its two major subtypes across individuals of different ancestries (European, African, East Asian, Latin American). The NCI-3 GWAS includes 12,315 cases and 73,091 controls from 25 centers in North America, South America and Europe, genotyped using the Illumina Global Screening Array v2.0. SNP-level results from this GWAS were combined by meta-analysis with results from two earlier NCI European-ancestry GWAS (RCC; phs000351: 1,311 cases and 3,424 controls and phs001736: 2,417 cases and 4,391 controls), a NCI GWAS of African Americans (phs000863; 255 cases and 375 controls), GWAS conducted at other institutions [International Agency for Research on Cancer (scan 1: 2,438 cases and 5,071 controls; scan 2: 2,781 cases and 2,940 controls), The University of Texas MD Anderson Cancer Center (scan 1: 893 cases and 556 controls, scan 2: 1,241 cases and 1,712 controls) and the Institute for Cancer Research, UK (944 cases and 4,024 controls)] and GWAS analyses of data from three large biobanks (Biobank Japan: 523 cases and 86,306 controls; FinnGen: 2,095 cases and 304,956 controls; UK Biobank: 1,807 cases and 348,824 controls). Only individual-level data from NCI-3 and the two MD Anderson Cancer Center scans are included in this dbGaP submission. All study-specific and meta-analysis summary statistics are included.

Study phs003505

Rearrangements of Viral and Human Genomes at Human Papillomavirus Integration Events and Their Allele-Specific Impacts on Cancer Genome Regulation

We discovered genomic and epigenomic dysregulation originating at sites of human papillomavirus (HPV) integration following the Oxford Nanopore long-read analysis of 72 cervical cancer genomes. The integration events had allele-specific effects on the genome, methylome, and transcriptome, which sometimes resulted in the activation of cancer genes. We also examined the 72 samples using Illumina short-read analysis in phs000528. We also produced long-read cDNA-sequencing data on 29 cervical cancer samples from phs000528 (of which 27 also have long-read WGS data available) for further analysis of HPV-human transcripts derived from HPV integration events.

Study phs003780

HINTS Geo-Coded Data 2019 (HINTS 5 Cycle 3)

The Health Information National Trends Survey (HINTS) is a nationally representative survey which has been administered every few years by the National Cancer Institute since 2003. HINTS 5 includes four mail-mode data collection cycles over the course of four years. The third round of data collection for HINTS 5 (Cycle 3) was conducted from January 22 to April 30, 2019 with a goal of obtaining 3,500 completed questionnaires. A push-to-web pilot test was conducted alongside the fielding of Cycle 3 (referred to as the Web Pilot). The Web Pilot was conducted from January 29 to May 7, 2019 with a goal of obtaining 2,046 additional completed questionnaires. A total of 5,438 respondents are included in the final sample.

Study phs004216

Incidental Detection of Maternal Neoplasia through Non-Invasive Cell-Free DNA Analysis (IDENTIFY), a Natural History Study

Prenatal cell-free (cf) DNA sequencing for fetal aneuploidy incidentally detects circulating tumor DNA in the plasma of asymptomatic pregnant women. Distinguishing the subset of women with malignant tumors detected by prenatal sequencing from those with benign conditions, such as uterine fibroids, is critical to maternal medical management. The Incidental Detection of Maternal Neoplasia Through Non-Invasive Cell-Free DNA Sequencing (IDENTIFY) study at the National Institutes of Health in Bethesda, MD, offers standardized cancer screening and cfDNA sequencing to asymptomatic or minimally symptomatic pregnant women with nonreportable prenatal cfDNA sequencing results. We previously reported that whole-body magnetic resonance imaging (WB-MRI) and a specific genome-wide sequencing pattern of chromosomal gains and losses involving three or more chromosomes could reliably differentiate which women had cancer. We continue to explore additional noninvasive biomarkers to identify the subset of women with nonreportable prenatal cfDNA sequencing results who have cancer and to predict tissues of origin, particularly when patients or their providers are reluctant to pursue diagnostic testing, WB-MRI studies are unavailable, or imaging findings are indeterminate. Here, cfDNA sequence analysis was performed to identify cancer driver somatic mutations that might aid in distinguishing between pregnant women who have a high likelihood of occult malignancy from those who do not. In this pilot study, prospectively collected blood samples from 65 pregnant or postpartum women with and without occult cancers were analyzed blindly for cfDNA somatic mutations in 275 cancer-associated genes.

Study phs004107

GU16-257: Neoadjuvant Gemcitabine, Cisplatin, Plus Nivolumab in Patients with Muscle-Invasive Bladder Cancer with Selective Bladder Sparing

This is a phase 2 trial seeking to define the safety and activity of gemcitabine, cisplatin, plus nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer and to define the role of clinical complete response (cCR) in predicting benefit in patients opting to avoid cystectomy. Primary Objectives Determine the cCR rate with gemcitabine, cisplatin, plus nivolumab;Determine the ability of cCR (cT0 or cTa) to predict benefit from treatment. Benefit was defined as, among the patients achieving a cCR, either being (a) 2-year metastasis-free in patients forgoing immediate cystectomy or (b) FindingsSeventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of the 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1).

Study phs003372

Methylation-Based Immune Deconvolution in Prostate Cancer Patients Before and After Radical Prostatectomy

To explore whether surgical treatment for prostate cancer leads to long-term immune changes, we conducted a pilot study of n=11 prostate cancer patients treated with radical prostatectomy. We also included n=8 patients managed with active surveillance as a comparison group. We examined intra-individual changes in circulating immune cell subsets using serial blood samples collected pre- and approximately 6-months post-prostatectomy, and from matched time points for the patients managed on active surveillance. Immune cell subsets were deconvoluted using genome-wide methylation data. We observed no meaningful changes in circulating immune cell subsets in either patient group, suggesting that any surgery-induced immune changes to the circulating immune profile may not be long-lasting. The genome-wide methylation data from the two time points will be made available through dbGaP.

Study phs003660

A Prospective Study of the Oral Microbiome and Pancreatic Cancer

Two prospective cohort studies - the Black Women's Health Study and the Southern Community Cohort Study - were used to investigate the oral microbiome in relation to pancreatic cancer risk. Using a nested case-control study design, 148 cases and 510 matched controls were included (122 Black American pancreatic cancer cases and 409 matched controls). DNA was extracted from oral wash samples, using the PowerSoil Pro kit. Paired-end whole metagenomic shotgun sequencing was performed, using the Illumina HiSeq2000 platform with a read length of 100 bp (insert size 350 bp).

Study phs002454

Integrative Analysis for Multi-Omics Data in Non-Small-Cell Lung Cancer

We conducted epigenetic and transcriptomic mapping of primary non-small cell lung tumors and non-neoplastic tissues. 20 non-neoplastic lung tissues and 18 non-small cell lung tumors were obtained from Biorepository and Tissue Technology Shared Resource at Moores Cancer Center, UC San Diego. All tumor samples were in pathological stages I and II. 8 pairs of samples were "matched", meaning that the tumor and normal tissues came from the same patient. Microfluidic oscillatory washing–based chromatin immunoprecipitation followed by sequencing (MOWChIP-seq) was used to profile the binding of H3K4me1, H3K4me3, H3K9me3, H3K27ac and H3K27me3. SmartSeq-2 was used to map mRNA expression. We identified a large number of differentially modified regions for both epigenetic and transcriptomic markers between tumors and normal tissues. Deep learning model showed extensive transcription factor network rewiring. Raw sequencing data of the ChIP-seq and RNA-seq libraries are available through this dbGaP submission.

Study phs003113

APOLLO-BRCA-1: Proteogenomic Analysis of Invasive Breast Tumors in Young (less than 40 years old) vs Older Patients (greater than or equal to 60 years old)

Breast cancer in women under the age of 40, accounting for ~5% of breast cancer diagnosed in the U.S., is more aggressive with worse outcomes than breast cancer in older women. The aim of this study is to to identify molecular features that may underlie the worse outcomes in young women with breast cancer. We performed a first-ever integrated proteogenomic study from a matched cohort of laser-microdissected tumors of 34 young (age Proteomic Data Commons at the National Cancer Institute.

Study phs003636

Kids First: Genomic Analysis of Pediatric Rhabdomyosarcoma

The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the genomic and phenotypic data from this study are accessible through dbGaP. The data is also available at the Kids First Portal, where other Kids First datasets can also be accessed in the cloud for data analysis, data visualization, collaboration and interoperability, open to all researchers and developers. Rhabdomyosarcoma (RMS) is one of the most common and deadly sarcomas in children and adolescents, but very little is known about its genetic epidemiology. This study will explore the role of new (i.e., de novo) mutations in both known cancer predisposition genes and novel susceptibility genes on the risk of RMS. A better understanding of the genetic risks for RMS may lead to prevention strategies, better risk stratification, and even the identification of new therapeutic targets.

Study phs004306

Detecting and Subtyping Lung Cancer Through Analysis of Circulating Tumor DNA

Small cell lung cancer (SCLC) is among the most aggressive tumors with poor clinical outcomes. Tumors are rarely resected, which is a major barrier to molecular profiling of tumor tissue; therefore, non-invasive approaches using circulating tumor DNA (ctDNA) from liquid biopsies are needed to help advance research and clinical care for patients with SCLC. We developed a targeted capture panel that profiles SCLC genes and transcriptional regulation sites, including transcription start sites (TSS) and transcription factor binding sites (TFBS). This is a single assay that detects genomic mutations and transcriptional regulation activity based on ctDNA fragment patterns reflecting epigenetic nucleosomal positions. We applied this assay to sequence patient-derived xenograft (PDX) and patient plasma samples. We also performed whole genome sequencing (WGS) for a subset of the PDX plasma samples to validate the capture data. We developed new algorithms to quantify activity of key SCLC marker genes of ASCL1, NEUROD1, POU2F3, and ATOH1 and to classify SCLC subtypes based on activity of these markers. Furthermore, we developed a model to classify SCLC from non-small cell lung cancer (NSCLC), which has potential important applications for monitoring transdifferentiation and tumor plasticity.

Study phs003570

NRG-GY017: Atezolizumab before and/or with Chemoradiotherapy in Immune System Activation in Patients with Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer

Locally advanced cervical cancer remains an area of high therapeutic unmet need, with ~50% of patients developing disease recurrence despite treatment with chemotherapy combined with radiation. Combination of immune checkpoint blockade with chemoradiation has been explored in this setting, but optimal sequencing of these modalities is unknown. To address this question, we developed and conducted the NCI sponsored trial “Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently with Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer”, randomizing patients to atezolizumab administration prior to and concurrent with chemoradiation therapy (CRT) vs. concurrent with CRT (NRG-GY017; N=40, ClinicalTrials.gov Identifier: NCT03738228). Patients were randomized to atezolizumab neoadjuvant and concurrent (Arm A) or concurrent with CRT (Arm B). The study closed to successful accrual of 36 evaluable patients in June 2020. Out of 40 patients consented patients, 4 were never treated. The reasons for that are: 2 were screen failures, 1 withdrew consent, and 1 was not treated due to physician preference. The study incorporated comprehensive collection of pre- and on-treatment tumor biopsies as well as multitime point blood collections. T cell receptor (TCR) sequencing was performed on the tumors as well as pre- and on-treatment peripheral blood, and the data are included with dbGaP submission. Among the 36 eligible and treated patients, there were 30 (17 on Arm A and 13 on Arm B) with pre- and on-treatment peripheral TCR sequencing data. Twenty-five patients (14 in Arm A and 11 in Arm B) had additional tumor TCR sequencing data available, which enabled tracking of tumor-associated TCR clones in peripheral blood. We demonstrate that neoadjuvant atezolizumab administration results in peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B and is associated with favorable 2-year disease-free survival (DFS). No new safety signals were identified. These findings support further evaluation of the neoadjuvant IO and CRT sequencing strategy in locally advanced cervical cancer.

Study phs003833

NCTN: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome (AAML1531)

Study ID: AAML1531 NCT Number: NCT02521493 Children's Oncology Group (COG) Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome (AAML1531) Trial Description: This phase III trial studies response-based chemotherapy in treating newly diagnosed acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Response-based chemotherapy separates patients into different risk groups and treats them according to how they respond to the first course of treatment (Induction I). Response-based treatment may be effective in treating acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome while reducing the side effects. Clinical data presented in the following publication(s): • PMID 34320162 Disease type(s): • Hematopoietic Neoplasm/Leukemia - Acute Myeloid Leukemia • Hematopoietic Neoplasm/Leukemia - Myelodysplastic Syndrome Clinical Dataset(s) included:• NCT02521493-D1 (PMID 34320162): There are 2 datasets associated with PMID 34320162, NCT02521493-D1 through NCT02521493-D2. The NCT02521493-D1 dataset is a patient level dataset (single row per patient) containing patient characteristics, laboratory findings (hemoglobin, peripheral WBC, peripheral platelet), cytogenetics, outcome (overall survival and event-free survival), neutrophil recovery, ICU admission, select toxicity data, and targeted sequencing data for eligible myeloid leukemia in children with Down syndrome (ML-DS) enrolled on the AAML1531 clinical trial. • NCT02521493-D2 (PMID 34320162): There are 2 datasets associated with PMID 34320162, NCT02521493-D1 through NCT02521493-D2. The NCT02521493-D2 dataset is an adverse event level dataset (single row per adverse event, period, and patient) containing information of the micro-organisms associated with adverse events by period in the AAML1531 clinical trial. Additional genomic data are available for this trial under phs002187.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004081

Genomic Alterations in Normal Breast Tissues Preceding Breast Cancer Diagnosis (GANPBC)

This study was designed to examine the genomic alterations in histologically normal breast tissues of women who subsequently developed breast cancer and compare it to breast tissues from women who did not. Breast core needle biopsy tissues from 160 healthy women at the Susan G. Komen Tissue Bank were requested for this study and sequenced using whole exome sequencing. The samples included tissues from 79 participants who, during the annual follow-up with Susan G. Komen self-reported a subsequent diagnosis of invasive or non-invasive breast cancer after tissue submission; these cases were classified as pre-diagnosis normal tissues. The remaining 81 samples were from women who had no cancer diagnosis at their last follow-up and were classified as healthy control samples. Among the pre-diagnosis samples, the average time from tissue donation to breast cancer diagnosis was 4.7 years (range: 0-11). For the healthy controls, the average time from tissue donation to the last follow up was 6.1 years (range: 0-14).

Study phs003822

NCTN: A Randomized Double-Blinded Phase III Study Comparing Gemcitabine, Cisplatin, and Bevacizumab to Gemcitabine, Cisplatin, and Placebo in Patients with Advanced Transitional Cell Carcinoma (CALGB-90601)

Study ID: CALGB-90601NCT Number: NCT00942331 Alliance for Clinical Trials in OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Randomized Double-Blinded Phase III Study Comparing Gemcitabine, Cisplatin, and Bevacizumab to Gemcitabine, Cisplatin, and Placebo in Patients with Advanced Transitional Cell Carcinoma (CALGB-90601)Trial Description: This randomized phase III trial studies gemcitabine hydrochloride, cisplatin, and bevacizumab to see how well they work compared with gemcitabine hydrochloride and cisplatin in treating patients with urinary tract cancer that has spread to other places in the body. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with bevacizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether gemcitabine hydrochloride and cisplatin are more effective when given with or without bevacizumab in treating patients with urinary tract cancer. Clinical data presented in the following publication(s):PMID 33989025 Disease type(s): Urothelial Tract Neoplasm - Urothelial Tract/Bladder CancerClinical Dataset(s) included:NCT00942331-D1 (PMID 33989025): Dataset NCT00942331-D1 is one of 3 datasets associated with PubMed ID 33989025. This dataset contains all patient level data including baseline characteristics, survival status and time to event, progression free survival and time to event, treatment summaries, off treatment reasons for chemotherapy and bev/placebo, best response, tumor scans, the occurrence of grade 3/4 thrombocytopenia, the occurrence of a serious adverse event, and the occurrence of a dose delay or reduction.NCT00942331-D2 (PMID 33989025): Dataset NCT00942331-D2 is one of 3 datasets associated with PubMed ID 33989025. This dataset contains dose modification reasons for all patients with at least one dose reduction or delay. There is also a variable distinguishing the dose modification between cisplatin and gemcitabine.NCT00942331-D3 (PMID 33989025): Dataset NCT00942331-D3 is one of 3 datasets associated with PubMed ID 33989025. This dataset contains adverse event information.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004243

Targeting SS18-SSX Biology in Synovial Sarcomagenesis

This study investigates the biological consequences of BRD9 degradation in synovial sarcoma, a cancer driven by the SS18::SSX (SSX1 or SSX2) fusion oncoprotein. The study includes human synovial sarcoma cell lines, patient-derived xenograft (PDX) models. Molecular profiling was performed using RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq).The primary aim was to determine how depletion of the GBAF chromatin remodeling complex subunit BRD9 affects chromatin remodeling activity, transcriptional regulation, and tumor growth in synovial sarcoma. The study found that BRD9 degradation does not disrupt GBAF complex assembly but instead enhances chromatin remodeling activity, maintains or increases chromatin accessibility, and promotes expression of SS18::SSX target genes despite reduced chromatin occupancy. These findings provide a mechanistic explanation for the limited clinical efficacy of BRD9 degraders in synovial sarcoma.Data available through dbGaP will include raw and processed human genomic and epigenomic datasets generated from patient-derived tumors, including RNA-seq, ChIP-seq, ATAC-seq, together with associated experimental and clinical metadata necessary for data interpretation.

Study phs004771

Sequencing of Rare Pancreatic Tumors That Respond to PD-1 Blockade

Pancreatic cancer is nearly always refractory to immunotherapy, except in a rare subset of patients whose tumors have a high mutational burden (TMB), usually due to mismatch-repair deficiency. We collected tumors and matched blood from patients with pancreatic cancer, some of whom had high-TMB disease. We performed single-cell RNA-seq analyses of those samples to understand the correlates in the pancreatic tumor microenvironment of productive responses to immunotherapy. We found that different T cell populations responded to PD-1 blockade in TMB-high vs TMB-low tumors. This dataset consists of Illumina NovaSeq sequencing output (as FASTQ files) for blood and tumor libraries prepared using 10X Genomics Single Cell 5' Immune Profiling kits. FASTQs are provided for GEX, TCR, and (for multiplexed samples) HTO libraries.

Study phs004257

Transfer Learning Associates CAFs with EMT and Inflammation in Tumor Cells in Human Tumors and Organoid Co-Culture in Pancreatic Ductal Adenocarcinoma

This study examined the transcriptional changes induced by cancer associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma patient-derived tumor organoids. We hypothesized that cancer associated fibroblasts impacted tumor cell transcription to promote tumorigenic behavior. Using patient-matched cells from 3 patients, we compared the transcriptional profiles of patient-derived organoids in monoculture to patient-derived organoids co-cultured with CAFs. Similarly, we looked at the transcriptional changes in matched patient-derived cancer associated fibroblasts grown in monoculture or co-cultured with patient-derived organoids. With a focus on intercellular crosstalk, we identified crosstalk between cancer associated fibroblasts and patient-derived organoids through VEGFA and NRP1. This was identified by bulk RNA sequencing and examined dynamically in organoid-CAF co-culture. This dbGaP deposit is the bulk RNA sequencing data for these 3 patients.

Study phs003563

Lung Cancer Genetic Study Among Asian Never Smokers

The Lung Cancer Genetic Study Among Asian Never Smokers includes data from four population-based studies conducted among Asian women: the Shanghai Women's Health Study (SWHS), the Hwasun Cancer Epidemiology Study (HCES1 and HCES2), the Female Lung Cancer Consortium in Asia (FLCCA, including sFLCA), and the Guangzhou Lung Cancer Study (GLCS). Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Lung cancer patients identified in the SWHS and non-cases were included in the current study.Hwasun Cancer Epidemiology Study-Lung Cancer (HCES1 and HCES2): The HCES is a hospital-based case-control study whose goal is to identify factors of the cancer development and clinical progression in a Korean population. Included in this project were 299 female lung cancer cases from HCES2, who were diagnosed between April 2004 and February 2013 at Chonnam National University Hwasun Hospital, a cancer specified hospital in Jeollanam-do province, South Korea. Controls were randomly selected from women with no previous cancer diagnosis at enrollment in the Namwon Study and the Dong-gu study, ongoing community-based cohort studies in South Korea. A total of 1,103 controls (273 from HCES1 and 830 from HCES2) were genotyped by MEGA. Guangzhou Lung Cancer Study (GLCS): The GLCS is a case-control study including never-smoking women lung cancer cases and controls from Guangzhou, China.In this study, the DNA samples of 1,195 subjects from SWHS and GLCS were genotyped using whole exome sequencing (WES), and the DNA samples of 7,174 subjects from SWHS, HCES1, HCES2, FLCCA, and sFLCA were genotyped using the Multi-Ethnic Global Array (MEGA).

Study phs002366

Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors

This phase Ib/II single-arm study evaluated atezolizumab + bevacizumab for patients with treatment-refractory metastatic HPV+ anal cancer. The primary endpoint was best overall response, and secondary endpoints included progression-free survival, overall survival, and safety/tolerability. Paired tissue biopsies were collected in patients before treatment and at the time of first restaging and analyzed for whole-exome sequencing, RNAseq (Bulk), and multiplex immunofluorescence. The overall response rate among 20 patients was 10%. WES and RNAseq data are provided here.

Study phs003845

A Clone's Genomic Stability as a Biomarker of Its DNA-Damage Resilience

A main problem in the treatment of advanced cancers, including gastric cancers and glioblastoma, is the incertitude at which we predict how individual patients will respond to DNA-damaging agents, especially on the long run. Knowing the mechanism behind a patient's response, or the lack thereof, will help us depart from the oversimplified “more-is-better” and “one-size-fits-all” principles according to which DNA-damaging agents are administered. This will improve clinical outcome by allowing us to pinpoint those who would respond better and longer to lower doses than to higher doses of DNA-damaging agents. Under the assumption that the success of DNA-damaging therapy increases with the proliferation rate of a relatively homogeneous tumor population, there was little reason to assume anything other than monotonic dose-response relations. With the recent paradigm shift that most cancers are in fact DNA mosaic products of ongoing evolution, comes the urgency to reconsider these fundamental principles behind DNA-damaging therapy administration. As the developers of one of the first DNA deconvolution methods and with access to technologies to profile the transcriptomes of up to 10,000 cells simultaneously, we are equipped to embark on first personalized dose-finding strategies for DNA-damaging therapies. We will test the potential of the very long-term legacy that DNA-damage entails on a cell “genomic instability” as new biomarker of DNA-damage response. Our preliminary studies showed that, for most cancer types, DNA-damaging agents change a clone's genomic instability and that clones succumb to a limit in the amount of genomic instability they can tolerate. In particular, our results showed that patients with intermediate genomic instability have a very poor outcome and that this relation is only evident among treatment-naive patients, but not among patients treated with DNA-damaging agents. Further they show that we can measure genomic instability per clone and that clones with extreme genomic instability typically don't grow large. Our hypothesis that genomic instability, rather than proliferation rate, determines how sensitive a tumor is to DNA-damaging agents on the long-term, is founded on two unexpected findings. Patients with extremely high genomic instability per tumor clone have an exceptionally good outcome. Aim 1 will integrate exome- and single cell RNA-Seq (scRNA-Seq) data to characterize clones and to measure how much genomic instability they can tolerate. Low genomic instability is associated with reduced benefit from DNA-damaging agents. Aim 2 will use comet assays and treatment history to quantify DNA damage per clone, relating it to the clones' ability to tolerate DNA damage and to changes in the genomic instability of therapy-surviving clones.

Study phs003762

NCTN: A Randomized Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid to Prevent Skeletal Related Events in Men with Prostate Cancer Metastatic to Bone (CALGB-90202)

Study ID: CALGB-90202NCT Number: NCT00079001Alliance for Clinical Trials in OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Randomized Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid to Prevent Skeletal Related Events in Men with Prostate Cancer Metastatic to Bone (CALGB-90202)Trial Description:RATIONALE: Zoledronate may prevent or decrease skeletal (bone)-related events (such as pain or fractures) caused by bone metastases and androgen deprivation therapy. It is not yet known whether treatment with zoledronate is effective in preventing bone-related events in patients who have prostate cancer and bone metastases.PURPOSE: This randomized phase III trial is studying how well zoledronate works in preventing bone-related events in patients who are receiving androgen deprivation therapy for prostate cancer and bone metastases. Clinical data presented in the following publication(s):PMID 24590644Additional unpublished data from CALGB-90202Disease type(s): Reproductive System Neoplasm, Male - Prostate CancerClinical dataset(s) included:NCT00079001-D1 (PMID 24590644): NCT00079001-D1 is one of 3 datasets that contain the data published in the analyses of PubMed ID 24590644 (-D1 through -D3). This dataset contains baseline characteristics, stratification factors, prior therapy, and metastatic site data.NCT00079001-D2 (PMID 24590644): NCT00079001-D2 is one of 3 datasets that contain the data published in the analyses of PubMed ID 24590644 (-D1 through -D3). This dataset contains primary analysis (time to skeletal-related event), time-to-event analysis, and treatment discontinuation data.NCT00079001-D3 (PMID 24590644): NCT00079001-D3 is one of 3 datasets that contain the data published in the analyses of PubMed ID 24590644 (-D1 through -D3). This dataset contains the toxicity data reported.NCT00079001-D4 (Unpublished data): Dataset NCT00079001-D4 contains data collected on Alliance trial CALGB-90202 which are not published in the primary publication for the trial. NCT00079001-D4 includes data on type of progression, time to progression, cause of death and clinical follow-up data.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004392

Evaluation of Local Response of Prostate Cancer to Irradiation Using Multiparametric MRI and MR-Guided Biopsies

The purpose of this study was to determine the rate of local recurrence in patients with intermediate and high risk prostate cancer treated with radiotherapy. In this study, multiparametric MRI was first performed, and biopsy tissue was acquired from cancerous regions detected on MRI. Blood samples were also taken. DNA and RNA were extracted from tissue taken at baseline. DNA was used for whole exome sequencing (WES). RNA was used for gene expression microarray. Each patient then received radiation therapy with androgen deprivation therapy.

Study phs001821

Multi-Omics Study of Lung Cancer in Smokers From EAGLE

EAGLE (Environment And Genetics in Lung cancer Etiology) is a population-based case-control study examining the full spectrum of lung cancer etiology from smoking initiation, smoking dependency to lung cancer development and outcome. It combines a traditional molecular epidemiology design with more integrative approaches by examining epidemiological, molecular, and clinical data together. To comprehensively investigate the effect of tobacco smoking behaviors on genomic or epigenomic alterations, we performed a multi-omics study including whole-genomic, transcriptomic, and epigenomic profiles in a total of 221 individuals from the EAGLE study.

Study phs002992

DirectHRD Enables Sensitive Scar-Based Classification of Homologous Recombination Deficiency (HRD)

Homologous recombination deficiency (HRD)-induced genomic scars are an FDA-approved biomarker for identifying cancers likely to respond to PARP inhibitors. However, detecting HRD scars from blood biopsies has been challenging due to the low tumor content in blood samples. To address this limitation, we developed DirectHRD, a genomic scar-based HRD classifier leveraging whole-genome sequencing (WGS) data for non-invasive blood biopsy testing. DirectHRD was applied to 90 cell-free DNA (cfDNA) samples across four cancer types: breast, ovarian, prostate, and pancreatic. The method achieved an AUC of 0.87 and demonstrated the ability to detect HRD at tumor fractions as low as 1%, offering a tenfold increase in sensitivity compared to state-of-the-art methods.

Study phs003760

Genomic and Immune Profiling of Breast Cancer Brain Metastases

Previous work has shown that breast cancer brain metastases (BCBrM) can have unique molecular profiles compared to extracranial tumors (ECTs), resulting in some patients demonstrating subtype switching between primary/extracranial tumors and brain metastases. Description of the biology of BCBrM and associations between biological features and clinical outcomes, particularly between molecular intrinsic subtypes, will facilitate the design of rational therapies for patients with BCBrM. To better characterize the molecular profiles of BCBrM, we conducted whole exome sequencing (WES) and total RNA sequencing (RNA-Seq) on BCBrM tissues, regardless of clinical or molecular subtype, obtained from a cohort of 42 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations, copy number alterations, gene expression profiles, and immune populations within and between BCBrM patients and other similar cohorts. The Duke BCBrM cohort includes clinical and molecular annotation of the 42 patient specimens and their associated WES and RNA-Seq data. Clinical and molecular (PAM50) intrinsic subtypes in ECTs and brain metastases were largely concordant within patients. There were observed differences in intrinsic subtype calls between frozen and FFPE specimens of the same tissue, with discordance mostly observed with LumB calls. Copy number alterations in chromosomal regions included clinically relevant genes, and somatic alterations were largely conserved within patients across matched samples, with few genes, including TP53, being recurrently altered in the majority of patient specimens. In matched FFPE brain metastasis and ECT samples, we observed differentially expressed genes and pathways that had increased or decreased expression in brain metastasis, including in oxidative phosphorylation and DNA repair. Survival outcomes for patients differed by intrinsic molecular subtypes, with some association between expression of select gene pathways and survival. Data available through dbGaP will be the sequencing data and sample attributes from BCBrM tissues obtained from 42 patients from Duke University Medical Center.

Study phs003673

Long-Read Sequencing to Identify Inherited Mutations Predisposing to Breast Cancer

We aimed to detect deeply intronic mutations within genes linked to breast/ovarian cancer that are potentially under-reported in clinical testing due to technical limitations. Current DNA and RNA tests typically exclude these regions, which harbor many variants within complex repetitive sequences that short-read sequencing cannot align. By employing targeted long read sequencing together with recent in silico prediction tools, we assessed the implications of rare deep intronic variants in severely affected patients with breast, ovarian, and/or metastatic prostate cancer, who had previously tested negative using standard genomic or cDNA methods. Through this approach, we identified participants who carried deep intronic mutations in tumor suppressor genes, resulting in abnormal transcripts causing premature truncations and loss of gene function. This study underscores the potential of long read DNA and cDNA sequencing in enhancing mutation discovery efforts.

Study phs003638

California Teachers Study (CTS): Whole Genome Sequences From Under-Represented Populations

The California Teachers Study (CTS) is a prospective observational cohort of N=133,477 adult women who have been followed since 1995. Participants completed up to six surveys and have been linked with cancer, hospitalization, and mortality data. In 2013-2016, over 14,000 CTS participants donated blood samples for future research. For this project, DNA was extracted in 2023 from 1694 buffy coats and 56 blood clots from N=1750 CTS participants whose self-reported race/ethnicity was Asian (398), Asian or Pacific Islander (18), Black or African American (189), Native American (128), Native Hawaiian or Other Pacific Islander (66), White Hispanic (719), or more than one race (232). Whole genome sequencing (WGS) was performed at CIDR in 2023-2024. WGS data and accompanying phenotype data are available through dbGaP. In addition, all CTS data are available to the research community via the CTS Researcher Platform (www.calteachersstudy.org), a secure cloud-based environment that includes data, software, documentation, and collaboration workspaces.

Study phs002918

Phase 2 Study of Pembrolizumab in Combination with Gemcitabine and Cisplatin as Neoadjuvant Therapy

The purpose of the clinical trial (NCT02690558) is to evaluate whether adding pembrolizumab (Keytruda) to the combination of gemcitabine and cisplatin will improve shrinkage of the tumor before having a cystectomy, for people with muscle-invasive bladder cancer (MIBC).

Study phs003452

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

Brief SummaryThis randomized phase II trial studies the side effects of durvalumab and tremelimumab to see how well they work with or without high or low-dose radiation therapy in treating patients with colorectal (CRC) or non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic). Immunotherapy with durvalumab and tremelimumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving durvalumab and tremelimumab with radiation therapy may work better in treating patients with colorectal or non-small cell lung cancer.Detailed DescriptionPRIMARY OBJECTIVES:I. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 (durvalumab) and tremelimumab alone or with high or low-dose radiation in non-small cell lung cancer (NSCLC). (NSCLC Cohort) II. To compare the overall response (excluding the irradiated lesion[s]) between combined checkpoint blockade with MEDI4736 and tremelimumab alone or combined checkpoint blockade with low or high dose radiation. (NSCLC Cohort) III. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 and tremelimumab with high or low-dose radiation. (Colorectal Cohort) IV. To determine the overall response rate (excluding the irradiated lesion[s]) with combined checkpoint blockade with MEDI4736 and tremelimumab with either low or high dose radiation. (Colorectal Cohort)SECONDARY OBJECTIVES:I. To estimate median progression-free survival and overall survival. (NSCLC Cohort) II. To determine local control within the irradiated field(s) and abscopal response rates. (NSCLC Cohort) III. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells and overall response. (NSCLC Cohort) IV. To explore changes in PD-L1 expression, circulating T-cell populations, T-cell infiltration, ribonucleic acid (RNA) expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (NSCLC Cohort) V. To estimate median progression-free survival and overall survival. (Colorectal Cohort) VI. To determine local control within the irradiated field and abscopal response rates. (Colorectal Cohort) VII. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+ CD8+ T-cells and overall response. (Colorectal Cohort) VIII. To evaluate changes between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells induced by targeted low or high dose radiation. (Colorectal Cohort) IX. To explore changes in circulating T-cell populations, T-cell infiltration, RNA expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (Colorectal Cohort)OUTLINE: Patients are assigned to 1 of 2 cohorts. NOTE: This Study is only for Cohort 2. Please see phs003295 for Cohort 1COHORT 1: Patients with NSCLC are randomized to 1 of 3 arms.ARM A: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions.ARM B: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14.ARM C: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses.COHORT 2: Patients with CRC are randomized to 1 of 2 arms.ARM A: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions.ARM B: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14.After completion of study treatment, patients are followed for up to 12 weeks.Official TitleA Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC Conditions Metastatic Colorectal CarcinomaMetastatic Lung Non-Small Cell CarcinomaStage IV Colorectal Cancer AJCC v7Stage IV Lung Non-Small Cell Cancer AJCC v7Stage IVA Colorectal Cancer AJCC v7Stage IVB Colorectal Cancer AJCC v7 Intervention/Treatment Biological: DurvalumabRadiation: Radiation TherapyBiological: Tremelimumab Other Study ID Numbers NCI-2016-01325NCI-2016-01325 ( Registry Identifier ) (REGISTRY: CTRP (Clinical Trial Reporting Program))17-71910021 ( Other Identifier ) (OTHER: Dana-Farber - Harvard Cancer Center LAO)10021 ( Other Identifier ) (OTHER: CTEP) Molecular Technologies/AssaysIHCmIFOlinkCyTOFRNAseqWES

Study phs003294

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