scholarly journals A novel 20-gene prognostic score in pancreatic adenocarcinoma

2019 ◽  
Author(s):  
Secil Demirkol Canli ◽  
Ege Dedeoglu ◽  
Muhammad Waqas Akbar ◽  
Baris Kucukkaraduman ◽  
Murat Isbilen ◽  
...  
Keyword(s):  
Immune Cell ◽  
Prognostic Score ◽  
Performance Status ◽  
Cyclin B1 ◽  
Pancreatic Tissue ◽  
Tnm Staging ◽  
Prognostic Indicators ◽  
Ductal Adenocarcinoma ◽  
Primary Tumors ◽  
And Performance

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. The only FDA approved prognostic biomarker for PDAC patients is CA19-9. This, along with AJCC TNM staging and performance status, are considered important prognostic indicators in clinical practice. In order to better prognosticate patients with PDAC, we identified a novel panel of genes by utilizing publically available microarray and RNAseq data of PDAC tumors from GEO and TCGA. Expression of 20 genes were significantly associated with overall survival in four datasets and event-free survival in TCGA. A score generated based on the expression matrix of these genes could be validated in two independent cohorts. We find that this “Pancreatic cancer prognostic score 20 – PPS20” is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological sub-groups but can predict response to targeted therapy options as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.

Identification of a microRNA (miRNA) based signature for survival in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with cisplatin-vinorelbine: A ELCWP study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18006-e18006
Author(s):  
Thierry Berghmans ◽  
Luc Willems ◽  
Marianne Paesmans ◽  
Lieveke Ameye ◽  
Jean-Jacques Lafitte ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Prognostic Score ◽  
Performance Status ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Cox's Regression ◽  
And Performance ◽  
A Prospective Study ◽  
Nsclc Patients

e18006 Background: Main prognostic factors for survival in NSCLC pts are stage and performance status (PS) while sex, histology and others are reported. However, these variables do not allow predicting individual prognosis, justifying further research. MiRNA are small non-coding RNAs regulating gene expression. As a secondary aim of a prospective study, we looked at the prognostic value of tumour miRNA on survival in NSCLC pts treated by cisplatin (60 mg/m2 D1) and vinorelbine (25 mg/m2, D1+8) 1st line chemotherapy. Methods: During the diagnostic bronchoscopy, a biopsy was lysed into Tripure Isolation Reagent (Roche Diagnostics) on ice, snap frozen and stored at -80°C. MiRNA expression was assessed using TaqMan Low Density Arrays (756 human miRNA panel, Applied Biosystems) and normalized using the delta delta CT method to RNU48 (SNORD48) CT value for every sample. Survival was measured from the registration date. Results: The main characteristics of 38 eligible pts were: median age 60 years, male 27 (71%), 80-100 Karnofsky PS in 26 (68%), adenocarcinoma 20 (53%), stage IV 30 (79%). At time of analysis, 25 pts were dead. After stepwise selection among 756 analysed miRNA, a combination of 4 miRNA including miR-200c, miR-424, miR-29c and miR-124 provided a prognostic signature for survival. Using a linear combination of the miRNA CT values with Cox's regression coefficients as weights, we constructed a prognostic score. With a cut-off of 52, the signature distinguished pts with good (n = 18) and poor (n = 20) prognosis with respective median survival of 47.3 months (95% CI 29.8-52.4) and 15.5 months (95% CI 9.1-22.8) (p <0.001; hazard ratio 21.1, 95% CI 4.7-94.9). The same signature discriminated pts with “good progression-free survival” (median 19.8 months; 95% CI 15.3-33.8) from the others (median 9.1 months; 95% CI 6.3-15.5) (p <0.001; hazard ratio 3.8, 95% CI 1.7-8.7). Conclusions: A 4 miRNA signature is associated with improved survival in patients with advanced stage NSCLC treated with 1st line cisplatin and vinorelbine. These results need confirmation in an independent cohort and the signature has to be compared to conventional prognostic factors.

Real-world treatment patterns and outcomes in HER2 positive MBC patients with brain metastasis in the U.S. community oncology setting.

2016 ◽  
Vol 34 (7_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
Debra A. Patt ◽  
Eileen Fonseca ◽  
Bongin Yoo ◽  
Thomas Wilson ◽  
Hans-Peter Goertz ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Performance Status ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Primary Tumors ◽  
Whole Brain Radiation ◽  
Community Oncology ◽  
Estrogen Receptor Positive ◽  
And Performance ◽  
Metastatic Sites

92 Background: Patients (pts) with HER2 positive (HER2+) metastatic breast cancer (MBC) have different patterns of disease and treatment (tx) from HER2 negative MBC. Brain metastasis (BM) frequently occurs and txs vary. Methods: This retrospective study included adult HER2+ MBC pts from a community oncology network electronic health record (EHR) database and diagnosed between 2009-2011, with follow-up until 11/2014. Pts with other primary tumors were excluded. Two cohorts were defined: pts diagnosed with BM and pts with no evidence of BM (NBM), and were initially matched on age and performance status at MBC diagnosis (dx) and stage. Eligibility and txs were examined in electronic chart review. Overall survival (OS) from MBC dx was estimated using a weighted Kaplan-Meier method. Results: The final sample consisted of 86 BM and 101 NBM pts. All baseline MBC demographics were similar across cohorts. Median age was 54 and 52 years for BM and NBM, respectively. The cohorts (BM:NBM) included 57%:75% Caucasians, 12%:6% Blacks, and 31%:19% other/unknown. There were fewer estrogen receptor positive pts in the BM cohort (58%:74%; p = 0.02). Except for bone (p = 0.01), both cohorts had similar prevalence of metastatic sites: liver 35%:35%; lung 31%:30%; bone 41%:62. Of all the BM pts, 54% had first CNS imaging after symptoms, 37% were first imaged for other known reasons. After BM dx, 20% had surgical resection, 67% whole brain radiation (XRT), 37% stereotactic XRT, and 22% palliative XRT (not mutually exclusive). 25% of pts had both XRT and surgery while 72% had only XRT. Among pts receiving systemic therapy after BM dx, the first regimen contained trastuzumab in 55% of pts and lapatinib in 41% of pts. Among pts changing txs after BM dx, 1/3 switched to a trastuzumab but not lapatinib-based regimen; 1/3 to a lapatinib but not trastuzumab-based regimen; 17% to a lapatinib + trastuzumab-based regimen; and 17% to non-HER2-based therapy. Weighted median OS from MBC dx for BM vs. NBM pts was 30.2 and 46.1 months (p = 0.01). Conclusions: For HER2+ MBC pts, survival was shorter for pts with BM vs. NBM and a high degree of tx variability for BM existed. Understanding how detection and tx impacts outcomes will improve care of BM pts.

High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4021-4021
Author(s):  
Andreas Seeber ◽  
Florian Kocher ◽  
Andreas Pircher ◽  
Alberto Puccini ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Tumor Regression ◽  
Signal Transduction Pathway ◽  
Cxcr4 Expression ◽  
Ductal Adenocarcinoma ◽  
Rna Expression ◽  
Primary Tumors ◽  
Pathway Gene ◽  
Molecular Landscape

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.

Poor prognostic indicators for patients treated with radiosurgery for brain metastases.

2016 ◽  
Vol 34 (26_suppl) ◽  
pp. 32-32 ◽  
Author(s):  
Michael A Garcia ◽  
Wendy Anderson ◽  
Shannon E. Fogh ◽  
Jean L. Nakamura ◽  
Philip Theodosopoulos ◽  
...  
Keyword(s):  
Brain Metastases ◽  
San Francisco ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Whole Brain Radiotherapy ◽  
Median Number ◽  
Prognostic Indicators ◽  
Imaging Data ◽  
Primary Tumors ◽  
Brain Radiotherapy

32 Background: Radiosurgery (SRS) is a standard palliative treatment for patients with limited number of brain metastases. Growing evidence supports the use of SRS for more extensive disease. As SRS is increasingly used in advanced cancer, we sought to identify predictors of survival after SRS to help better inform patients about prognosis. Methods: We reviewed patients treated with SRS for brain metastases at the University of California, San Francisco (UCSF) from Jan 2010-Dec 2013. Before SRS, all patients were screened for appropriateness of SRS at a multidisciplinary conference. Post-SRS overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank tests. Frequencies of death within 30 days of SRS were compared by chi-squared tests. Results: Demographic and imaging data was available for 326 SRS patients. At SRS consult, 90% patients were Karnofsky Performance Status (KPS) ≥ 70. Median number of brain metastases at consult was 2 (range 1-37). Median follow up was 13 months. Median OS after SRS was 11 months. Median OS was shorter for patients with KPS < 70 (4 months) compared to those with KPS ≥ 70 (12 months) (p < 0.001). Overall, frequency of death within 30 days of SRS was 5.4%. Within 30 days of SRS, 13% of patients with KPS < 70 died compared to 3.8% with KPS ≥ 70 (p = 0.03). Death within 30 days of SRS was more common among patients with uncontrolled (10%) versus controlled primary tumors (3%) (p = 0.02). Both uncontrolled primary tumor and KPS < 70% were associated with death within 30 days of SRS on multivariate analysis (p = 0.02 and p = 0.03, respectively). Patients with both KPS < 70 and uncontrolled primary tumors had frequency of death within 30 days of 29%. Factors not associated with death within 30 days were age, extracranial metastatic disease burden, histology, number of brain metastases, prior whole brain radiotherapy, SRS, or neurosurgery. Conclusions: Death within 30 days of SRS within the UCSF cohort is uncommon, likely due to multidisciplinary screening for patients expected to live long enough to benefit from SRS. Most patients who die within 30 days of SRS have both KPS < 70 and uncontrolled primary tumors. The potential for poor prognosis should be discussed with these patients during shared-decision making.

scholarly journals Pancreatic ductal adenocarcinoma: Prognostic indicators of advanced disease

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262439
Author(s):  
Deirdré Kruger ◽  
Nicola Lahoud ◽  
Yandiswa Y. Yako ◽  
John Devar ◽  
Martin Smith
Keyword(s):  
Risk Factors ◽  
Platelet Count ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tumour Marker ◽  
Tnm Staging ◽  
Prognostic Indicators ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Gm Csf ◽  
Presenting Symptoms

Background/Objectives Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with high metastatic risk. Prognosis remains poor even after resection. Previously our group identified biomarkers that improved diagnostic accuracy in PDAC beyond the established diagnostic tumour marker, CA19-9. Risk factors, symptoms and circulating biomarkers associated with a PDAC diagnosis may differ from those that alter disease progression and metastasis. This study aimed at assessing the risk factors, presenting symptoms and potential prognostic biomarkers in PDAC and determine their relationship with PDAC stage and/or metastatic status. Methods Seventy-two PDAC patients with imaging available for TNM staging at presentation were enrolled following informed consent. Demographic and clinical data were captured. Blood was collected and 38 cytokines/angiogenic factors measured. Nonparametric association tests, univariate and multivariate logistic regression were performed using STATA version 14.2. A p-value≤0.05 was considered significant and odds ratios reported for effect size. Results Most risk factors and symptoms did not differ across the stages of cancer. Although male gender and smoking are risk factors for PDAC, the majority of study patients with metastatic PDAC were non-smoking females. In addition to CA19-9, the platelet count (p<0.01), IL-15 (p = 0.02) and GM-CSF (p<0.01) were significant, independent negative predictors of metastatic PDAC. Moreover, using specific cut-off values in a combined panel, the odds in a patient with all three biomarker levels below the cut-offs is 21 times more likely to have metastatic PDAC (p<0.0001). Conclusions Platelet count, IL-15 and GM-CSF are potential prognostic indicators of metastatic disease in PDAC patients from our local South African population.

scholarly journals An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

2020 ◽  
Author(s):  
Katherine E Baxter ◽  
Christiano Tanese de Souza ◽  
Lee-Hwa Tai ◽  
Pasha Yaghini ◽  
Manijeh Daneshmand ◽  
...  
Keyword(s):  
Murine Model ◽  
Immune Cell ◽  
Therapeutic Benefit ◽  
Treatment Modalities ◽  
Ductal Adenocarcinoma ◽  
Primary Tumors ◽  
Immune Phenotyping ◽  
Immunocompetent Mice ◽  
And Function ◽  
Post Implantation

AbstractBackgroundAlthough surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations.Materials and MethodsSurgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass.ResultsAs expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery.ConclusionThis represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.

scholarly journals Using Exome Sequencing to Improve Prediction of FOLFIRINOX First Efficacy for Pancreatic Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1851
Author(s):  
Julie Lecuelle ◽  
Anne Aarnink ◽  
Zoé Tharin ◽  
Caroline Truntzer ◽  
François Ghiringhelli
Keyword(s):  
Exome Sequencing ◽  
Cox Regression ◽  
Prognostic Score ◽  
Performance Status ◽  
Progression Free Survival ◽  
Copy Number Variant ◽  
Clinical Score ◽  
Tumor Stage ◽  
Ductal Adenocarcinoma ◽  
First Line

Purpose: The first line treatment of advanced pancreatic ductal adenocarcinoma cancer (PDAC) comprises a FOLFIRINOX regimen for most patients with good performance status. However, no biomarker to predict efficacy is currently available. We investigated whether exome sequencing could be used to predict progression-free and overall survival in patients undergoing FOLFIRINOX for PDAC. Methods: In this single-center observational study, we included 78 patients with advanced PDAC who underwent somatic and germline exome analyses during first line therapy with FOLFIRINOX or gemcitabine. Exome-derived variables associated with outcome were then used in Cox regression models to generate a composite biomarker. Results: Performance status, tumor stage, liver metastasis, and lung metastasis were retained to generate a prognostic clinical score associated with overall and progression-free survival. Clonality, ploidy, and copy number variant (CNV) signatures 1 and 5, as well as gene variants in the calcium, non-homologous end-joining (NHEJ), and spliceosome pathways, were retained to generate a genomic prognostic score. The addition of genomic score improved the prediction of prognosis compared to the clinical score alone. Conclusions: This study underlines that structural and pathway genomic features could be used to predict FOLFIRINOX survival in patients with advanced PDAC.

Clinical performance of blood-based RNA signatures (GemciTest) for the gemcitabine response in advanced pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16238-e16238
Author(s):  
David Piquemal ◽  
Roman Bruno ◽  
Florian Noguier ◽  
Fabien Pierrat ◽  
Amelia Gamez ◽  
...  
Keyword(s):  
Clinical Performance ◽  
Performance Status ◽  
Strong Association ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
University Of Wisconsin ◽  
Clinical Benefit Response ◽  
And Performance ◽  
The University

e16238 Background: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal often presents at a later stage. Gemcitabine is still an important component in PDAC treatment however there is no routine biomarker to predict its efficacy. We had previously performed a discovery cohort of two separate RNA-blood signatures in 60 patients (NCT00789633) showing an association with PFS and OS. Called GemciTest, this CE-IVD molecular test requires 2.5ml whole blood sample before starting the patient's 1st line chemotherapy. From this liquid biopsy, IVD measures the expression levels of nine genes using real-time PCR processes. This abstract presents the clinical validation of GemciTest. Methods: In this study, clinical validations were done on 214 patients (mean 68.7-year-old; 37-88) from 3 distinct cohorts with the University of Wisconsin Biobank, GemciPANC trial (NCT03599154), and BACAP (NCT02818829). These cohorts included first-line treatment,with either a gemcitabine or fluoropyrimidine based regimen. Results: Patients with a clinical benefit response identified by GemciTest (31.5%) had a significantly longer progression free survival (PFS) (5.4 months vs. 3.1 months p = 0.0032) and a longer overall survival (OS) (13.1 months vs. 5.4, p < 0.0003). In multivariate analyses including tumor localization and performance status, this signature continued to be associated with PFS (HR = 0.52 (0.34–0.81) p = 0.003) and OS (HR = 0.44 (0.28 – 0.69) p = 0.0002).Conclusions: GemciTest validation was performed, showing a strong association with PFS and OS.[Table: see text]

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