Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
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PROVIDER: PRJNA814304 | ENA |
REPOSITORIES: ENA
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Project description:The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggest patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab. Please note that the RANGE clinical trial data generated in this study have been deposited at www.vivli.org. RANGE clinical trial data are available under restricted access to protect patient privacy, and access can be obtained by submitting a request. For details on submitting a request, see the instructions provided at www.vivli.org. For specific study details, see here: https://search.vivli.org/?search=NCT02426125.
2022-03-14 | GSE198269 | GEO
Project description:Cisplatin-based combination chemotherapy (CHT) is standard of care in locally advanced and metastatic urothelial cancer (mUC). No predictive biological biomarkers are available for clinical use. Here, we investigate the impact of molecular subtypes in relation to response and survival in mUC patients treated with first-line CHT. Molecular subtype classification according to Lund taxonomy was performed by tumour transcriptomic profiling and immunostaining in a retrospective cohort with mUC patients treated with CHT. We analyze overall response rate (ORR) and secondary endpoint overall survival (OS) in comparison to prespecified molecular subtypes. Differential gene expression and association to treatment response was explored. Ninety-five patients with mUC were classified into urothelial (Uro, 43%), genomically unstable (GU, 26%), basal/squamous (Ba/Sq, 20%), mesenchymal like (Mes-like, 8%) and small-cell/neuroendocrine-like (Sc/NE, 3%) subtypes. Gene expression data is available for 86 patients. Patients with Mes-like tumours had significantly lower ORR (14%), compared to Uro (70%), GU (77%), Ba/Sq (75%) and Sc/NE, 67%), p = 0.020. Further, patients with the Mes-like subtype had significantly shorter mOS (HR 3.13, 95% CI: 1.37-7.13, p = 0.007), with Uro as reference. An enrichment of down-regulated stromal- and immune-related genes was seen in responders. Down-regulation of interferon-induced transmembrane protein 2 (IFITM2), an inflammation related gene, was associated with increased ORR and improved OS. In patients treated with CHT for mUC, the Mes-like subtype showed significantly lower response rate and shorter overall survival. Down-regulation of IFITM2 was associated with clinical benefit, suggesting the presence of IFITM2 to be a possible unfavourable prognostic marker in mUC.
2024-10-09 | GSE250194 | GEO
Project description:The clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer (BC) is not firmly established. We aimed to validate previous prognostic findings in triple negative breast cancer (TNBC) and investigate predictive associations with trastuzumab benefit in HER2 overexpressing disease (HER2+).
2022-07-16 | GSE47994 | GEO
Project description:Molecular subtypes are associated with clinical benefit in cisplatin-treated metastatic urothelial cancer patients
| PRJNA1052658 | ENA
Project description:DNA-methylation targets specific for urothelial cancer (UC) were identified by genome-wide methylation difference analysis of human urothelial (RT4, J82, 5637), prostate (LNCAP, DU-145, PC3) and renal (RCC-KP, CAKI-2, CAL-54) cancer cell lines with their respective primary epithelial cells
2020-07-28 | GSE149387 | GEO
Project description:The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva; a humanized monoclonal antibody against circulating VEGF-A) when added to CCNU chemotherapy in recurrent GBM patients. In this study, we have performed gene expression profiling (DASL and RNA-seq) on formalin fixed, paraffin embedded (FFPE) tumor material from patients treated within the BELOB trial to identify recurrent GBM patients who benefit most from combined beva/CCNU treatment. We first extensively validate the use of FFPE tissues for expression profiling on both DASL and RNA-seq. Our data show that tumors assigned to IGS-18 or ‘classical’ GBMs show a significant benefit in progression free survival (PFS) and a trend towards benefit in overall survival (OS) from beva+CCNU treatment; other subtypes do not show such benefit. In particular, expression of FMO4 and OSBPL3 were associated with treatment response. All molecular glioma subtypes are evenly distributed along the different study arms and the improved outcome in the beva/CCNU arm therefore is not explained by an uneven distribution of prognostically favorable subtypes. Analysis of RNA-seq data highlighted genetic changes, including mutations, gene fusions (and identification of the exact genomic breakpoint), and copy number changes (albeit with limited resolution) within this well-defined cohort of tumors. When validated in an independent dataset, the predictive markers identified in this study will allow selection of recurrent GBM patients that benefit from beva+CCNU treatment.
2016-01-19 | GSE72951 | GEO
Project description:Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial
| PRJEB45010 | ENA
Project description:Purpose: Utility of immunological treatment in cancer has increased; however, many patients do not respond to treatment. Identification of robust predictive biomarkers is required to correctly stratify patients. Although clinical trials based on adoptive T cell therapy (ACT) have yielded high response rates and many durable responses in melanoma, 50-60% of the patients have no clinical benefit. Herein, we searched for predictive biomarkers to ACT in melanoma. Methods: Whole exome- and transcriptome sequencing, neoantigen prediction and immune cell signature analysis were applied to pre-treatment melanoma samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously been treated with other immunotherapies. Results: We found that clinical benefit was associated with significantly higher neoantigen load (P=0.025). High mutation and neoantigen load were significantly associated with improved progression-free and overall survival (P=8x10^-4 and P=0.001, respectively). Further, gene-expression analysis of pre-treatment biopsies showed that clinical benefit was associated with strong immune activation signatures including a high MHC-I antigen processing and presentation score. Conclusions: These results improve our understanding of clinical benefit of ACT in melanoma, which can lead to clinically useful predictive biomarkers to be used for selecting patients that benefit from these highly intensive treatment regimens.
2017-12-04 | GSE100797 | GEO
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. A total of 349 (bevacizumab arm, n = 171; placebo arm, n = 178) pretreatment specimens from AVAglio patients (total n = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.
2016-07-06 | E-GEOD-84010 | biostudies-arrayexpress
Project description:Gene expression data of HER2+ breast tumor samples Increasing evidence indicates that a subset of patients with HER2-positive breast cancer may achieve significant clinical benefit with anti-HER2 targeted therapy without chemotherapy. Thus, identification of biomarkers of long-term benefit from anti-HER2 agents is needed, especially in the metastatic setting. In the HERLAP study (NCT00842998), patients with HER2-positive metastatic breast cancer were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. Chemotherapy was added to anti-HER-2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded in 17 primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. The association of the expression of each biomarker with clinical outcome endpoints was evaluated. Nineteen patients were enrolled. In 4 patients (21.1%) we observed disease control lasting longer than 12 months with single agent anti-HER2 therapy (range 14.9-38.8 months). High expression of 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were found significantly associated with 8-week overall response rate and with the duration of disease control during single agent anti-HER2 therapy. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile, was found associated with reduced benefit from single agent anti-HER2 therapy. Conclusions: Our data indicate that gene expression-based biomarkers can identify patients with HER2-positive metastatic breast cancer that benefit substantially from single agent chemo-free anti-HER2 targeted therapy. In the study presented here, a well-defined cohort of 21 breast cancer cases from the HERLAP trial, was used to acquire expression profiles of a total of 105 unique genes
2013-10-25 | E-GEOD-46350 | biostudies-arrayexpress