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

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.

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

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211033704 ◽

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.

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High serum microRNA-335 level predicts aggressive tumor progression and unfavorable prognosis in pediatric acute myeloid leukemia

Clinical & Translational Oncology ◽

10.1007/s12094-014-1237-z ◽

2014 ◽

Vol 17 (5) ◽

pp. 358-364 ◽

Cited By ~ 19

Author(s):

X. Lin ◽

Z. Wang ◽

R. Zhang ◽

W. Feng

Keyword(s):

Acute Myeloid Leukemia ◽

Tumor Progression ◽

Myeloid Leukemia ◽

High Serum ◽

Pediatric Acute Myeloid Leukemia ◽

Serum Microrna ◽

Aggressive Tumor ◽

Acute Myeloid

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Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

Applied Sciences ◽

10.3390/app9224784 ◽

2019 ◽

Vol 9 (22) ◽

pp. 4784

Author(s):

Vietsch ◽

Peran ◽

Suker ◽

van den Bosch ◽

Sijde ◽

...

Keyword(s):

Cancer Progression ◽

B Lymphocyte ◽

Immune Cell ◽

Tumor Resection ◽

Progression Free Survival ◽

Tumor Stroma ◽

Recurrence Risk ◽

High Serum ◽

Ductal Adenocarcinoma ◽

Before And After

Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+; Trp53R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.

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Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival

Cancers ◽

10.3390/cancers13071612 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1612

Author(s):

Julie Earl ◽

Emma Barreto ◽

María E. Castillo ◽

Raquel Fuentes ◽

Mercedes Rodríguez-Garrote ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Somatic Mutation ◽

Disease Status ◽

Clinical Analysis ◽

Cytotoxic Agents ◽

Disease Stage ◽

Ductal Adenocarcinoma ◽

Familial Pancreatic Cancer ◽

Circulating Free Dna

Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.

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Abstract PO-052: A pilot study of miRNA expression profile in surgically resected pancreatic ductal adenocarcinoma: Initial report from a bi-institutional cohort

10.1158/1538-7445.panca21-po-052 ◽

2021 ◽

Author(s):

Luca Pompella ◽

Michela Falco ◽

Carlo Caputo ◽

Anna Grimaldi ◽

Giuseppe Tirino ◽

...

Keyword(s):

Pilot Study ◽

Pancreatic Ductal Adenocarcinoma ◽

Expression Profile ◽

Mirna Expression ◽

Mirna Expression Profile ◽

Ductal Adenocarcinoma ◽

Initial Report

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FET PET Radiomics for Differentiating Pseudoprogression from Early Tumor Progression in Glioma Patients Post-Chemoradiation

Cancers ◽

10.3390/cancers12123835 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3835

Author(s):

Philipp Lohmann ◽

Mai A. Elahmadawy ◽

Robin Gutsche ◽

Jan-Michael Werner ◽

Elena K. Bauer ◽

...

Keyword(s):

Tumor Progression ◽

Negative Predictive Value ◽

Predictive Value ◽

Diagnostic Performance ◽

Data Augmentation ◽

Response Assessment ◽

Lower Sensitivity ◽

Fet Pet ◽

Early Tumor ◽

Dynamic Fet Pet

Currently, a reliable diagnostic test for differentiating pseudoprogression from early tumor progression is lacking. We explored the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) radiomics for this clinically important task. Thirty-four patients (isocitrate dehydrogenase (IDH)-wildtype glioblastoma, 94%) with progressive magnetic resonance imaging (MRI) changes according to the Response Assessment in Neuro-Oncology (RANO) criteria within the first 12 weeks after completing temozolomide chemoradiation underwent a dynamic FET PET scan. Static and dynamic FET PET parameters were calculated. For radiomics analysis, the number of datasets was increased to 102 using data augmentation. After randomly assigning patients to a training and test dataset, 944 features were calculated on unfiltered and filtered images. The number of features for model generation was limited to four to avoid data overfitting. Eighteen patients were diagnosed with early tumor progression, and 16 patients had pseudoprogression. The FET PET radiomics model correctly diagnosed pseudoprogression in all test cohort patients (sensitivity, 100%; negative predictive value, 100%). In contrast, the diagnostic performance of the best FET PET parameter (TBRmax) was lower (sensitivity, 81%; negative predictive value, 80%). The results suggest that FET PET radiomics helps diagnose patients with pseudoprogression with a high diagnostic performance. Given the clinical significance, further studies are warranted.

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Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma

Genes ◽

10.3390/genes10100766 ◽

2019 ◽

Vol 10 (10) ◽

pp. 766 ◽

Cited By ~ 3

Author(s):

Yao-Yu Hsieh ◽

Tsang-Pai Liu ◽

Chia-Jung Chou ◽

Hsin-Yi Chen ◽

Kuen-Haur Lee ◽

...

Keyword(s):

Cell Cycle ◽

Pancreatic Ductal Adenocarcinoma ◽

Gene Deletion ◽

Transforming Growth Factor ◽

Ductal Adenocarcinoma ◽

Gene Copy ◽

Chemotherapy Response ◽

Specific Cell ◽

Smad4 Gene ◽

Therapeutic Benefits

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.

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Nomogram for Predicting Survival in Patients Treated with Liposomal Irinotecan Plus Fluorouracil and Leucovorin in Metastatic Pancreatic Cancer

Cancers ◽

10.3390/cancers11081068 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1068 ◽

Cited By ~ 5

Author(s):

Chen ◽

Macarulla ◽

Blanc ◽

Mirakhur ◽

Jong ◽

...

Keyword(s):

Carbohydrate Antigen ◽

Phase Iii ◽

Disease Stage ◽

Ductal Adenocarcinoma ◽

Karnofsky Performance Score ◽

Neutrophil Lymphocyte Ratio ◽

Baseline Factors ◽

Liposomal Irinotecan ◽

Aid Decision ◽

Post Hoc

NAPOLI-1 (NCT01494506) was a phase III study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This post hoc analysis of NAPOLI-1 aimed to develop a predictive nomogram for overall survival (OS) at 6 and 12 months. Analyses were derived from all patients in NAPOLI-1 randomized to receive nal-IRI+5-FU/LV, nal-IRI monotherapy, or 5-FU/LV combination therapy. OS was associated with baseline factors using univariate and multivariable Cox analyses. A predictive nomogram was derived and validated using a concordance index and calibration plots. The univariate analyses identified 21 independent factors that contributed to OS, with eight factors significantly associated with OS. The Karnofsky Performance Score contributed the largest number of points (100), followed by presence of liver metastasis (98) and randomization to nal-IRI+5-FU/LV (96). The other baseline factors showing effects were albumin (g/dL), neutrophil/lymphocyte ratio, carbohydrate antigen 19-9 (U/mL), disease stage at diagnosis, and body mass index (kg/m2). The nomogram was used to predict the 6- and 12-month survival probability. The mean absolute errors between the observed and predicted probabilities for OS at 3, 6, and 9 months were 0.07, 0.08, and 0.07, respectively. This nomogram, based on NAPOLI-1, provides additional insight to aid decision-making for patients with mPDAC after previous gemcitabine-based therapy.

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