Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study.
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ABSTRACT:
SUBMITTER: Woo SM
PROVIDER: S-EPMC8582446 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Circulating tumor cells (CTCs) are useful biomarkers of many solid tumors, but are infrequently detected in early stage pancreatic ductal adenocarcinomas (PDACs). The first drainage of pancreatic venous blood flow come to portal vein and pass through the liver, and they finally go out for peripheral blood. We thought that comparing CTCs from portal vein and peripheral blood could enable us to understand the clinical meaning of CTCs from each different site in PDACs. Therefore, we aimed to determine 1) whether CTCs could be reliably identified in early stages (operable) of PDACs, 2) if there are any differences in the detected number of CTC in portal vein blood and peripheral blood, and 3) whether CTCs can be sensitive biomarkers for the prognosis of resectable PDAC patients. Newly diagnosed PDAC patients who underwent operation with curative intention between 2013 and 2015 were prospectively enrolled. Blood draws from portal and peripheral vein ran through the microfabricated porous filter, and anti-epithelial cell adhesion molecule (EpCAM) and anti-Plectin-1 antibodies were used for CTC identification. Baseline clinical characteristics, tumor characteristics, treatment, and clinical outcomes were assessed. The clinical stages of the 32 enrolled patients were as follows: IA/IB 1 (3.1%); IIA 9 (28.1%); IIB 17 (53.1%); III 5 (15.6%). Twenty-seven patients (84.4%) received R0 resection, while five patients (15.6%) received R1 resection. EpCAM+ CTCs were detected in 20 portal blood (62.5%) and 22 peripheral blood (68.8%). Plectin-1+ CTCs were identified in 14 portal blood (43.8%) and 16 peripheral blood (50%). Plectin-1-expressing CTCs were picked from CTC platform (microfabricated porous filter) and we could find out all KRAS mutation. Patients with detectable EpCAM+ CTC less than one in peripheral blood showed longer overall survival (OS) compared to patients with detectable CTCs more than one (35.5 months vs. 16.0 months). EpCAM and Plectin-1 successfully identified CTCs at the early stage of PDACs. Also, the number of CTCs could be a prognostic marker for survival in resectable PDACs.
| S-EPMC7930477 | biostudies-literature
Project description:BACKGROUND:Accumulating evidence demonstrated immune/inflammation-related implications of basophils in affecting tissue microenvironment that surrounded a tumor, and this study aimed to elucidate the clinical value of serum basophil count level. METHODS:Between December 2007 and September 2013, 1029 patients diagnosed with stage I-III CRC in Fudan University Shanghai Cancer Center meeting the essential criteria were identified. The Kaplan-Meier method was used to construct the survival curves. Several Cox proportional hazard models were constructed to assess the prognostic factors. A simple predictor (CB classifier) was generated by combining serum basophil count and serum carcinoembryonic antigen (CEA) level which had long been accepted as the most important and reliable prognostic factor in CRC. RESULTS:The preoperative basophils count <?0.025*109/L was strongly associated with higher T stage, higher N stage, venous invasion, perineural invasion, elevated serum CEA level, and thus poor survival (P?<?0.05). Moreover, multivariate Cox analysis showed that patients with low level of preoperative basophils count had an evidently poorer DFS [Hazard ratio (HR)?=?2.197, 95% CI 1.868-2.585]. CONCLUSIONS:As a common immune/inflammation-related biomarker available from the blood routine examination, low level of preoperative serum basophil count was associated with aggressive biology and indicated evidently poor survival. Preoperative serum basophil count would be a useful and simple marker for the management of CRC patients.
| S-EPMC7008108 | biostudies-literature
Project description:BackgroundIn pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse.MethodsThe stable isotope labeling of amino acids in cell culture (SILAC)-approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker.ResultsSILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001).ConclusionsCTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation.
| S-EPMC9497091 | biostudies-literature
Project description:BackgroundGenomic instability (GI) is a critical feature of cancer which plays a key role in the occurrence and development of pancreatic adenocarcinoma (PAAD). Long non-coding RNA (LncRNA) is an emerging prognostic biomarker because it is involved in regulating GI. Recently, researchers used such GI-related LncRNAs (GILncRNAs) to establish a prognostic signature for patients with cancer and helped in predicting the overall prognosis of the patients. However, it is evident that patients with PAAD still lack such prognostic signature constructed with GILncRNA.MethodsThe present study screened GILncRNAs from 83 patients with PAAD. Prognosis-related GILncRNAs were identified by univariate Cox regression analysis. The correlation coefficients of these GILncRNAs were obtained by multivariate Cox regression analysis and used to construct a signature. The signature in the present study was then assessed through survival analysis, mutation correlation analysis, independent prognostic analysis, and clinical stratification analysis in the training set and validated in the testing as well as all TCGA set. The current study performed external clinical relevance validation of the signature and validated the effect of AC108134.2 in GILncSig on PAAD using in vitro experiments. Finally, the function of GILncRNA signature (GILncSig) dependent on Gene Ontology enrichment analysis was explored and chemotherapeutic drug sensitivity analysis was also performed.ResultsResults of the present study found that a total of 409 GILncRNAs were identified, 5 of which constituted the prognostic risk signature in this study, namely, AC095057.3, AC108134.2, AC124798.1, AL606834.1, and AC104695.4. It was found that the signature of the present study was better than others in predicting the overall survival and applied to patients with PAAD of all ages, genders, and tumor grades. Further, it was noted that the signature of the current study in the GSE102238, was correlated with tumor length, and tumor stage of patients with PAAD. In vitro, functional experiments were used in the present study to validate that AC108134.2 is associated with PAAD genomic instability and progression. Notably, results of the pRRophetic analysis in the current study showed that the high-risk group possessed reverse characteristics and was sensitive to chemotherapy.ConclusionsIn conclusion, it was evident that the GILncSig used in the present study has good prognostic performance. Therefore, the signature may become a potential sensitive biological indicator of PAAD chemotherapy, which may help in clinical decision-making and management of patients with cancer.
| S-EPMC9012103 | biostudies-literature
Project description:BACKGROUND:The accurate prognosis definition to tailor treatment for early luminal invasive breast carcinoma patients remains challenging. MATERIALS AND METHODS:Two hundred fourteen early luminal breast carcinomas were genotyped with single nucleotide polymorphisms (SNPs) array to determine the number of chromosomal breakpoints as a marker of genomic instability. Proliferation was assessed by KI67 (immunohistochemistry) and genomic grade index (transcriptomic analysis). IHC3 (IHC4 score for HER2 negative tumors) was also determined. RESULTS:In the training set (109 cases), the optimal cut-off was 34 breakpoints with a specificity of 0.94 and a sensitivity of 0.57 (Area under the curve (AUC): 0.81[0.71; 0.91]). In the validation set (105 cases), the outcome of patients with > 34 breakpoints (11 events / 22 patients) was poorer (logrank test p < 0.001; Relative Risk (RR): 3.7 [1.73; 7.92]), than that of patients with < 34 breakpoints (19 events / 83 patients).Whereas genomic grade and KI67 had a significant prognostic value in univariate analysis in contrast to IHC3 that failed to have a statistical significant prognostic value in this series, the number of breakpoints remained the only significant parameter predictive of outcome (RR: 3.47, Confidence Interval (CI [1.29; 9.31], p = 0.014)) in multivariate analysis . CONCLUSION:Genomic instability, defined herein as a high number of chromosomal breakpoints, in early stage luminal breast carcinoma is a stronger prognostic marker than proliferation.
| S-EPMC3797106 | biostudies-literature
Project description:The role of circulating tumor cells (CTCs) as a marker for disease progression in metastatic cancer is controversial. The current review will serve to summarize the evidence on CTCs as a marker of disease progression in patients with metastatic breast cancer. The immunohistochemistry(IHC)-based CellSearch® is the only FDA-approved isolation technique for quantifying CTCs in patients with metastatic breast cancer. We searched PubMed and Web of Knowledge for clinical studies that assessed the prognostic and predictive value of CTCs using IHC-based isolation. The patient outcomes reported include median and Cox-proportional hazard ratios for overall-survival (OS) and progression-free-survival (PFS). All studies reported shorter OS for CTC-positive patients versus CTC-negative. A subset of the selected trials reported significant lower median PFS for CTC-positive patients. The reported trials support the utility of CTC enumeration for patient prognosis. But further studies are required to determine the utility of CTC enumeration for guiding patient therapy. There are three clinical trials ongoing to test this hypothesis. These studies, and others, will further establish the role of CTCs in clinical practice.
| S-EPMC4405902 | biostudies-literature
Project description:BackgroundCurrently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC.MethodsTumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival.ResultsSomatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616-188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4.ConclusionsPersonalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.
| S-EPMC7860194 | biostudies-literature
Project description:BackgroundThe tumor microenvironment (TME) plays a crucial role in the progression of pancreatic adenocarcinoma (PAAD). However, challenges remain regarding the role played by TME associated genes in the prognosis of PAAD.MethodsThe scores of tumor infiltrating immune cells (TICs), the immune and stroma scores of 182 PAAD patients in the Cancer Genome Atlas (TCGA) database were determined using CIBERSORT and ESTIMATE calculations. The final genes were identified by protein-protein interaction (PPI) networks and univariate Cox regression of differentially expressed genes. Finally, the correlation between gene expression and TCGA and clinical characteristics of patients in local hospital database was discussed. Gene set enrichment analysis (GSEA), the association between CXCL10 expression and TICs components were conducted.ResultsIn TCGA database and local hospital data, CXCL10 expression was correlated with the survival rate and TNM classification of patients with PAAD. Immune-related activities were enriched in the CXCL10 high expression group, while metabolic pathways were enriched in the CXCL10 low expression group. The expression of CXCL10 correlated with the proportion of TICs. CXCL10 expression was correlated with the proportion of TICs.ConclusionCXCL10 is a potential prognostic marker for PAAD and provide additional insights into the treatment of PAAD based on TME transformation. However, more independent experimentation with the CXCL10 is need.
| S-EPMC9926744 | biostudies-literature
Project description:We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC).PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification.Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45.Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02).CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.
| S-EPMC4936958 | biostudies-literature
Project description:BackgroundDiabetes is a risk factor for pancreatic cancer but its association with survival from pancreatic cancer is poorly understood. Our objective was to investigate the association of diabetes with survival among pancreatic cancer patients in a prospective cohort-based study where diabetes history was ascertained before pancreatic cancer diagnosis.MethodsWe evaluated survival by baseline (1993-2001) self-reported diabetes history (n=62) among 504 participants that developed exocrine pancreatic cancer within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using Cox proportional hazards model, adjusted for age, sex, body mass index, race, smoking, and tumour stage (local, locally advanced, and metastatic).ResultsThe multivariable-adjusted HR for mortality comparing participants with diabetes to those without was 1.52 (95% CI=1.14-2.04, P-value <0.01). After excluding those diagnosed with pancreatic cancer within 3 years of study enrolment, HR for mortality among those with diabetes was 1.45 (95% CI=1.06-2.00, P-value=0.02).ConclusionsUsing prospectively collected data, our findings indicate that diabetes is associated with worse survival among patients with pancreatic cancer.
| S-EPMC4090724 | biostudies-literature