scholarly journals Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

2021 ◽  
Vol 13 ◽  
pp. 175883592110337
Author(s):  
Fleur van der Sijde ◽  
Zakia Azmani ◽  
Marc G. Besselink ◽  
Bert A. Bonsing ◽  
Jan Willem B. de Groot ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Germline Variant ◽  
Early Tumor ◽  
Disease Stages ◽  
Generation Sequencing ◽  
Independent Cohort

Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control ( n = 30) or progressive disease ( n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.

scholarly journals Serum miR-373-3p and miR-194-5p Are Associated with Early Tumor Progression during FOLFIRINOX Treatment in Pancreatic Cancer Patients: A Prospective Multicenter Study

2021 ◽  
Vol 22 (20) ◽  
pp. 10902
Author(s):  
Fleur van der Sijde ◽  
Marjolein Y. V. Homs ◽  
Marlies L. van Bekkum ◽  
Thierry P. P. van den Bosch ◽  
Koop Bosscha ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Mirna Expression ◽  
Progressive Disease ◽  
High Serum ◽  
Disease Stage ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Total N ◽  
Serum Microrna ◽  
Early Tumor

In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD −0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10–14.49; miR-194-5p OR 0.91, 95% CI 0.83–0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.

scholarly journals Genomic Assessment of Blood-Derived Circulating Tumor DNA in Patients With Colorectal Cancers: Correlation With Tissue Sequencing, Therapeutic Response, and Survival

2019 ◽  
pp. 1-16 ◽  
Author(s):  
Shumei Kato ◽  
Maria C. Schwaederlé ◽  
Paul T. Fanta ◽  
Ryosuke Okamura ◽  
Lawrence Leichman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Partial Response ◽  
Stable Disease ◽  
Multivariable Analysis ◽  
Complete Response ◽  
Circulating Tumor Dna ◽  
Colorectal Cancers ◽  
Tumor Dna ◽  
Generation Sequencing

Purpose Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with colorectal cancers were correlated with clinical outcomes. Patients and Methods Next-generation sequencing of ctDNA (54- to 73-gene panel) was performed in 94 patients with colorectal cancer. Results Most patients (96%) had metastatic or recurrent disease at the time of blood draw. The median number of nonsynonymous alterations per patient was three (range, zero to 30). The most frequently aberrant genes were TP53 (52.1% of patients), KRAS (34%), and APC (28.7%). Concordance between tissue and blood next-generation sequencing ranged from 63.2% ( APC) to 85.5% ( BRAF). Altogether, 74 patients (79%) had one or more nonsynonymous alterations, 69 (73%) had one or more potentially actionable alterations, and 61 (65%) had an alteration actionable by a drug approved by the US Food and Drug Administration (on or off label). Lung metastases correlated with improved survival from diagnosis in univariable analysis. ctDNA of 5% or more from blood tests as well as EGFR and ERBB2 (HER2) nonsynonymous alterations correlated with worse survival (but only ERBB2 remained significant in multivariable analysis). No two patients had identical molecular portfolios. Overall, 65% versus 31% of patients treated with matched (n = 17) versus unmatched therapy (n = 18) after ctDNA testing achieved stable disease for 6 months or more, partial response, or complete response ( P = .045); progression-free survival, 6.1 versus 2.3 months ( P = .08); and survival not reached versus 9.4 months ( P = .146; all by multivariable analysis). Conclusion Patients with colorectal cancer have heterogeneous ctDNA profiles, and most harbor potentially actionable ctDNA alterations. Matched therapy yielded higher rates of stable disease for 6 months or more, partial response, or complete response. ctDNA assessment may have clinical utility and merits further investigation.

Variations of circulating KRAS amount as a biomarker to monitor chemotherapy response in pancreatic cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15794-e15794 ◽  
Author(s):  
Marzia Del Re ◽  
Caterina Vivaldi ◽  
Eleonora Rofi ◽  
Enrico Vasile ◽  
Mario Miccoli ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Current Treatment ◽  
Response To Therapy ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Analysis Tool ◽  
First Line ◽  
Imaging Evaluation ◽  
Significant Difference

e15794 Background: Current treatment of pancreatic ductal adenocarcinoma (PDAC) is FOLFIRINOX or gemcitabine + nab-paclitaxel, and CA19-9 is the only approved biomarker to monitor tumor response. However, CA19-9 has several limitations (i.e. sensitivity and specificity), highlighting the need for new biomarkers. Being the majority of PDAC (75-95%) KRAS mutated (mutKRAS), the present study developed an analysis tool based on circulating tumor DNA (ctDNA) to monitor the variation of mutKRAS in PDAC undergoing first-line chemotherapy. Early variation of ctDNA mutKRAS after 15 days of treatment was correlated with response to therapy. Methods: Three ml of plasma were collected from patients with PDAC undergoing first-line FOLFIRINOX or gemcitabine + nab-paclitaxel. Patients underwent standard disease evaluation by imaging according to RECIST 1.1 criteria. Blood samples were drawn prior to cycle 1, after 14 days and at each radiological evaluation. ctDNA was extracted using a QIAmp Circulating nucleic acid Kit (Qiagen, Valencia, CA) and the KRAS codon 12 and p.G13D analysis was performed by digital droplet PCR (ddPCR, BioRad, Hercules, CA). Results: A total of 27 patients with locally advanced (15%) and metastatic (85%) PDAC were included in this study. mutKRAS in ctDNA was detected in 19 patients (70.3%) at baseline. There were no statistically significant differences in median PFS and OS in patients with baseline positive or negative ctDNA mutKRAS (p = 0.15). However, there was a statistically significant difference in PFS and OS between patients with increase vs. stability/reduction of ctDNA at the 14 day-evaluation (median PFS: 2.5 vs 7.5 months, p = 0.03; median OS: 9 vs 11.5 months p = 0.009). The imaging evaluation performed at 2 months after initiation of therapy demonstrated that all patients with an increase in ctDNA at 14 days had radiological progression of disease. Conclusions: The results of this pilot study support the use of ctDNA as a new marker for monitoring treatment outcome and disease progression in PDAC, suggesting that ctDNA mutKRAS is a non-invasive predictive factor of response in PDAC.

scholarly journals Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Hitendra Patel ◽  
Ryosuke Okamura ◽  
Paul Fanta ◽  
Charmi Patel ◽  
Richard B. Lanman ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Prognostic Factor ◽  
Median Number ◽  
Circulating Tumor Dna ◽  
Ductal Adenocarcinoma ◽  
Next Generation ◽  
Poor Prognostic Factor ◽  
Resectable Disease ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. Methods ctDNA was analyzed in 112 patients with PDAC (54–73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. Results The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0–6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85–10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months. Conclusions Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

scholarly journals Clinical Implications of Pathogenic Germline Variants in Small Intestine Neuroendocrine Tumors (SI-NETs)

2021 ◽  
pp. 808-816
Author(s):  
Kimberly Perez ◽  
Matthew H. Kulke ◽  
Anu Chittenden ◽  
Chinedu Ukaegbu ◽  
Kristina Astone ◽  
...  
Keyword(s):  
Small Intestine ◽  
Neuroendocrine Tumors ◽  
Susceptibility Gene ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Inherited Susceptibility ◽  
Germline Variant ◽  
Hereditary Susceptibility ◽  
Generation Sequencing ◽  
Independent Cohort

PURPOSE An inherited basis for presumed sporadic neuroendocrine tumor (NET) has been suggested by evidence of familial clustering of NET and a higher incidence of second malignancies in patients and families with NET. To further investigate a potential heritable basis for sporadic neuroendocrine tumors, we performed multigene platform germline analysis to determine the frequency of hereditary susceptibility gene variants in a cohort of patients with sporadic small intestine NET (SI-NET). METHODS We performed a multigene platform germline analysis with Invitae's 83-gene, next-generation sequencing panel using DNA from 88 individuals with SI-NET from a clinically annotated database of patients with NET evaluated at Dana-Farber Cancer Institute (DFCI) who are considered high risk for inherited variants. Additionally, we evaluated the prevalence of pathogenic variants in an unselected cohort of patients with SI-NET who underwent testing with Invitae. RESULTS Of the 88 patients in the DFCI cohort, a pathogenic germline variant was identified in eight (9%) patients. In an independent cohort of 120 patients with SI-NET, a pathogenic germline variant was identified in 13 (11%) patients. Pathogenic variants were identified in more than one patient in the following genes: ATM, RAD51C, MUTYH, and BLM. Somatic testing of tumors from the DFCI cohort was suboptimal because of insufficient coverage of all targeted exons, and therefore, analysis was limited. CONCLUSION We demonstrate a 9%-11% incidence of pathogenic germline variants in genes associated with inherited susceptibility for malignancy not previously described in association with SI-NET. The association of these germline variants with neuroendocrine carcinogenesis and risk is uncertain but warrants further characterization.

scholarly journals Panel of serum miRNAs as potential non-invasive biomarkers for pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Imteyaz Ahmad Khan ◽  
Safoora Rashid ◽  
Nidhi Singh ◽  
Sumaira Rashid ◽  
Vishwajeet Singh ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Early Stage ◽  
Ductal Adenocarcinoma ◽  
Next Generation ◽  
Serum Samples ◽  
Tissue Samples ◽  
Non Invasive ◽  
Specific Symptoms ◽  
Generation Sequencing

AbstractEarly-stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to non-specific symptoms. Circulating miRNAs in body fluids have been emerging as potential non-invasive biomarkers for diagnosis of many cancers. Thus, this study aimed to assess a panel of miRNAs for their ability to differentiate PDAC from chronic pancreatitis (CP), a benign inflammatory condition of the pancreas. Next-generation sequencing was performed to identify miRNAs present in 60 FFPE tissue samples (27 PDAC, 23 CP and 10 normal pancreatic tissues). Four up-regulated miRNAs (miR-215-5p, miR-122-5p, miR-192-5p, and miR-181a-2-3p) and four down-regulated miRNAs (miR-30b-5p, miR-216b-5p, miR-320b, and miR-214-5p) in PDAC compared to CP were selected based on next-generation sequencing results. The levels of these 8 differentially expressed miRNAs were measured by qRT-PCR in 125 serum samples (50 PDAC, 50 CP, and 25 healthy controls (HC)). The results showed significant upregulation of miR-215-5p, miR-122-5p, and miR-192-5p in PDAC serum samples. In contrast, levels of miR-30b-5p and miR-320b were significantly lower in PDAC as compared to CP and HC. ROC analysis showed that these 5 miRNAs can distinguish PDAC from both CP and HC. Hence, this panel can serve as a non-invasive biomarker for the early detection of PDAC.

scholarly journals Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
S. Dhara ◽  
S. Chhangawala ◽  
H. Chintalapudi ◽  
G. Askan ◽  
V. Aveson ◽  
...  
Keyword(s):  
Low Cost ◽  
Disease Free Survival ◽  
Chromatin Accessibility ◽  
Cancer Prognosis ◽  
Ductal Adenocarcinoma ◽  
Binding Motifs ◽  
Free Survival ◽  
Array Technology ◽  
Treatment Naïve ◽  
Generation Sequencing

AbstractUnlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed “ATAC-array”, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

scholarly journals PCV for Oligodendroglial Tumors: In Search of Prognostic Factors for Response and Survival

2001 ◽  
Vol 28 (3) ◽  
pp. 215-223 ◽  
Author(s):  
David Fortin ◽  
David. R. Macdonald ◽  
J. Gregory Cairncross ◽  
Larry Stitt
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Survival Rates ◽  
Multivariable Analysis ◽  
Cancer Center ◽  
Chemotherapy Response ◽  
Initial Symptom ◽  
Oligodendroglial Tumors ◽  
Vascular Proliferation ◽  
Predicting Outcome

Background:We report survival and pretreatment prognostic factors for survival and chemosensitivity in 53 oligodendrogliomas treated with PCV (procarbazine, lomustine and vincristine) chemotherapy.Methods:A total of 53 patients with histologically proven oligodendroglioma, anaplastic oligodendroglioma or oligo-astrocytoma and treated with PCVwere extracted from the London Regional Cancer Center database. A retrospective review was conducted to evaluate overall survival and pretreatment prognostic factors for survival and chemosensitivity.Results:The median survival time from diagnosis was 123.6 months. The overall five- and ten-year survival rates were 72.7% and 52.7% respectively. Age <40, seizure as an initial symptom, absence of cognitive deficit and presence of a homogeneous hypodense lesion without contrast enhancement on the initial pretreatment CT scan were all factors independently associated with favorable outcome. The presence of increased cellularity, pleomorphism, mitosis, vascular proliferation and grading as an anaplastic lesion using these surrogates on pathological assessment, were all associated with an unfavorable outcome in univariable analysis. In multivariable analysis, only the anaplastic grading and presence of increased cellularity were significant determinants of unfavorable survival. The only factor adversely associated with chemosensitivity was the presence of a focal symptom at presentation.Conclusion:Overall survival is significantly longer in oligodendroglial lesions than in fibrillary astrocytic tumors. A two tier grading system using standard morphological features seems accurate in predicting outcome in these patients. The presence of a neoplastic astrocytic component does not seem to impact the outcome. No clinical, radiological or pathological factor could be identified to reliably predict chemotherapy response.

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