KRAS gene mutation quantification in the resection or venous margins of pancreatic ductal adenocarcinoma is not predictive of disease recurrence (original) (raw)
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2021
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) patients eligible for curative surgery undergo unpredictable disease relapse. Post-surgery tools’ prognostic value is insufficient. Even patients with good pathological response after neo-adjuvant treatment (NAT) remain susceptible to recurrent PDAC. Molecular analysis of R0 margins may identify patients with worse prognosis. Methods: Retrospective analysis of patients, either eligible for up-font surgery (UFS, n=17) or resected patients who underwent NAT with good pathological responses (n=18), collected progression-free and overall survivals 33 months ±17 months post-surgery and examined the molecular status of mutant KRAS by droplet digital PCR.Results: Expectedly, KRAS mutant allele frequencies (MAF) were higher in UFS than in NAT tumor tissues or remnants, and in the ypT1 than the ypT0 tumors in the NAT group. Mutant KRAS positivity or MAFs in margins did not identify patients with detectable pathological disease in...
KRAS mutational analysis in ductal adenocarcinoma of the pancreas and its clinical significance
Pathology - Research and Practice, 2014
Mutations of KRAS are detectable in 70-90% of pancreatic duct adenocarcinomas (PDAC), using direct sequencing. We used a highly sensitive molecular method in order to investigate: (a) the frequency and prognostic significance of different KRAS mutations and, (b) whether the presence of KRAS mutations in histologically-negative resection margins of PDAC could explain local tumor recurrence after surgery.
Pancreas, 2019
Objective: Although complete surgical resection is the only curative method for pancreatic cancer, the radial resection margins of pyloruspreserving pancreaticoduodenectomy specimens might be underevaluated. Methods: KRAS mutation was assessed with droplet digital polymerase chain reaction on cells collected from the radial resection margins of 81 patients, and the results were compared with those of conventional pathologic resection margin (pRM) evaluation. Results: KRAS mutation was detected in 76 patients (94%), and molecular resection margin (mRM) positivity defined by a KRAS mutation rate of 4.19% or greater was observed in 18 patients (22%). Patients with mRMpositive had significantly worse recurrence-free survival (RFS) than those with mRM-negative in entire groups (P = 0.008) and in subgroups without chemotherapy or radiation therapy (all, P < 0.001). When combined pRMs-mRMs were evaluated, patients with combined pRM-mRM-positive (either pRM-or mRM-positive) had significantly worse RFS than those with combined resection margin-negative (both pRM and mRM negative) by univariate (P = 0.002) and multivariate (P = 0.03) analyses. Conclusions: KRAS mutational analysis with ultrasensitive droplet digital polymerase chain reaction of the radial resection margin in pancreatic cancer patients who underwent pylorus-preserving pancreaticoduodenectomy can provide more accurate information on RFS by using alone or in combination with conventional pRM evaluation, especially in patients without chemotherapy or radiation therapy.
Cells
Background: KRAS G12D mutation subtype is present in over 40% of pancreatic ductal adenocarcinoma (PDAC), one of the leading global causes of cancer death. This retrospective cohort study aims to investigate whether detection of the KRAS G12D mutation subtype in PDAC patients is a determinant of prognosis across all stages of disease. Methods: We reviewed the medical records of 231 patients presenting with PDAC at a large tertiary hospital, and compared survival using the Kaplan Meier, log-rank test and Cox proportional hazards regression model. Results: KRAS G12D mutation subtype was not significantly associated with poorer survival compared across the whole population of PDAC patients (p = 0.107; HR 1.293 95% CI (0.946–1.767)). However, KRAS G12D patients who were resectable had a shorter median survival time of 356 days compared to all other genotypes (median survival 810 days) (p = 0.019; HR 1.991 95% CI (1.121–3.537)). Conclusions: KRAS G12D patients who were resectable at diag...
Journal of Morphological Sciences, 2020
Pancreatic adenocarcinoma is the seventh cause of death of all malignant tumors worldwide and has the worst prognosis of all solid tumors. In Europe, it is the sixth most common cause of cancer related death and in United States it is the fifth cause of death after lung cancer, prostate cancer, breast and colorectal cancer. Numerous molecular studies have analyzed genetic and epigenetic changes as responsible for the histological variants of this cancer, their correlation with family predisposition, and opportunities for better treatment and survival. This study included 42 patients with pancreatic adenocarcinoma. Tumor tissue samples obtained from surgical specimen were histopathologicaly examined and genetic mutations were determinate. Prior to surgery, patients were diagnosed by imaging modalities (abdominal ultrasound and/or CT), clinical and laboratory examinations. Histopathological analyses included: T category, grade of tumor differentiation, vascular invasion, lymph node involvement and metastasis. We obtained the KRAS and EGFR gene mutations on the Randox investigator diagnostic platform. The aim of the study was to determine the frequency of KRAS and EGFR mutations in pancreatic adenocarcinoma and their correlation with multiple tumor characteristics. No one patient had EGFR mutation. The results showed that more of the patients with KRAS genetic mutations are frequently associated with advanced disease stage and worse prognosis, although the difference was not statistically significant in comparison to patients without KRAS mutations.
KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma
Clinical and Translational Gastroenterology, 2016
OBJECTIVES: There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer. METHODS: The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment. RESULTS: A total of 219 patients (men: 116; mean age: 67 ± 9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P = 0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P = 0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P = 0.0013; G12D (n = 49): 8 months, wild type (n = 56): 10 months, G12V (n = 38): 10 months, G12R (n = 19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P = 0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P = 0.02). CONCLUSIONS: The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.
Effect of Subtype of K-Ras Mutation on Survival in Resected Pancreatic Adenocarcinoma
Journal of the Pancreas, 2015
Objective The purpose is to determine if the different Kras mutations found in pancreatic ductal adenocarcinoma (PDA) confer different survivals after adjuvant gemcitabine, docetaxel and capecitabine (GTX) therapy, a regimen that affects Kras signaling. Methods We evaluated the survival with the type of Kras mutation in 53 patients who had resected PDA. All patients were treated either with neoadjuvant or adjuvant GTX therapy. The types and frequencies of Kras mutations in our PDA patients were compared to those in the literature for PDA, lung cancer and colon cancer. Results We found that 79% of our patients had a mutation in Kras at codon 12, with replacement of the glycine for either aspartic acid (47%), valine (19%), arginine (9%) or cysteine (4%). Serine and alanine substitutions and codon 13 mutations were not found. The frequency of Kras mutations detected in PDA differs markedly from those found in lung and colon cancer. Our PDA patients with aspartic acid or valine substitu...
Pancreas, 2012
Objectives: The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied. Methods: KRAS and BRAF mutations were analyzed in formalinfixed, paraffin-embedded tumor samples from primarily chemotherapynaive patients operated on with radical intentions for PDAC (n = 170) and A-AC (n = 107). Results: Eighty percent of PDAC patients had KRAS mutations (codon 12 mutations: 74%) and 67% with A-AC (codon 12 mutations: 54%). BRAF mutations were less common, 16% in PDAC and 12% in A-AC, and no V600E mutations were found. Fourteen percent with PDAC and 7% with A-AC had mutations in both KRAS and BRAF. Multivariate analysis, including KRAS status, stage, and American Society of Anesthesiologists physical status classification system score, demonstrated that KRAS mutations in patients with A-AC were associated with short recurrence-free survival (RFS) (hazard ratio, 2.45; 95% confidence interval, 1.19Y5.06; P = 0.015) and overall survival (OS) (1.93, 95% 1.12Y3.31; P = 0.018). KRAS mutations in patients with PDAC were not associated with RFS and OS. BRAF mutations were not associated with RFS and OS. Conclusions: KRAS mutations frequencies were high in PDAC and A-AC. KRAS mutations were associated with poor prognosis in patients with A-AC, but not in patients with PDAC.