16488 results for "sec+and+unspecified+malignant+neoplasm"

in 27.75 milliseconds.

• Programs, Origins, and Immunomodulatory Functions of Myeloid Cells in Gliomas

  Gliomas are challenging malignancies characterized by an immunosuppressive microenvironment filled with myeloid cells, whose roles in immune modulation are not fully understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data from 85 primary human glioma tumors, related blood samples, and brain tumor organoid models. We found that nearly all glioma-associated myeloid cells express at least one of four distinct immunomodulatory activity programs. These programs include:1. Scavenger Immunosuppressive Program2. Complement Immunosuppressive Program3. Microglial Inflammatory Program4. Systemic Inflammatory ProgramAll four programs are found in both lower-grade and high-grade gliomas and are expressed across various myeloid cell types, whether derived from blood or resident origins. We validated the remarkable plasticity of myeloid cells by showing that the introduction of peripheral blood monocytes into glioma organoid models can induce the emergence of identities resembling microglia, macrophages, and dendritic cells, as well as all four immunomodulatory programs. Our study provides a valuable resource and a new framework for understanding the role of immunomodulatory myeloid cells in gliomas, laying the groundwork for developing effective immunotherapy strategies for glioma patients.

  Study phs003756

• The taxonomic composition of the human microbiome of CRC patients and healthy donors

  In this study, single homogenized human stool samples from five healthy donors and one CRC patient were analyzed by shotgun sequencing to generate a baseline for the establishment of humanized microbiome to be transferred into mice. Briefly, fecal DNA was isolated from these samples using the DNeasy PowerSoil DNA Isolation Kit (Qiagen), according to the kit manual, except that samples were homogenized using the TissueLyzerII for five minutes at 40Hz instead of intense vortexing. The extracted DNA was further purified and concentrated using the DNA Clean and Concentrator Kit (Zymo Research). This DNA was thawed and refrozen once at -80°C for 16s sequencing before being thawed again for WGS. 200 ng of DNA was used for metagenomic library preparation using the Next Generation Sequencing DNA Library Prep Kit (Westburg), according to the user manual using an average insert size of libraries of 450 base pairs. Following quantification and quality control (Qubit® dsDNA BR Assay Kit (Thermofisher Scientific); Bioanalyzer High Sensitivity DNA Analysis Kit (Agilent Technologies)), sequencing was performed on a NextSeq500 instrument using 2×150 base pair read lengths.

  Study EGAS50000000759

• scRNA-seq of HSPC treated with gemcitabine and carbplatin

  The study used cryopreserved hematopoietic stem and progenitor cells (HSPCs) harvested from one patient with chronic myelogenous leukemia (CML). The cells were thawed and acclimatized for 48 hours in StemMACS HSC Expansion Media XF (Miltenyi Biotec) supplemented with StemMACS HSC Expansion Cocktail (Miltenyi Biotec) at 37°C in a humidified atmosphere containing 5% CO2. 4 samples of 2000000 HSPCs in 2 ml media each were then prepared and treated for 24 hours: carboplatin-high: 150 µg/ml carboplatin carboplatin-low: 18.75 µg/ml carboplatin gemcitabine: 25 ng/ml gemcitabine control: no drug Single-cells were subsequently extracted using the ddSEQ™ Single-Cell Isolator (Bio-Rad) and later sequenced using the SureCell™ Whole Transcriptome Analysis 3' Library Prep Kit (Illumina) on the NextSeq 500 System (Illumina) using the NextSeq 500/550 High Output Kit v2.5 150 Cycles (Illumina) all following the manufacturer's instructions. FASTQ-files were then processed following the ddSeeker (Romagnoli, D., et al., BMC Genomics 2018, doi:10.1186/s12864-018-5249-x) and Drop-seq (Macosko, E.Z., et al., Cell 2015, doi:10.1016/j.cell.2015.05.002) protocols for processing scRNA-seq data to yield the final digital gene expression for each cell.

  Study EGAS00001004381

• The identification of genetic vulnerabilities in head and neck cancers for the development of novel treatments.

  The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia. It is the sixth most common cancer worldwide and the second most common in Malaysia, with approximately 600,000 new cases per year globally. Longterm survival remains less than 50%, underscoring the need for better therapeutic strategies. In this proposal we aim to bring new technological advancements in the identification of critical genes in HNSCC and the identification of compounds for the development of new therapies in HNSCC. We propose to genomically characterise 16 unique Asian H&N cancer cell lines, to classify sub groups where identification of essential genes that can be targeted for tumor control can be applied in a more rational way. Further, we propose to use zebrafish, an established drug discovery platform to identify promising pathway-specific compounds that could be further studied using CRISPR/Cas9 lethality screens and biological models to better identify novel therapeutic strategies to combat this major health problem in Asia.

  Study EGAS00001002682

• Evolutionary analysis of primary tumors and metastatic lesions from 20 breast cancer patients (99 samples in total) using exome sequencing data.

  Metastatic breast cancers are still incurable. Characterizing their evolutionary landscape including the role of metastatic axillary lymph nodes to seed distant organ metastasis can provide rational basis for effective treatments. Here, we describe the genomic analyses of the primary tumors and metastatic lesions from 20 breast cancer patients (99 samples). Our evolutionary analyses revealed diverse spreading and seeding patterns governing tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, where multiple metastatic subclones originated from primary tumor and/or other distant metastases. Synchronous axillary lymph node metastasis, a well-established prognosticator of breast cancer, was not involved in seeding distant metastasis, suggesting haematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably a significant increase in apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) associated mutagenesis. Our data provide the first genomic evidence regarding the role of axillary lymph node metastasis in seeding distant organ metastasis and elucidates the evolving mutational landscape during cancer progression.

  Study EGAS00001002737

• PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

  The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

  Study EGAS00001002903

• Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

  Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor-reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor-reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer – two tumor types for which T cell infiltrates form a positive prognostic marker. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two out of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

  Study EGAS00001003119

• Discovery of a highly widespread bacteriophage family and its associations to metabolic syndrome gut microbiomes

  There is significant interest in altering the course of cardiometabolic disease development via the gut microbiome. Nevertheless, the highly abundant phage members of the complex gut ecosystem -which impact gut bacteria- remain understudied. Here, we characterized gut virome changes associated with metabolic syndrome (MetS), a highly prevalent clinical condition preceding cardiometabolic disease, in 196 participants with a combination of whole genome shotgun and virus like particle sequencing. MetS gut virome populations exhibited decreased richness and diversity, but larger inter-individual variation. These populations were enriched in phages infecting Bacteroidaceae and depleted in those infecting Ruminococcaeae. Differential abundance analysis identified eighteen viral clusters (VCs) as significantly associated with either MetS or healthy viromes. Among these are a MetS-associated Roseburia VC that is related to healthy control-associated Faecalibacterium and Oscillibacter VCs. Further analysis of these VCs revealed the Candidatus Heliusviridae, a highly widespread gut phage lineage found in 90+% of the participants. The identification of the temperate Ca. Heliusviridae provides a novel starting point to a better understanding of the effect that phages have on their bacterial hosts and the role that this plays in MetS

  Study EGAS00001006260

• University of Pennsylvania CAR T Cell Responding and Non-responding Patients

  The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products. In a follow-up study, we report multiplex CRISPR-Cas9 gene editing on T cells in humans to test the hypothesis that disrupting genes encoding the endogenous T cell receptor (TCR), TCRα (TRAC) and TCRβ (TRBC), as well as PD-1 (PDCD1) would enhance the efficacy of autologous T cells engineered to express a transgenic NY-ESO TCR. We used single cell RNA-seq to comprehensively characterize the transcriptomic phenotype of this T cell product and its evolution over time in a patient with sarcoma. Notably, this patient's transferred T cells that persisted in vivo demonstrated increases in expression of genes associated with a central memory state (IL7R, TCF7). These findings may guide future trials involving administration of genetically redirected, genome -edited T cells.In this follow-up study, we investigated whether CRISPR-Cas9-mediated disruption of PDCD1 and/or CTLA-4 could restore CART dysfunction in healthy donors and/or CLL patients. We show that depletion of CTLA-4 rescues the function of T cells from leukemia patients that previously failed CART cell treatment. We performed single-cell RNA sequencing and characterized the transcriptomic landscape of CTLA-4 KO CART19 cells that showed higher proliferation and anti-tumor efficacy by permitting unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under stress-test conditions of chronic antigen exposure. Our findings reveal that selective disruption of CTLA-4 invigorates dysfunctional patient T cells, providing a strategy for increasing patient responses to CART cell therapy.

  Study phs001707

• Coagulation and Fibrinolysis in a Pediatric Insulin Titration Trial

  Summary of the Design and Aims: The Coagulation and Fibrinolysis in a Pediatric Insulin Titration Trial (CAF-PINT) is an ancillary study to the HALF PINT (NCT01565941) randomized, controlled trial that was originally designed to study changes in inflammatory and thrombosis pathways in the setting of an interventional trial. The parent HALF PINT study was designed to study the impact of tight glycemic control (TGC) using an explicit insulin titration algorithm to safely achieve a normal glucose in target range of 80-110 mg/dL versus 150-180mg/dL on clinical outcomes among critically ill hyperglycemic children with Heart and Lung Failure. The CAF PINT study collected blood samples pre randomization and at 2 and 4 days after randomization. Blood samples collected in EDTA tubes were centrifuged at local sites to separate the plasma from cell pellets and frozen prior to shipment. In addition, 0.5 mL of whole blood collected in PAXgene tubes modified for use in pediatrics frozen 24 hours after collection prior to shipment.Population Information: Setting: Twenty-one academic children's hospitals (HALF-PINT) and 1 academic children's hospital (IIT-SBPP). Participants: Critically ill hyperglycemic children requiring mechanical ventilation/vasoactive support (n=293).Interventions and Exposures: Patients in HALF PINT were randomized to achieve a low target glucose (80-110 mg/dL) vs. a higher target (150-180 mg/dL). The primary trial was stopped early due to low likelihood of achieving a statistically significant difference in the primary outcomes. Molecular Technologies Employed: Plasma biomarkers were assayed on thawed plasma using a Luminex panel. RNA was extracted from PAXgene Blood RNA Kits modified for pediatric use. Extracted RNA was sequenced with the Novaseq S4 system (Illumina) to generate 2 x 150 base paired end reads to a target depth of 50 million read-pairs per sample.Principal Findings of the Study: We tested for heterogeneity of treatment effects according to baseline blood inflammatory proteins using logistic regression with individual biomarkers as interaction terms and Cox regression analysis using biomarker-derived latent classes. Children with higher inflammatory proteins including TNFR-1, IL-6, IL-8, and IL-10 had lower mortality when treated with insulin to a target glucose of 80-110 mg/dL as compared to 150-180 mg/dL (interaction p<0.05). Causal forest estimates ranged from a 40% mortality reduction to a 15% mortality increase with TGC, depending on each patient’s individual biomarker profile. Latent class categorization strongly interacted with TGC with respect to mortality (Cox regression interaction p=0.005). Specifically, patients with higher inflammation benefited from TGC (6% mortality with TGC vs. 48% mortality, p=0.004) whereas hypoinflamed patients showed a trend towards harm (14% mortality with TGC vs. 7% mortality, p=0.055).Data available through dbGaP: Transcriptomic (Gene Counts) and phenotype data

  Study phs003016

• FIGHT-207: Anonymized Genomic Alterations and Clinical Responses

  Background: FIGHT-207 was a phase 2 study of the FGFR1-FGFR3 inhibitor pemigatinib in patients with previously treated, locally advanced/metastatic or unresectable solid tumor malignancies harboring activating fibroblast growth factor receptor (FGFR) gene alterations. Population information: 107 patients were divided into 3 cohorts: FGFR1–FGFR3 fusions/rearrangements; n=49 Activating FGFR1–FGFR3 non-kinase domain single nucleotide variants (SNVs); n=32 FGFR1–FGFR3 kinase domain mutations or variants of unknown significance (VUS) with potential pathogenicity; n=26 Participants on study had tumors that were grouped into the following histologies based on ≥ 5 patients: Cholangiocarcinoma, gynecologic cancers (cervical, endometrial, uterine), central nervous system (glioblastoma, low-grade pediatric glioma, astrocytoma), pancreatic cancer, breast cancer, urothelial tract/bladder cancer, non-small cell lung cancer, and other (adrenal cancer, anal cancer, cancer of unknown primary origin, colorectal cancer, gastric/gastroesophageal cancer, gallbladder cancer, giant cell bone tumor, head and neck cancer, lung neuroendocrine cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, renal cell cancer, sarcoma, solitary fibrous tumor). Among the efficacy-evaluable participants, 99 had both independent review committee (IRC) central best overall response (BOR) and tissue NGS- data; 2 additional patients had Not Evaluable (NE) as central BOR Baseline tissue targeted NGS data (F1CDx, Foundation Medicine Inc.) of genomic alterations are reported for N=101 participants Baseline plasma targeted NGS analysis (PredicineCare, Predicine Inc.) of genomic data are reported for N=83 participants; data at disease-progression are reported for N=78 participants. Principal Findings: The FIGHT-207 study provided evidence of clinical benefit of pemigatinib in multiple histologies, explored the clinical actionability of various FGFR1-FGFR3 gene alterations, and leveraged the depth of translational data from targeted NGS analysis of baseline samples and plasma samples obtained at baseline and end of treatment to provide key insights into the biology of FGFR inhibition and the clinical utility of FGFR inhibitors. The FIGHT-207 article (pending in Nat.Med. NMED-A128973B) reports evidence suggesting clinical acquired resistance to FGFR inhibition via secondary FGFR mutations as well as emerging co-mutations in other oncogenic and tumor suppressor pathways. This study also provides evidence of acquired resistance to FGFR inhibition in multiple histologies beyond cholangiocarcinoma and urothelial cancers in a systemic correlative analysis of post-progression ctDNA in a trial. Data available through dbGaP: Anonymized information for 101 participants with both IRC central BOR evaluation (including 2 patients with NE as BOR) and tissue NGS data, including tumor histology, enrollable FGFR alteration, and outcome. Genomic alterations determined by baseline tissue NGS (F1CDx, Foundation Medicine Inc.) Genomic alterations determined by plasma NGS analysis (PredicineCare, Predicine Inc.) of ctDNA analysis at baseline (n=83) and at end of treatment/ disease progression (n=78) including genomic alterations that were not assessed to be Germline SNPs.

  Study phs003590

• Data Access Commitee for Dietrich and Wendisch et al., SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis (Submitted)

  Dac EGAC00001001884

• Data Access Commitee for Dietrich and Wendisch et al., SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis (Submitted)

  Dac EGAC00001002335

• MethylationEPIC_JMML_tech_Schoenung

  DNA methylation analysis of JMML patients from Europe, Japan and USA using EPIC arrays

  Dataset EGAD00010001998

• MethylationEPIC_JMML_valid_Schoenung

  DNA methylation analysis of JMML patients from Europe, Japan and USA using EPIC arrays

  Dataset EGAD00010002000

• Methylation450k_JMML_meta_Schoenung

  DNA methylation analysis of JMML patients from Europe, Japan and USA using 450k arrays

  Dataset EGAD00010001999

• Genome-wide array data from Eivissa and Menorca

  DAC for the Genome-wide array data from 22 Eivissan and 20 Menorcan individuals.

  Dac EGAC50000000297

• Genetic investigation of 12q-amplified osteosarcomas

  Genetic investigation of 12q-amplified osteosarcomas using both whole genome short- and longread and transcriptome sequencing.

  Dac EGAC50000000340

• Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations

  Study EGAS00001007477

• AngioPredict CNV and Exome data

  AngioPredict CNV and Exome data

  Dataset EGAD00001004031

• H3K4me3, IgG, and Input ChIP-seq in overexpression of pLV Control, CS-FL and CS-ΔEx4 in SW1116 cells.

  none

  Study EGAS00001008121

• IL-17 Signaling in Human iPSC-derived Midbrain Neurons in Parkinson's Disease

  To determine IL-17-induced global transcriptome changes in midbrain neurons derived from induced pluripotent stem cells (iPSC) from three sporadic Parkinson's disease (PD) patients and three age- and sex-machted controls, deep RNA sequencing (RNA-Seq) of IL-17-treated and untreated PD and control iPSC-dderived midbrain neurons was performed. Total RNA was isolated from untreated and IL-17-treated cells with the TruSeq RNA Sample Preparation Kit v2 (Illumina). RNA libraries were quantified using the KAPA SYBR FAST ABI Prism Library Quantification Kit (Kapa Biosystems) and cluster generation was performed on the cBot with the TruSeq SR Cluster Kit v3 (Illumina). The sequencing run was performed on a HiSeq 1000 instrument (Illumina) using the indexed, 50 cycles single read (SR) protocol and the TruSeq SBS v3 Kit (Illumina). Image analysis and base calling resulted in .bcl files that were then converted into .fastQ files by the CASAVA1.8.2 software. FastQ files were aligned to the human genome (hg19) using STAR.and annotated with gencode.v19. DESeq2 was used to determine differential expression. Criteria to determine significantly dysregulated genes were as follows: adjusted p-value below 0.05 and log2FC (fold change) of greater than one. Only genes with a mean expression value of greater than one RPKM (reads per kilobase per million mapped reads) throughout the dataset were considered. Control and PD samples were analyzed as two independent datasets. Upon IL-17 treatment only 17 genes were found to be dysregulated in controls but 125 genes were dysregulated in iPSC-derived midbrain neurons from PD patients. The 125 IL-17-dependent genes in PD iPSC-derived neurons separated the treated from untreated PD samples using an unsupervised, hierarchical clustering applying an Euclidean distance metric. More detailed study information can be found in Sommer A, Maxreiter F, Krach F, Fadler T, Grosch J, Maroni M, Graef D, Eberhardt E, Riemenschneider MJ, Yeo GW, Kohl Z, Xiang W, Gage FH, Winkler J, Prots I, Winner B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell. 2018 Jul 5;23(1):123-131.e6. doi: 10.1016/j.stem.2018.06.015. PMID: 29979986

  Study phs001686

• Genetic Factors associated with Conversion from Active Surveillance to Treatment for Prostate Cancer

  This is a genome-wide association study (GWAS) of conversion from active surveillance (AS) for prostate cancer (PC) to treatment. AS is the monitoring with screening tests and/or biopsies over time of men usually with low-risk, early-stage PC to avoid harmful side effects of PC treatment. "Conversion" refers to patients who withdraw from AS (switch to active treatment) due to changes in their cancer development, anxiety about delayed treatment, or other reasons. Patients who converted because of anxiety alone were censored in the GWAS analysis. The overall goal of this study is to develop an easily measurable, germline-based panel of genetic variants to aid in selecting PC patients appropriate for AS and/or the intensity of monitoring. In total, 6,324 PC patients from 28 collaborating institutions are included in this study. Patients are those with PC who are either on AS or who have previously converted from AS to treatment. In this study, 70% of all subjects were diagnosed with very low-risk, low-risk, or low-volume intermediate-risk PC (Kryvenko and Epstein, 2016; PMID: 26709152) and have been enrolled in an AS program. DNA was extracted from blood, saliva, or formalin-fixed, paraffin-embedded (FFPE) tissue collected from the study subjects at the participating sites. Genotyping, quality control processes, and imputation were performed at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. CIDR used the Illumina Infinium Multi-Ethnic Global Array (MEGA) version 1, which included genome-wide tag SNPs and 10,000 SNPs selected with custom content. Quality control and assurance (QC/QA) checks on genotyped data involved four domains: sample-level checks, batch effects, SNP-level checks, and preliminary association tests. Samples and SNPs passing the QC/QA checks were imputed to appropriate reference panels (HRC r1.1 for patients of European ancestry) using the Michigan Imputation Server (PMID: 27571263). Unmeasured genetic variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) Imputation Server, with 97,256 reference samples and 308,107,085 SNPs. Variants with imputation quality (INFO) score < 0.3 were excluded, leaving a total of 22,691,641 SNPs successfully imputed. After QC steps, a total of 5,936 samples genotyped at CIDR remained for inclusion in the GWAS.

  Study phs002056

• A Genome-Wide Association Study in Participants Experiencing Breast Cancer Events in High-Risk Postmenopausal Women Receiving Selective Estrogen Receptor Modulators on NSABP Trials P-1 and P-2. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The primary aim of this study is to identify genes related to the occurrence of breast events, defined as occurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), in women at high risk of developing breast cancer who have received a Selective Estrogen Receptor Modulator (SERM - tamoxifen or raloxifene) on the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 or P-2 trials. Cases and controls were selected from the tamoxifen arm in the P-1 and from the tamixifen and raloxifene arms in the P-2 trial. For the P-1 trial, cases and controls were required to be 50 years of age or older at time of entry. Cases were females who experienced an invasive breast cancer or DCIS on P-1 or P-2. Controls were females who did not experience an invasive breast cancer or DCIS. A nested matched case-control design was used, with matching on the following factors: 1) trial and treatment arm (P-1 tamoxifen, P-2 tamoxifen, P-2 raloxifene); 2) age at trial entry (when controls could not be exactly matched on age, we incremented the age of matching by +/- 1 year, in sequence until a match was obtained without exceeding +/- 5 years); 5-year predicted breast cancer risk based on the Gail model ( <2.00%, 2.01-3.00, 3.01-5.00, >5.01), 3) history of lobular carcinoma in situ (yes vs. no); 4) history of atypical hyperplasia in breast (yes vs. no); 5) time on study (controls must be on study at least as long as the time to diagnosis of the breast event for the case). Because 94.2% of the participants on P-1 and P-2 treated with tamoxifen or raloxifene were Caucasian, this study was restricted to only Caucasians. Two cases and two controls were randomly chosen as duplicates for quality control of genotype concordance. The DNA samples were plated into 96-well plates, with cases and controls randomly distributed across the plates. A Caucasian parent-child CEPH trio from the HapMap project was included to check for Mendelian transmission of alleles. Genotypes were determined by the RIKEN Center for Genomic Medicine with the Illumina Human610-Quad.

  Study phs000305

• Clinical outcomes in ctDNA-positive urothelial carcinoma patients treated with adjuvant immunotherapy

  Minimally invasive approaches to detect residual disease after surgery are urgently needed to select patients at highest risk for metastatic relapse for additional therapies. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease (MRD) and relapse,1-3 but its clinical value has yet to be demonstrated in a randomised clinical trial. We evaluated outcomes in post-surgical ctDNA-positive (+) patients in a randomised phase III trial of adjuvant atezolizumab versus observation. IMvigor010 enrolled 809 patients with muscle-invasive urothelial carcinoma and did not meet its primary endpoint of disease-free survival (DFS) in the intent-to-treat population. Within the study, an exploratory planned analysis of prospectively collected plasma was performed, which tested the utility of ctDNA to identify patients who may benefit from adjuvant atezolizumab treatment. ctDNA was measured at the start of therapy (cycle 1 day 1; C1D1) and at week 6 (cycle 3 day 1; C3D1), and 581 patients were evaluable for ctDNA. The prevalence of ctDNA positivity at C1D1 was 37% (n=214), and ctDNA positivity identified patients with poor prognosis (observation arm DFS HR= 6.19 (4.29, 8.91), p<0.0001). Here we show that ctDNA(+) patients had improved DFS and overall survival (OS) with atezolizumab versus observation (DFS HR= 0.56 (0.41-0.77); p=0.0003 and OS HR= 0.58 (0.4-0.86); p=0.0063). No difference in DFS or OS between arms was noted for ctDNA-negative patients. The rate of ctDNA clearance was higher with atezolizumab (18%) versus observation (4%) (p=0.0041). Transcriptomic analysis revealed that tumours from ctDNA(+) patients had higher expression of cell cycle and keratin genes. Within the ctDNA(+) patient population in the atezolizumab arm, non-relapsing patients were further enriched in prominent immune response signatures including PD-L1, IFNG, CXCL9, and high tumour mutational burden, whereas relapse was associated with angiogenesis and fibroblast-transforming growth factor-beta signatures (F-TBRS). TCGA molecular subset analysis revealed increased efficacy of atezolizumab in patients with basal-squamous tumours, consistent with underlying tumour-immune contexture. Together these findings suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in this high-risk ctDNA(+) population. These findings, if validated in other settings, would shift approaches to post-operative cancer care.

  Study EGAS00001004997