Molecular subtypes are associated with clinical benefit in cisplatin-treated metastatic urothelial cancer patients
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PROVIDER: PRJNA1052658 | ENA |
REPOSITORIES: ENA
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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.
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Project description:For patients with muscle-invasive bladder cancer, there are no biomarkers in clinical use that can identify patients that are sensitive or resistant to neoadjuvant chemotherapy. This study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cis-platin based chemotherapy by tumor classification using transcriptomic profiling and a 13-marker immunostaining panel. Furthermore, we explored to what extent gene expression signatures can predict chemotherapy response beyond molecular subtypes. We observed improved pathological response rates and survival outcomes for patients presenting with genomically unstable (GU) and urothelial-like (Uro) subtypes compared to the basal-squamous (BASQ) subtype following neoadjuvant chemotherapy and radical cystectomy. Also, SPP1, coding for osteopontin, displayed a clear subtype-dependent effect on chemotherapy response, confirmed at the protein level. Based on our findings, we hypothesize that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy which may influence patient selection pending further research.
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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.
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Project description:Bladder cancer is a major and mortal disease in urological area. Cisplatin is a key drug for bladder cancer especially for muscle invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin is critical for patient’s prognosis. Thus, treatment strategy for cisplatin resistant bladder cancer is essential to improve current prognosis. In this study, we established cisplatin resistant bladder cancer line (CR cells) using a urothelial carcinoma line UM-UC-3 cells. We screened potential targets for CR cells and found that claspin is overexpressed in CR cells. Claspin mRNA knockdown revealed that claspin has a role in cisplatin resistance in CR cells. In our previous study, we found HLA-A*02:01-restricted CLSPN peptide by an HLA ligandome analysis. We thus generated CLSPN peptide specific CTL clone and found that CLSPN peptide-specific CTL clone recognized CR cells at higher levels compared with that of UM-UC-3 wild type cells. These findings indicate that claspin is a driver for cisplatin resistance and claspin peptide-specific immunotherapy is effective for cisplatin resistant cases.
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Project description:<p>Cisplatin-based chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, and some patients with metastatic disease achieve complete responses to these therapies. However, the molecular determinants of cisplatin response are incompletely understood. We performed whole exome sequencing on tumor and germline DNA from patients with muscle invasive or metastatic urothelial carcinoma who received cisplatin-based chemotherapy to identify somatic mutations that occurred preferentially in cisplatin responders.</p>
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Project description:This study was conducted to identify transcriptional profiles predictive of a clinical response of metastatic gastric cancer patients to cisplatin and fluorouracil (CF) combination chemotherapy.
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