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CALGB 80303: Genome-Wide Association Study of Advanced Pancreatic Cancer Patients

ABSTRACT:

CALGB 80303 was a randomized, phase III study in advanced pancreatic cancer patients treated with Gemcitabine plus either Bevacizumab or placebo. No difference in overall survival (OS) was observed between the two arms. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS).

PROVIDER: phs000250 | dbGaP |

SECONDARY ACCESSION(S): PRJNA75655PRJNA75653

REPOSITORIES: dbGaP

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CALGB 80303:Genome-Wide Association Study of Advanced Pancreatic Cancer Patients - A Randomized Phase III trial of Gemcitabine Plus Bevacizumab versus Gemcitabine Plus Placebo in Patients with Advanced Pancreatic Cancer

Project description:<p>CALGB 80303 was a randomized, phase III study in advanced pancreatic cancer patients treated with Gemcitabine plus either Bevacizumab or placebo. No difference in overall survival (OS) was observed between the two arms. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS).</p>

| phs000250.v1.p1 | EGA

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

Project description:The AVAglio and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy/temozolomide. To establish whether certain patient subgroups derived OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy assessed for each patient subgroup. A multivariate analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with Proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the Proneural subtype biomarker and treatment arm (P = .023). The group of patients with Mesenchymal and Proneural tumors derived a PFS benefit from bevacizumab, compared with placebo; however, this translated to an OS benefit in the Proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type Proneural glioblastoma may derive OS benefit from first-line bevacizumab treatment. The predictive value of the Proneural subtype observed in AVAglio should be validated in an independent dataset.

2016-07-06 | GSE84010 | GEO

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

2016-07-06 | E-GEOD-84010 | biostudies-arrayexpress

Tumor immunogenomic features determine outcomes in metastatic colorectal cancer patients treated with standard-of-care combinations of bevacizumab and cetuximab

Project description:CALGB/SWOG 80405 was a randomized phase III trial in first-line mCRC patients treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on OS. Primary tumors (N=554) were profiled by RNAseq. Immune signatures of macrophages, lymphocytes, TGF-β, INF-γ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured. Increased M2 macrophage score (HR 6.30, 95% CI 3.0-12.15) and TGF-β signature expression (HR 1.35, 95% CI 1.05-1.77) were associated with shorter OS. Increased scores of plasma cells (HR 0.55, 95% CI 0.38-0.87) and activated memory CD4+ T cells (HR 0.34, 95% CI 0.16-0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0-1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8-47.8), to 31.0 (28.8-34.4), 25.2 (20.6-27.9), and 17.7 (13.5-20.4) months respectively (p-value 3.48e-11). New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.

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Expression analysis in pancreatic and liver tissues of diabetic db/db mice in response to dietary supplementation with selenate

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Multi-omics analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 antibody

Project description:Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teffs). We prospectively collected and applied multi-omics analysis to paired, pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of GVAX vaccine +/- nivolumab (anti-PD-1) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX+nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX+nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA-sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 required for optimal T cell activation. These findings provide new insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.

2022-03-07 | GSE197613 | GEO

Transcription profiling of human samples of bone morrow or peripheral blood mononuclear cells from adult patients with untreated acute myeloid leukemia to develop a prognostic gene signature for normal karyotype AML

Project description:Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes) which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P=0.002), EFS (HR, 1.73; P=0.001), and RFS (HR, 1.76; P=0.025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR, 4.11; P<0.001), EFS (HR, 2.90; P<0.001), and RFS (HR, 3.14, P<0.001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene expression signature that offers additional prognostic information for patients with CN-AML. Experiment Overall Design: Analysis of 163 samples of bone morrow or peripheral blood mononuclear cells from adult patients with untreated acute myeloid leukemia

2008-10-26 | E-GEOD-12417 | biostudies-arrayexpress

Expression analysis in pancreatic and liver tissues of diabetic db/db mice in response to dietary supplementation with selenate

2014-03-07 | GSE55636 | GEO

Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA Associated Pancreatic Cancer in the Clinical and Pre-clinical Setting

Project description:Germline BRCA-associated pancreatic ductal adenocarcinoma(glBRCA-PDAC) tumors aresusceptible to platinum/PARP-inhibition. The clinical outcomesof 125 glBRCA-PDAC patients was stratified based on the spectrum of response to platinum/PARP-inhibition: i)Refractory(OS<6 months) ii)Durable response followed by acquired-resistance(OS<36 months); iii)Long-term responders(OS>36 months). Patient-derived-xenografts(PDX) were generated from 25 glBRCA-PDAC patients at different clinical time-points. Response to platinum/PARP-inhibition in-vivo and ex-vivo culture(EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA-PDAC and identified homologous recombination(HR)-proficiency and secondary-mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient(HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor-mutational-burden(TMB) was high in HRD-PDAC and significantly higher in tumors with secondary mutations. Anti-PD1 attenuated tumor growth in a novel humanized glBRCA-PDAC PDX-model. This work demonstrates the utility ofpreclinicalmodels, including EVOC, to predict response of glBRCA-PDAC to treatment, whichhas potential to inform time-sensitive medical decisions.

2023-07-13 | GSE235843 | GEO

Microarray gene-expression profiles of 50 pancreatic tumors tissue from patients with pancreatic ductal adenocarcinoma

Project description:In order to identify biologically relevant tumor markers, and novel therapeutic target we have compared the tumor gene expression profiles of long (OS>=24 months,n=14) and short (OS <=7months, n=11) survival patients. Then we conducted Kaplan-Meier survival analysis using all the 50 samples listed here. The Affymetrix gene-expression data of these 50 samples were also included in the earlier submission by us as GEO accession number GSE62452.

2017-01-01 | GSE78229 | GEO

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